Crohn's Disease Disease Coverage

Crohn's disease Disease Coverage

Ref Code: DMKC5415 Authors: Dominique Fontanilla, Christina Vasiliou, Nicola Sawalhi-Leckenby, Astrid Kurniawan www.datamonitorhealthcare.com Disease Coverage | Crohn's disease 2

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CONTENTS

14 FORECAST: CROHN’S DISEASE (Published on 02 August 2018)

14 OVERVIEW

16 RECENT FORECAST UPDATES

17 MARKET DYNAMICS

23 FORECAST AND FUTURE TRENDS

33 MARKET DEFINITION AND METHODOLOGY

40 PRIMARY RESEARCH METHODOLOGY

43 BIBLIOGRAPHY

45 PRODUCT PROFILE: ALOFISEL

61 PRODUCT PROFILE: CIMZIA

75 PRODUCT PROFILE: ENTYVIO

92 PRODUCT PROFILE: HUMIRA

112 PRODUCT PROFILE: REMICADE

128 PRODUCT PROFILE: STELARA

142 PRODUCT PROFILE: TYSABRI

153 PRODUCT PROFILE (LATE STAGE): ETROLIZUMAB

166 PRODUCT PROFILE (LATE STAGE): FILGOTINIB

179 PRODUCT PROFILE (LATE STAGE): OZANIMOD

191 PRODUCT PROFILE (LATE STAGE): RISANKIZUMAB

205 PRODUCT PROFILE (LATE STAGE): UPADACITINIB

218 TREATMENT: CROHN’S DISEASE (Published on 07 August 2017)

218 OVERVIEW

219 EXECUTIVE SUMMARY

220 PRIMARY RESEARCH METHODOLOGY

222 PATIENT SEGMENTATION

225 CURRENT TREATMENT OPTIONS

234 PRESCRIBING TRENDS

252 COMPLIANCE

255 UNMET NEEDS IN CROHN’S DISEASE

259 PRESCRIBING INFLUENCES

263 IMPACT OF BIOSIMILARS

271 EPIDEMIOLOGY: CROHN’S DISEASE (Published on 15 May 2018)

271 OVERVIEW

272 DISEASE BACKGROUND

276 METHODOLOGY

286 FORECAST

291 BIBLIOGRAPHY

294 APPENDIX: ADDITIONAL SOURCES

295 MARKETED DRUGS: CROHN'S DISEASE (Published on 02 August 2018)

295 OVERVIEW

297 PRODUCT OVERVIEW

298 PRODUCT PROFILE: ALOFISEL

314 PRODUCT PROFILE: CIMZIA

328 PRODUCT PROFILE: ENTYVIO

345 PRODUCT PROFILE: HUMIRA

365 PRODUCT PROFILE: REMICADE

381 PRODUCT PROFILE: STELARA

395 PRODUCT PROFILE: TYSABRI

406 CROHN'S DISEASE AND ULCERATIVE COLITIS PRICING AND REIMBURSEMENT (Published on 16 March 2018)

406 OVERVIEW

407 EXECUTIVE SUMMARY

408 REGULATORY LABELS

417 GLOBAL ACCESS LEVERS

428 EVIDENCE AND VALUE

434 ACCESS TO RECENTLY APPROVED AND PIPELINE PRODUCTS

460 PRICING

464 US

496 JAPAN

498 BIOSIMILAR TNF-ALPHA INHIBITORS IN THE FIVE MAJOR EU MARKETS

511 FRANCE

554 GERMANY

566 ITALY

577 SPAIN

587 UK

608 METHODOLOGY

611 PIPELINE: CROHN’S DISEASE (Published on 02 August 2018)

611 OVERVIEW

612 CLINICAL PIPELINE OVERVIEW

613 ADDITIONAL PHARMA INTELLIGENCE PIPELINE RESOURCES

614 PRODUCT PROFILE (LATE STAGE): ETROLIZUMAB

627 PRODUCT PROFILE (LATE STAGE): FILGOTINIB

640 PRODUCT PROFILE (LATE STAGE): OZANIMOD

652 PRODUCT PROFILE (LATE STAGE): RISANKIZUMAB

666 PRODUCT PROFILE (LATE STAGE): UPADACITINIB

LIST OF FIGURES

17 Figure 1: Crohn’s disease – current and future market dynamics analysis

18 Figure 2: Datamonitor Healthcare’s assessment summary of key marketed and pipeline drugs for Crohn’s disease

23 Figure 3: Crohn’s disease sales across the US, Japan, and five major EU markets, by country, 2016–25

24 Figure 4: Crohn’s disease sales across the US, Japan, and five major EU markets, by class, 2016–25

25 Figure 5: Sales of Humira, Remicade, and their biosimilar versions across the US, Japan, and five major EU markets, 2016–25

27 Figure 6: Sales of Stelara, key branded anti-TNFs, and Entyvio across the US, Japan, and five major EU markets, by drug,

2016–25

30 Figure 7: Sales of filgotinib and upadacitinib across the US, Japan, and five major EU markets, by drug, 2016–25

31 Figure 8: Sales of risankizumab versus pipeline agents in the US, Japan, and five major EU markets, by drug, 2016–25

35 Figure 9: Datamonitor Healthcare’s Crohn’s disease forecast methodology

38 Figure 10: Price sources and calculations, by country

53 Figure 11: Alofisel for Crohn’s disease – SWOT analysis

54 Figure 12: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

55 Figure 13: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

58 Figure 14: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

68 Figure 15: Cimzia for Crohn’s disease – SWOT analysis

69 Figure 16: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

70 Figure 17: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

72 Figure 18: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country, 2016–25

83 Figure 19: Entyvio for Crohn’s disease – SWOT analysis

84 Figure 20: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

85 Figure 21: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

89 Figure 22: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

102 Figure 23: Humira for Crohn’s disease – SWOT analysis

103 Figure 24: Datamonitor Healthcare’s drug assessment summary of Humira in Crohn’s disease

104 Figure 25: Datamonitor Healthcare’s drug assessment summary of Humira in Crohn’s disease

108 Figure 26: Humira sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

119 Figure 27: Remicade for Crohn’s disease – SWOT analysis

120 Figure 28: Datamonitor Healthcare’s drug assessment summary of Remicade in Crohn’s disease

121 Figure 29: Datamonitor Healthcare’s drug assessment summary of Remicade in Crohn’s disease

124 Figure 30: Remicade sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

134 Figure 31: Stelara for Crohn’s disease – SWOT analysis

135 Figure 32: Datamonitor Healthcare’s drug assessment summary of Stelara in Crohn’s disease

136 Figure 33: Datamonitor Healthcare’s drug assessment summary of Stelara in Crohn’s disease

139 Figure 34: Stelara sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

146 Figure 35: Tysabri for Crohn’s disease – SWOT analysis

147 Figure 36: Datamonitor Healthcare’s drug assessment summary of Tysabri in Crohn’s disease

148 Figure 37: Datamonitor Healthcare’s drug assessment summary of Tysabri in Crohn’s disease

150 Figure 38: Tysabri sales for Crohn’s disease in the US, 2016–25

159 Figure 39: Etrolizumab for Crohn’s disease – SWOT analysis

160 Figure 40: Datamonitor Healthcare’s drug assessment summary of etrolizumab in Crohn’s disease

161 Figure 41: Datamonitor Healthcare’s drug assessment summary of etrolizumab in Crohn’s disease

163 Figure 42: Etrolizumab sales for Crohn’s disease across the US and five major EU markets, by country, 2016–25

172 Figure 43: Filgotinib for Crohn’s disease – SWOT analysis

173 Figure 44: Datamonitor Healthcare’s drug assessment summary of filgotinib in Crohn’s disease

174 Figure 45: Datamonitor Healthcare’s drug assessment summary of filgotinib in Crohn’s disease

176 Figure 46: Filgotinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

184 Figure 47: Ozanimod for Crohn’s disease – SWOT analysis

185 Figure 48: Datamonitor Healthcare’s drug assessment summary of ozanimod in Crohn’s disease

186 Figure 49: Datamonitor Healthcare’s drug assessment summary of ozanimod in Crohn’s disease

188 Figure 50: Ozanimod sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

198 Figure 51: Risankizumab for Crohn’s disease – SWOT analysis

199 Figure 52: Datamonitor Healthcare’s drug assessment summary of risankizumab in Crohn’s disease

200 Figure 53: Datamonitor Healthcare’s drug assessment summary of risankizumab in Crohn’s disease

202 Figure 54: Risankizumab sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

211 Figure 55: Upadacitinib for Crohn’s disease – SWOT analysis

212 Figure 56: Datamonitor Healthcare’s drug assessment summary of upadacitinib in Crohn’s disease

213 Figure 57: Datamonitor Healthcare’s drug assessment summary of upadacitinib in Crohn’s disease

215 Figure 58: Upadacitinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

223 Figure 59: Severity of diagnosed Crohn’s disease patients, by country

234 Figure 60: Mean percentage of Crohn’s disease patients receiving pharmacological therapy or non-pharmacological therapy

only, by country

241 Figure 61: Mean percentage use of systemic and non-systemic corticosteroids in the US, Japan, and five major EU markets,

by line of therapy

242 Figure 62: Mean percentage of drug-treated Crohn’s disease patients receiving monotherapy versus combination therapy, by

line of therapy

244 Figure 63: Mean percentage of drug-treated Crohn’s disease patients receiving anti-TNF therapy, by country and line of

therapy

246 Figure 64: Mean percentage use of biologic therapies for the treatment of drug-treated Crohn’s disease patients, by biologic

and line of therapy

253 Figure 65: Mean compliance rates for drug-treated Crohn’s disease patients, by formulation type

256 Figure 66: Top treatment challenges in Crohn’s disease

267 Figure 67: Summary of future usage of biosimilar infliximab at one year and three years post-launch

269 Figure 68: Physician confidence in prescribing biosimilars for Crohn’s disease approved on the basis of indication

extrapolation, by country

290 Figure 69: Trends in diagnosed prevalent cases of Crohn’s disease in the US, Japan, and five major EU markets, by country,

2017–37

306 Figure 70: Alofisel for Crohn’s disease – SWOT analysis

307 Figure 71: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

308 Figure 72: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

311 Figure 73: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

321 Figure 74: Cimzia for Crohn’s disease – SWOT analysis

322 Figure 75: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

323 Figure 76: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

325 Figure 77: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country, 2016–25

336 Figure 78: Entyvio for Crohn’s disease – SWOT analysis

337 Figure 79: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

338 Figure 80: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

342 Figure 81: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

355 Figure 82: Humira for Crohn’s disease – SWOT analysis

356 Figure 83: Datamonitor Healthcare’s drug assessment summary of Humira in Crohn’s disease

357 Figure 84: Datamonitor Healthcare’s drug assessment summary of Humira in Crohn’s disease

361 Figure 85: Humira sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

372 Figure 86: Remicade for Crohn’s disease – SWOT analysis

373 Figure 87: Datamonitor Healthcare’s drug assessment summary of Remicade in Crohn’s disease

374 Figure 88: Datamonitor Healthcare’s drug assessment summary of Remicade in Crohn’s disease

377 Figure 89: Remicade sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

387 Figure 90: Stelara for Crohn’s disease – SWOT analysis

388 Figure 91: Datamonitor Healthcare’s drug assessment summary of Stelara in Crohn’s disease

389 Figure 92: Datamonitor Healthcare’s drug assessment summary of Stelara in Crohn’s disease

392 Figure 93: Stelara sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

399 Figure 94: Tysabri for Crohn’s disease – SWOT analysis

400 Figure 95: Datamonitor Healthcare’s drug assessment summary of Tysabri in Crohn’s disease

401 Figure 96: Datamonitor Healthcare’s drug assessment summary of Tysabri in Crohn’s disease

403 Figure 97: Tysabri sales for Crohn’s disease in the US, 2016–25

609 Figure 98: Price sources and calculations for the US and EU, by country

620 Figure 99: Etrolizumab for Crohn’s disease – SWOT analysis

621 Figure 100: Datamonitor Healthcare’s drug assessment summary of etrolizumab in Crohn’s disease

622 Figure 101: Datamonitor Healthcare’s drug assessment summary of etrolizumab in Crohn’s disease

624 Figure 102: Etrolizumab sales for Crohn’s disease across the US and five major EU markets, by country, 2016–25

633 Figure 103: Filgotinib for Crohn’s disease – SWOT analysis

634 Figure 104: Datamonitor Healthcare’s drug assessment summary of filgotinib in Crohn’s disease

635 Figure 105: Datamonitor Healthcare’s drug assessment summary of filgotinib in Crohn’s disease

637 Figure 106: Filgotinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

645 Figure 107: Ozanimod for Crohn’s disease – SWOT analysis

646 Figure 108: Datamonitor Healthcare’s drug assessment summary of ozanimod in Crohn’s disease

647 Figure 109: Datamonitor Healthcare’s drug assessment summary of ozanimod in Crohn’s disease

649 Figure 110: Ozanimod sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

659 Figure 111: Risankizumab for Crohn’s disease – SWOT analysis

660 Figure 112: Datamonitor Healthcare’s drug assessment summary of risankizumab in Crohn’s disease

661 Figure 113: Datamonitor Healthcare’s drug assessment summary of risankizumab in Crohn’s disease

663 Figure 114: Risankizumab sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

672 Figure 115: Upadacitinib for Crohn’s disease – SWOT analysis

673 Figure 116: Datamonitor Healthcare’s drug assessment summary of upadacitinib in Crohn’s disease

674 Figure 117: Datamonitor Healthcare’s drug assessment summary of upadacitinib in Crohn’s disease

676 Figure 118: Upadacitinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

LIST OF TABLES

39 Table 1: Exchange rates used for calculating prices

40 Table 2: Gastroenterologists surveyed for the Crohn’s disease primary research study, 2016

45 Table 3: Alofisel drug profile

47 Table 4: Alofisel Phase III data in Crohn’s disease

50 Table 5: Alofisel Phase III trial in Crohn’s disease

52 Table 6: Alofisel Phase I/II data in Crohn’s disease

59 Table 7: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

61 Table 8: Cimzia drug profile

63 Table 9: Cimzia pivotal trial data in Crohn’s disease

66 Table 10: Cimzia late-phase trial data in Crohn’s disease

73 Table 11: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country ($m), 2016–25

75 Table 12: Entyvio drug profile

77 Table 13: Entyvio pivotal trial data in Crohn’s disease

80 Table 14: Entyvio ongoing late-phase trials in Crohn’s disease

90 Table 15: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

92 Table 16: Humira drug profile

94 Table 17: Humira pivotal trial data in adult Crohn’s disease

98 Table 18: Humira pivotal trial data in pediatric Crohn’s disease

101 Table 19: Humira ongoing trials in Crohn’s disease

109 Table 20: Humira sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

112 Table 21: Remicade drug profile

114 Table 22: Remicade pivotal trial data in adult Crohn’s disease

118 Table 23: Remicade pivotal trial data in pediatric Crohn’s disease

125 Table 24: Remicade sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

128 Table 25: Stelara drug profile

130 Table 26: Stelara pivotal trial data in Crohn’s disease

140 Table 27: Stelara sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

142 Table 28: Tysabri drug profile

144 Table 29: Tysabri pivotal trial data in Crohn’s disease

151 Table 30: Tysabri sales for Crohn’s disease in the US ($m), 2016–25

154 Table 31: Etrolizumab drug profile

155 Table 32: Ongoing pivotal trials for etrolizumab in Crohn’s disease

159 Table 33: Other late-phase trials for etrolizumab in Crohn’s disease

164 Table 34: Etrolizumab sales for Crohn’s disease across the US and five major EU markets, by country ($m), 2016–25

166 Table 35: Filgotinib drug profile

168 Table 36: Ongoing pivotal Phase III trials of filgotinib in Crohn’s disease

171 Table 37: Phase II trial data of filgotinib in Crohn’s disease

177 Table 38: Filgotinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

179 Table 39: Ozanimod drug profile

181 Table 40: Ozanimod Phase III trials in Crohn’s disease

183 Table 41: Ozanimod Phase II data in Crohn’s disease

189 Table 42: Ozanimod sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

191 Table 43: Risankizumab drug profile

193 Table 44: Risankizumab Phase III trials in Crohn’s disease

197 Table 45: Risankizumab Phase II data in Crohn’s disease

203 Table 46: Risankizumab sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

205 Table 47: Upadacitinib drug profile

207 Table 48: Upadacitinib Phase III trials in Crohn’s disease

210 Table 49: Upadacitinib Phase II data in Crohn’s disease

216 Table 50: Upadacitinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

220 Table 51: Gastroenterologists surveyed for the Crohn’s disease primary research study, 2016

226 Table 52: Treatment guidelines: initial treatment of active Crohn’s disease, by severity

230 Table 53: Treatment guidelines: maintenance of medically induced remission of Crohn’s disease and other therapy

recommendations

232 Table 54: Summary of key classes and products included in Datamonitor Healthcare’s Crohn’s disease survey

235 Table 55: Crohn’s disease patients receiving pharmacological therapy or non-pharmacological therapy only, by country

237 Table 56: Mean percentage of drug-treated Crohn’s disease patients receiving each drug class, by line of therapy and country

(%)

243 Table 57: Mean percentage of drug-treated Crohn’s disease patients receiving monotherapy or combination therapy, by line

of therapy and country (%)

248 Table 58: Mean percentage of drug-treated Crohn’s disease patients receiving each biologic therapy, by line of therapy and

country (%)

254 Table 59: Compliance rates for Crohn’s disease patients, by formulation type and country (%)

255 Table 60: Relative importance of treatment challenges in Crohn’s disease, by country

260 Table 61: Relative importance of factors that influence gastroenterologists’ prescription of biologics and aminosalicylates in

Crohn’s disease, by country

264 Table 62: Initial usage of biosimilar infliximab, according to respondents using biosimilar infliximab at the time of the survey,

by country (%)

265 Table 63: Expected usage of biosimilar infliximab, according to respondents who did not prescribe biosimilar infliximab at

the time of the survey, by country (%)

273 Table 64: Inflammatory bowel disease risk factors

275 Table 65: Montreal classification of Crohn’s disease

277 Table 66: Sources used for Crohn’s disease analysis in the US, Japan, and five major EU markets

283 Table 67: Crohn’s disease data processing methods in the US, Japan, and five major EU markets

287 Table 68: Diagnosed prevalent cases of Crohn’s disease in the US, Japan, and five major EU markets, by country, 2017–37

297 Table 69: Profiled key marketed drugs for Crohn’s disease

298 Table 70: Alofisel drug profile

300 Table 71: Alofisel Phase III data in Crohn’s disease

303 Table 72: Alofisel Phase III trial in Crohn’s disease

305 Table 73: Alofisel Phase I/II data in Crohn’s disease

312 Table 74: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

314 Table 75: Cimzia drug profile

316 Table 76: Cimzia pivotal trial data in Crohn’s disease

319 Table 77: Cimzia late-phase trial data in Crohn’s disease

326 Table 78: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country ($m), 2016–25

328 Table 79: Entyvio drug profile

330 Table 80: Entyvio pivotal trial data in Crohn’s disease

333 Table 81: Entyvio ongoing late-phase trials in Crohn’s disease

343 Table 82: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

345 Table 83: Humira drug profile

347 Table 84: Humira pivotal trial data in adult Crohn’s disease

351 Table 85: Humira pivotal trial data in pediatric Crohn’s disease

354 Table 86: Humira ongoing trials in Crohn’s disease

362 Table 87: Humira sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

365 Table 88: Remicade drug profile

367 Table 89: Remicade pivotal trial data in adult Crohn’s disease

371 Table 90: Remicade pivotal trial data in pediatric Crohn’s disease

378 Table 91: Remicade sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

381 Table 92: Stelara drug profile

383 Table 93: Stelara pivotal trial data in Crohn’s disease

393 Table 94: Stelara sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

395 Table 95: Tysabri drug profile

397 Table 96: Tysabri pivotal trial data in Crohn’s disease

404 Table 97: Tysabri sales for Crohn’s disease in the US ($m), 2016–25

409 Table 98: Marketed products and approved indications for Crohn’s disease drugs in the US, Japan, and five major EU markets

413 Table 99: Marketed products and approved indications for ulcerative colitis drugs in the US, Japan, and five major EU

markets

423 Table 100: Levers impacting access to IBD drugs in the US and five major EU markets, by country

461 Table 101: Pricing of key Crohn’s disease drugs in the US, Japan, and five major EU markets, by country

464 Table 102: Pricing of key ulcerative colitis drugs in the US, Japan, and five major EU markets, by country

465 Table 103: Top anti-inflammatory drug prescriptions filled by Medicare beneficiaries participating in Part B and D programs,

2015

467 Table 104: Specialty drug spend by Express Scripts commercial members (inflammatory diseases market), 2016

468 Table 105: CVS Caremark and Express Scripts’ formulary exclusions for IBD drugs, 2016–18

469 Table 106: Formulary placement of IBD medications in selected commercial formularies

474 Table 107: Formulary placement of IBD medications in selected Medicare formularies

478 Table 108: Selected formulary practices of top 10 Medicare Part D and Medicare Advantage IBD drugs

479 Table 109: Formulary placement of IBD medications in selected state Medicaid formularies

481 Table 110: Prior authorization criteria for Crohn’s disease drugs with major health insurers and pharmacy benefit managers

484 Table 111: Prior authorization criteria for ulcerative colitis drugs with major health insurers and pharmacy benefit managers

496 Table 112: Japan – pricing premiums given to medicines that can demonstrate benefit over comparators

507 Table 113: Market access tools used to promote biosimilar TNF-alpha inhibitor uptake in the five major EU markets, by

country

512 Table 114: Transparency Committee’s ASMR ratings and pricing implications

513 Table 115: Transparency Committee's SMR ratings and pricing implications

514 Table 116: Transparency Commission's assessment of Crohn’s disease treatments

531 Table 117: Transparency Commission's assessment of ulcerative colitis treatments

556 Table 118: G-BA assessment of key Crohn’s disease therapies

558 Table 119: G-BA assessment of key ulcerative colitis therapies

562 Table 120: Spending regulations for TNF-alpha inhibitors in the five largest physicians’ associations in Germany

568 Table 121: Reimbursement conditions for Crohn’s disease treatments in Italy

571 Table 122: Reimbursement conditions for ulcerative colitis treatments in Italy

574 Table 123: Italian regional formulary decisions for Crohn’s disease drugs

574 Table 124: Italian regional formulary decisions for ulcerative colitis drugs

578 Table 125: Therapeutic positioning reports for IBD drugs in Spain

582 Table 126: Spanish Society of Hospital Pharmacy ratings

583 Table 127: Regional MADRE assessments for Crohn’s disease drugs

585 Table 128: Regional MADRE assessments for ulcerative colitis drugs

589 Table 129: NICE assessments of key Crohn’s disease therapies

597 Table 130: NICE assessments of key ulcerative colitis therapies

610 Table 131: Exchange rates used for calculating drug prices

612 Table 132: Profiled pipeline products in development for Crohn’s disease

615 Table 133: Etrolizumab drug profile

616 Table 134: Ongoing pivotal trials for etrolizumab in Crohn’s disease

620 Table 135: Other late-phase trials for etrolizumab in Crohn’s disease

625 Table 136: Etrolizumab sales for Crohn’s disease across the US and five major EU markets, by country ($m), 2016–25

627 Table 137: Filgotinib drug profile

629 Table 138: Ongoing pivotal Phase III trials of filgotinib in Crohn’s disease

632 Table 139: Phase II trial data of filgotinib in Crohn’s disease

638 Table 140: Filgotinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

640 Table 141: Ozanimod drug profile

642 Table 142: Ozanimod Phase III trials in Crohn’s disease

644 Table 143: Ozanimod Phase II data in Crohn’s disease

650 Table 144: Ozanimod sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

652 Table 145: Risankizumab drug profile

654 Table 146: Risankizumab Phase III trials in Crohn’s disease

658 Table 147: Risankizumab Phase II data in Crohn’s disease

664 Table 148: Risankizumab sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m),

2016–25

666 Table 149: Upadacitinib drug profile

668 Table 150: Upadacitinib Phase III trials in Crohn’s disease

671 Table 151: Upadacitinib Phase II data in Crohn’s disease

677 Table 152: Upadacitinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

FORECAST: CROHN’S DISEASE

OVERVIEW

Description Datamonitor Healthcare uses a patient-based approach to size the commercial potential of the Crohn’s disease market across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). This analysis contains an assessment of key Crohn’s disease therapies on the market and in the late-phase pipeline, a discussion of Crohn’s disease market dynamics, and a 10- year patient-based sales forecast.

Recent forecast updates The anticipated launch of biosimilar adalimumab in the US has been delayed to Q1 2023 (September 2017)

Mongersen’s development program was suspended following disappointing data from the REVOLVE trial (October 2017)

Alofisel was approved in the EU (March 2018)

Highlights Datamonitor Healthcare estimates that the Crohn’s disease market was worth approximately $5.8bn in 2016 across the US, Japan, and five major EU markets. New product launches will play a pivotal part in future market dynamics, allowing the market to grow to approximately $9.8bn in 2025, with a CAGR of 6.11%. Key new products include the IL-12/23 inhibitor Stelara, which launched in the US and EU in late 2016, and the two oral JAK inhibitors filgotinib and upadacitinib, which are expected to launch from 2021. The growth in the Crohn’s disease market comes despite downward pressure from the entry of biosimilars of the key marketed anti-TNF biologics, Remicade and Humira, which will be marketed at a lower cost than the reference brands.

Datamonitor Healthcare forecasts Stelara to become the market-leading brand within Crohn’s disease, with estimated 2025 sales of approximately $2.2bn. Stelara’s strongest competitors, Humira and Remicade, are forecast to lose considerable patient share to biosimilars, while Stelara will remain patent-protected during the forecast period. Stelara’s position in the marketplace is further boosted by its promising clinical performance to date, favorable safety profile, and convenient dosing regimen. Furthermore, Stelara has a faster onset of action and comparable safety profile to Entyvio, which, up until Stelara’s approval, was gastroenterologists’ preferred non- TNF biologic.

Datamonitor Healthcare anticipates that the commercial success of filgotinib and upadacitinib will largely depend on their price at launch, particularly in light of the increasing availability of biosimilars of the leading anti-TNF brands. If the two JAK inhibitors are priced at parity to or higher than the anti-TNF biologics, they will likely be relegated to late lines of therapy. Datamonitor Healthcare expects payers to push for anti-TNF-naïve patients who are eligible for systemic therapy to be prescribed cheaper anti-TNF biosimilars in order to reduce treatment costs, resulting in the relegation of novel pipeline therapies to patients who are refractory to TNF inhibition, and decreasing their overall patient share.

Methodology Patient-based forecasting methodology utilizing epidemiology data and primary research with 240 prescribing gastroenterologists across the US, Japan, and five major EU markets. Pricing, dosing, and future event assumptions are added to create Datamonitor Healthcare's forecast.

RECENT FORECAST UPDATES

The list below summarizes recent market-impacting events included in this latest update of Datamonitor Healthcare’s Crohn’s disease forecast.

THE ANTICIPATED LAUNCH OF BIOSIMILAR ADALIMUMAB IN THE US HAS BEEN DELAYED TO Q1 2023 (SEPTEMBER 2017)

In September 2017, AbbVie announced a global resolution of all intellectual property-related litigation with Amgen, which will delay the launch of Amjevita in the US until January 2023 (AbbVie, 2017). While this does not preclude other biosimilar developers from undertaking an at-risk launch, successfully challenging patents held by AbbVie, or designing around patents and using their own patent estate to support a biosimilar launch, Datamonitor Healthcare believes that a biosimilar adalimumab launch in the US is unlikely prior to 2023.

MONGERSEN’S DEVELOPMENT PROGRAM WAS SUSPENDED FOLLOWING DISAPPOINTING DATA FROM THE REVOLVE TRIAL (OCTOBER 2017)

In October 2017, Celgene announced the discontinuation of the Phase III REVOLVE trial of mongersen in Crohn’s disease and the extension trial (SUSTAIN). This decision followed a recommendation of the data monitoring committee, which assessed overall risk/benefit during a futility analysis (Celgene, 2017).

ALOFISEL WAS APPROVED IN THE EU (MARCH 2018)

In March 2018, Alofisel (darvadstrocel; TiGenix/Takeda) was approved by the European Medicines Agency for the treatment of complex perianal fistulas in Crohn’s disease (TiGenix, 2018). The approval was supported by positive data from the pivotal Phase III ADMIRE-CD study (ClinicalTrials.gov identifier: NCT01541579).

MARKET DYNAMICS Figure 1: Crohn’s disease – current and future market dynamics analysis

Source: Datamonitor Healthcare

The figure below depicts Datamonitor Healthcare’s assessment of the clinical and commercial attractiveness of key marketed and pipeline drugs profiled as therapies for Crohn’s disease.

Figure 2: Datamonitor Healthcare’s assessment summary of key marketed and pipeline drugs for Crohn’s disease

Source: Datamonitor Healthcare

REMICADE SHARES PREFERRED FIRST-LINE BIOLOGIC STATUS WITH HUMIRA

Datamonitor Healthcare’s primary research survey of 240 gastroenterologists indicates that Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) has managed to maintain its status as the preferred biologic for patients who fail conventional therapy, but is now sharing the position with Humira (adalimumab; AbbVie/Eisai). Remicade’s long-standing success is largely due to its first-to-market status, its proven efficacy in both the induction and maintenance of clinical remission, its fast onset of action, and physician and patient familiarity with the drug. Key opinion leaders stress that the availability of efficacy data for infliximab in diverse patient types further boosts the drug’s clinical attractiveness.

“Remicade was the first biologic in Crohn’s disease, and it still has the best efficacy data we have seen so far, which explains its position as the preferred biologic...”

US key opinion leader

“It is the treatment that traditionally has more evidence in multiple aspects of the disease.”

EU key opinion leader

Humira is perceived to have an overall comparable efficacy profile to Remicade, and benefits from a more convenient subcutaneous formulation. A retrospective cohort study conducted using Medicare data from 2006–10 suggests that the efficacy of the two biologics is similar across several clinical endpoints, including persistence on therapy, surgery, and hospitalization (Osterman et al., 2014). However, key opinion leaders highlight that Remicade remains the preferred anti-TNF biologic for patients with more advanced or complicated Crohn’s disease.

“…I think that Humira is similarly effective in Crohn’s.”

US key opinion leader

“If patients have more severe or more complicated disease, I would prefer infliximab, which is the intravenous option. I think that infliximab works slightly – and I stress slightly – better than adalimumab in these patients.”

US key opinion leader

REMICADE IS THE ONLY BIOLOGIC APPROVED FOR THE TREATMENT OF FISTULIZING CROHN’S DISEASE

Remicade is the only biologic approved specifically for the treatment of fistulizing Crohn’s disease, which represents a key advantage over its major competitors.

“When we have a patient with fistulizing disease, then we definitely prescribe Remicade instead of Humira.”

US key opinion leader

Fistulizing Crohn’s disease is a difficult-to-treat condition that causes significant impairment in patients’ quality of life. Population- based studies have found that up to 50% of Crohn’s disease patients are affected by fistulas, with perianal fistulas being the most common (Gecse et al., 2013; Nielsen et al., 2009). Remicade’s approval for fistulizing Crohn’s disease has brought some relief to these patients, who previously had very limited treatment options. Key opinion leaders note that patients with fistulas typically receive antibiotics as first-line therapy, immunosuppressants at the second line, and surgery with Remicade at later lines (Nielsen et al., 2009).

“It is always a combination between surgery and drugs [for fistulizing Crohn’s disease patients], and as soon as there is perianal disease, this strongly influences the choice of anti-TNF because Remicade is by far the most effective in these patients.”

US key opinion leader

CIMZIA’S SC FORMULATION AND CONVENIENT DOSING ARE OVERSHADOWED BY ITS WEAKER EFFICACY COMPARED TO KEY RIVALS REMICADE AND HUMIRA

Cimzia’s (certolizumab pegol; UCB/Astellas) subcutaneous (SC) formulation is a clinical advantage over Remicade, which is an intravenous (IV) therapy. SC therapies are preferred by patients as they offer treatment flexibility as opposed to IV drugs, which must be administered in a clinical setting over a prolonged infusion period. In addition, Cimzia’s once-monthly dosing is a clinical advantage over rival SC therapy Humira’s fortnightly dosing frequency, although less desirable than Remicade’s dosing frequency of every other month.

However, these positive attributes of Cimzia are overshadowed by pivotal trial data suggesting it is a less effective Crohn’s disease therapy than Remicade or Humira. In the Phase III PRECiSE 1 pivotal study, the proportion of patients achieving a clinical response was only marginally higher in the Cimzia group than in the placebo group. In addition, there was no significant difference in clinical remission rates between treatment and placebo groups. Higher response and remission rates were observed in the PRECiSE 2 pivotal study, although these can largely be accounted for by the trial design: only patients who demonstrated response to Cimzia after four weeks were randomized into the maintenance phase of the study, which boosted the likelihood of a positive outcome. In contrast to Cimzia, pivotal data that led to marketing approvals of Remicade and Humira were more definitive, with wider margins in response and remission rates between treatment and placebo arms (see Datamonitor Healthcare’s drug profiles for more information). Key opinion leaders interviewed by Datamonitor Healthcare confirm that Cimzia is perceived as a less efficacious therapy than the well- established anti-TNFs.

“Cimzia appears to be less effective [than Humira and Remicade] based on the endoscopic data that we have published, and I must say that it is very rarely used now.”

US key opinion leader

“Certolizumab is like a watered-down version of infliximab and adalimumab. If infliximab is a 10 out of 10, adalimumab is a 9 out of 10, and certolizumab is only a 5 or 6 out of 10.”

US key opinion leader

STELARA’S CONVENIENT MAINTENANCE DOSING AND FAVORABLE SAFETY PROFILE HAVE LED TO A STRONG LAUNCH IN CROHN’S DISEASE

Stelara’s (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) strong uptake in its first year on the Crohn’s disease market was driven by its convenient dosing regimen and favorable safety profile. Stelara’s maintenance dosage consists of an SC injection every eight weeks (Stelara prescribing information, 2018), while Humira requires SC administration every other week, and Remicade is delivered via an IV infusion every eight weeks.

“The fact that it is administered subcutaneously every eight weeks will play a key role in its success. Patients will love having just one injection every three months, it’s very convenient for them.”

EU key opinion leader

In addition, Stelara does not carry any black box warnings. The anti-TNF biologics Remicade, Humira, and Cimzia carry black box warnings for serious infections and malignancy. Meanwhile, the anti-integrin monoclonal antibody Tysabri (natalizumab; Biogen/Eisai), which is approved for use in Crohn’s disease only in the US, carries a black box warning for an increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that can lead to death or severe disability.

“Stelara does not have a black box warning for infections or malignancy, and in fact studies showed that Stelara has a significantly lower rate of infections than what we see with the other biologics. Its safety profile is very positive.”

US key opinion leader

Interviewed gastroenterologists note that Stelara is primarily used in the same treatment setting as Entyvio (vedolizumab; Takeda): patients who are refractory to TNF inhibition, and in unique cases, as a first-line biologic. These unique cases include older patients who are starting biologic therapy, who are at high risk for infections, who have a history of malignancy, or who are concerned about

the side effects associated with anti-TNF therapy.

“The uptake of Stelara has already been strong in the US, especially in patients who have been refractory to anti-TNFs. Because of Stelara’s strong safety profile and convenient dosing, I suspect that it will be used a lot in Crohn’s disease, and it will be even used as a first-line biologic in some cases.”

US key opinion leader

“In some special cases, I will be prescribing Stelara as a first-line biologic instead of an anti-TNF. One example is patients at high risk for getting infections; Stelara does not have a black box warning for infections. Another example is older patients who are 65 [years of age] and are starting a biologic. You may also see patients with a personal history of malignancy that maybe had breast cancer several years ago and are now starting biologic therapy; in these cases, I feel more comfortable prescribing a biologic like Stelara that does not have a black box warning on malignancy risk. Of course, there is also a big group of patients who have read up on biologics or have seen too many Humira ads on TV – in the US we have direct-to-consumer ads – and are worried about the risk of malignancy or any side effects they have read or heard about.”

US key opinion leader

ENTYVIO HAS SEEN HIGH UPTAKE IN CROHN’S DISEASE DESPITE ITS MODEST EFFICACY IN TNF INHIBITOR-FAILURE PATIENTS AND OVERALL SLOW ONSET OF ACTION

Entyvio has seen relatively high use since its launch in Crohn’s disease in 2014. Takeda reported that Entyvio achieved global sales of $1.3bn in fiscal year 2016 (Takeda, 2017). Entyvio’s high use is largely due to its favorable safety profile and the limited availability of non-TNF biologic therapies. Up until Stelara’s approval in late 2016, Entyvio and Tysabri were the only non-TNF biologics available in Crohn’s disease. Tysabri is approved only in the US, and is rarely used due to the increased risk of PML associated with the drug.

Entyvio’s high use comes despite its modest efficacy in patients who are refractory to TNF inhibition. The pivotal GEMINI III study, which primarily recruited patients with prior TNF treatment failure (see Datamonitor Healthcare’s Marketed Drugs: Crohn’s Disease), did not meet the primary endpoint of clinical remission at week 6 in the TNF inhibitor-failure population. However, the study did meet secondary endpoints, such as clinical remission at week 10, and clinical response at weeks 6 and 10, in the TNF-failure patient subgroup.

“Entyvio works quite well in TNF-naïve patients, but the problem is that it is not used a lot in this patient population. Entyvio is mostly used in TNF-refractory patients, and based on my clinical experience and the trials we have seen, Entyvio is less effective in TNF-refractory patients than in TNF-naïve patients. This is a key disadvantage for the drug, since what we need in Crohn’s disease is more effective therapies for the TNF-refractory population…”

US key opinion leader

In addition, Entyvio has a slower onset of action than the anti-TNF biologics and Stelara. As such, when prescribing Entyvio, gastroenterologists note that they are candid with patients about the number of infusions required to accurately assess the drug’s efficacy.

“I believe Entyvio is a little bit less effective than an anti-TNF and Stelara. The speed of action and the efficacy rates are a bit lower, but in the long term the effects are superimposable.”

EU key opinion leader

US key opinion leader

FORECAST AND FUTURE TRENDS

CURRENT AND FUTURE MARKET DYNAMICS OVERVIEW

Datamonitor Healthcare estimates that the Crohn’s disease market was worth approximately $5.8bn in 2016 across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). New product launches will play a pivotal part in future market dynamics, allowing the market to grow to approximately $9.8bn in 2025, with a compound annual growth rate of 6.11%. Key new products include the interleukin (IL)-12/23 inhibitor Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe), which launched in the US and EU in late 2016, and several pipeline agents that are expected to launch over the forecast period, including the oral Janus kinase (JAK) inhibitors filgotinib (Galapagos/Gilead) and upadacitinib (AbbVie), the IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim), and the sphingosine receptor modulator ozanimod (Celgene). The growth in the Crohn’s disease market comes despite downward pressure from the entry of key marketed anti-tumor necrosis factor (TNF) biologics biosimilars of Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and Humira (adalimumab; AbbVie/Eisai), which will be marketed at a lower cost than the reference brands.

The figures below show Datamonitor Healthcare’s forecast of Crohn’s disease sales in the US, Japan, and five major EU markets over 2016–25, by country and class.

Figure 3: Crohn’s disease sales across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

THE ANTI-TNF CLASS IS SET TO RELINQUISH ITS DOMINANCE IN CROHN’S DISEASE

The entry of therapies with novel mechanisms of action during the forecast period will result in the anti-TNF class losing its market dominance. By 2025, anti-TNFs will only account for just under 30% of the Crohn’s disease market, down from approximately 79% in 2016.

Figure 4: Crohn’s disease sales across the US, Japan, and five major EU markets, by class, 2016–25

Source: Datamonitor Healthcare

REMICADE FACES INTENSE BIOSIMILAR COMPETITION IN ALL MAJOR MARKETS, WHILE HUMIRA IS FORECAST TO REMAIN PROTECTED UNTIL 2023 IN THE US

Remicade was the first anti-TNF to face biosimilar competition. Celltrion’s biosimilar infliximab (marketed as Remsima by Celltrion and Inflectra by Pfizer) launched in Japan and Europe in Q4 2014 and Q1 2015, respectively (GaBi, 2014; Hospira, 2015). In the US, Celltrion/Pfizer’s biosimilar infliximab was approved for use in all indications in Q2 2016, and launched at-risk in Q4 2016 (FDA, 2016; Pfizer, 2016). In Europe and the US, Humira is set to face biosimilar competition in Q4 2018 and Q1 2023, respectively.

Datamonitor Healthcare forecasts biosimilars to launch with up to a 30% discount compared to their branded counterparts, offering payers, physicians, and patients a lower-cost value proposition. Over the forecast period, Datamonitor Healthcare expects the

reference brands to decline in price by 30%, with biosimilars also declining equally in price to maintain the same price differential as observed at launch.

Humira and Remicade are forecast to lose up to 55% of patient share to biosimilars over the 10-year period. This erosion is forecast to initially be relatively slow, as a result of expected physician hesitation in prescribing biosimilars, particularly for patients already receiving the brand.

“I am not concerned about using biosimilars as first-line therapy, but I am still concerned about switching patients. Even though we now have data from the NOR-SWITCH study from Norway, I still believe there is a question mark about multiple switching. There is still a question mark about immunogenicity. Apart from that, it is very clear that biosimilars work as well as the originators with the same safety profile, so they will be used.”

US key opinion leader

Additionally, Datamonitor Healthcare believes that companies will aim to resist biosimilar erosion by leveraging the proven real-world efficacy, positive long-term safety data, and physician and patient familiarity associated with their products.

Figure 5: Sales of Humira, Remicade, and their biosimilar versions across the US, Japan, and five major EU markets, 2016–25

Source: Datamonitor Healthcare

STELARA IS FORECAST TO BE THE MARKET LEADER IN CROHN’S DISEASE BY 2025 Datamonitor Healthcare forecasts Stelara to become the market-leading brand in Crohn’s disease, with sales of approximately $2.2bn

in 2025. Stelara’s strongest competitors, Humira and Remicade, are forecast to lose considerable patient share to biosimilars, while Stelara will remain patent-protected during the forecast period. This will also result in Stelara having a much higher net price compared to the anti-TNFs over the forecast period.

Gastroenterologists interviewed by Datamonitor Healthcare appear impressed with Stelara’s clinical performance to date, and note its position in the marketplace is further boosted by its favorable safety profile and convenient dosing regimen. Unlike anti-TNF biologics, Stelara does not carry black box warnings for increased risk of infections or malignancies. In addition, for patients in maintenance, Stelara is administered subcutaneously only once every eight weeks (Stelara prescribing information, 2018, while Humira requires subcutaneous administration every other week, and Remicade is delivered via an intravenous infusion every eight weeks.

US key opinion leader

EU key opinion leader

Gastroenterologists note that Stelara has a faster onset of action and comparable safety profile to Entyvio (vedolizumab; Takeda), and it is therefore expected to directly impact Entyvio’s use. Up until Stelara’s approval, Entyvio and Tysabri (natalizumab; Biogen/Eisai) were the only non-TNF biologics in Crohn’s disease. Tysabri is approved for Crohn’s disease only in the US, and its use has been limited to an extremely small subset of patients due to safety concerns regarding increased risk of progressive multifocal leukoencephalopathy (PML).

“I think Entyvio is going to take a hit now that Stelara is approved. Stelara has a faster onset of action than Entyvio in Crohn’s disease, and it has a good safety profile, with no black box warnings, similar to Entyvio. Personally, I will be prescribing Stelara in cases where I would have typically prescribed Entyvio in the past. Stelara will in my opinion become the alternative to Humira and Remicade. Entyvio is definitely feeling a little pressure now.”

US key opinion leader

“To begin with, there were very few patients on Tysabri because of the PML risk. When Entyvio came out we started prescribing Tysabri even less. Now that Stelara is also available, Tysabri will be very, very rarely used.”

US key opinion leader

Datamonitor Healthcare forecasts Stelara to be used primarily in patients who are refractory to TNF inhibition, and in unique cases as a first-line biologic. These unique cases include older patients who are starting biologic therapy, who are at high risk for infections, who have a history of malignancy, or who are concerned about the side effects associated with anti-TNF therapy.

US key opinion leader

The figure below shows sales of Stelara versus key branded anti-TNFs and Entyvio across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK).

Figure 6: Sales of Stelara, key branded anti-TNFs, and Entyvio across the US, Japan, and five major EU markets, by drug, 2016–25

Source: Datamonitor Healthcare

ALOFISEL WILL ADDRESS A KEY UNMET NEED IN THE TREATMENT OF PERIANAL FISTULIZING CROHN’S DISEASE

Alofisel (darvadstrocel; TiGenix/Takeda), which received EU approval in March 2018, has the potential to address a high burden in the treatment of perianal fistulizing Crohn’s disease. Datamonitor Healthcare’s survey across the US, Japan, and five major EU markets reveals that the development of effective therapies to treat fistulas remains among the most important unmet needs in Crohn’s disease. Perianal fistulas are a very disabling manifestation and a significant source of morbidity for patients. Current treatment involves a combined surgical and pharmacological approach. First-line pharmacological treatment is usually antibiotics, with a step-up to immunosuppressants such as azathioprine or 6-mercaptopurine, and then anti-TNFs (either Remicade or its biosimilar versions) in patients who do not respond adequately to their previous treatments (Marzo et al., 2015).

“Cx601 [Alofisel] is going to fill a huge unmet medical need in the treatment of perianal Crohn’s disease. Fistulas are very distressing, they cause a lot of pain and can often turn into abscesses. Bad fistulizing perianal Crohn’s disease is one of the reasons why patients have to have

proctectomy or have their rectum removed. Patients can often deal with the stool frequency and the urgency, but it is the fistula pain and the abscesses that are very bothersome and that might drive them to have their rectum removed. Having your rectum removed means you will have a permanent ostomy. So, a therapy that can heal the fistulas could theoretically prevent these patients from having a really big, life- changing surgery; and even though we are talking about a very small percentage of patients, these patients will really appreciate having the possibility to try a therapy like this.”

US key opinion leader

Alofisel’s modest efficacy profile to date is counteracted by the fact that it is the first therapy showing efficacy in patients with perianal fistulas who have failed TNF therapy. Key opinion leaders stress that patients in this niche population will appreciate having another therapy option that could potentially help them avoid surgery (Panes et al., 2017).

“Looking at the one-year trial data that were presented at ECCO [European Crohn’s and Colitis Organisation], combined remission at week 52 was 56% for Cx601 [Alofisel] versus 39% for placebo, so it is not as big of a delta as I would like, but it is still a delta. Cx601 is going to be modestly effective. It is not a SONIC-type result. Like I said, the patients who are in that niche are going to appreciate having the possibility of trying this, but this is definitely not going to take over the market.”

US key opinion leader

GASTROENTEROLOGISTS EXPECT ETROLIZUMAB TO PERFORM SIMILARLY TO ENTYVIO

Etrolizumab (Roche) shares a similar mechanism of action to Entyvio, and gastroenterologists anticipate similar results (ie that etrolizumab will have an overall slower onset of action than other approved biologics, and modest efficacy in patients who are refractory to TNF inhibition). However, gastroenterologists stress that Phase III data from the BERGAMOT and JUNIPER studies are required to draw robust conclusions regarding etrolizumab’s clinical performance.

“Etrolizumab is an anti-integrin, so in theory, it will behave more like Entyvio (vedolizumab) in terms of its onset of action, and so it may not be a very efficacious Crohn’s disease drug.”

US key opinion leader

“We have absolutely no data for etrolizumab in Crohn’s disease. It could be risky because it’s an anti-integrin, like vedolizumab [Entyvio]. This means that its efficacy in Crohn’s disease could be a bit low. We have to wait for data from the Phase III trials in Crohn’s [disease] though to see how it works.”

EU key opinion leader

The lack of head-to-head studies against established biologics will be a disadvantage for etrolizumab’s positioning for both TNF-naïve and TNF-experienced patients. Datamonitor Healthcare forecasts etrolizumab to achieve sales of $134m in 2025.

THE UPTAKE OF JAK INHIBITORS WILL LARGELY DEPEND ON THEIR PRICE

payers to push for anti-TNF-naïve patients who are eligible for systemic therapy to be prescribed cheaper anti-TNF biosimilars in order to reduce treatment costs, resulting in the relegation of novel pipeline therapies to patients who are refractory to TNF inhibition, and decreasing their overall patient share.

“I think that [how they will be used] really depends here on where it gets tiered by the payers. “

US key opinion leader

Leading gastroenterologists interviewed by Datamonitor Healthcare also note that concerns around the long-term risk-to-benefit profile of JAK inhibitors in Crohn’s disease may limit their uptake. Clinical data from large-scale trials are required to accurately assess their clinical potential, particularly in light of the discontinuation of Xeljanz’s (tofacitinib; Pfizer) development program in Crohn’s disease due to inconsistent efficacy and a mixed safety profile.

“There is still a question mark about safety because we are still not sure how safe JAK inhibition is in the long term. We have experience in other diseases or with other JAK inhibitors showing that JAK inhibition may increase the risk of infections, viral infections, and so on. It is also worth noting that the study for tofacitinib [Xeljanz], another JAK, in Crohn’s disease was not positive.”

US key opinion leader

“…we need to see data on a large scale in order to be confident to use JAK inhibitors... “

EU key opinion leader

Gastroenterologists add that it is hard to differentiate between filgotinib and upadacitinib, based on the limited data available to date. Datamonitor Healthcare believes that AbbVie’s extensive experience in the immunology space will give upadacitinib a competitive edge over filgotinib.

“I mean there is no major difference in efficacy, there is no major difference in safety, there are some differences in terms of JAK inhibitor selectivity, but that is purely at the mechanism of action level, but in terms of the clinical level I do not see any difference between the two.”

US key opinion leader

“I guess you could argue AbbVie already has a marketing force for GI diseases, so it will relatively easy for the company to switch them to marketing upadacitinib, whereas Galapagos do not, so that might impede initial market penetration.”

US key opinion leader

Figure 7: Sales of filgotinib and upadacitinib across the US, Japan, and five major EU markets, by drug, 2016–25

Source: Datamonitor Healthcare

RISANKIZUMAB IS FORECAST TO CAPTURE THE GREATEST MARKET SHARE AMONG ALL LATE-PHASE AGENTS

The IL-23 inhibitor risankizumab is forecast to capture the greatest market share among all late-phase Crohn’s disease agents, with estimated 2025 sales of $793m. Gastroenterologists note that risankizumab’s clinical performance to date has been overall comparable to that of the IL-12/23 inhibitor Stelara, hence they anticipate using risankizumab in the same treatment setting where Stelara is currently used – primarily in non-responders on TNF inhibition.

“So, again it is anti-IL-23 inhibitor, so it is a more selective pathway inhibition, it is given as a biologic. The reported efficacy data in Crohn’s disease report remission rates of about 40%, there were no unexpected safety signals reported, so I think that looks like a useful agent that will be positioned in the same position where Stelara is right now[…] I know they are looking in the clinical trials at two different doses, so maybe they will find a dose that produces better efficacy, but that is not clear right now. But I would see that as an agent that will be in a similar space or equivalent to where we are currently using Stelara.”

US key opinion leader

Preclinical models suggest that IL-23 inhibition could be more important than IL-12 inhibition in Crohn’s disease (Bilsborough et al., 2016; McGovern and Powrie, 2007; Sands et al., 2016), potentially providing risankizumab with a more targeted action. Leading gastroenterologists suggest that risankizumab’s mechanism of action may translate to a cleaner side-effect profile compared to that

of Stelara; however, they stress this will need to be demonstrated in the clinical development program and real-world setting.

“Hypothetically, if it is only blocking one component of the pathway, you would expect that maybe the safety signal is cleaner, but you would need a lot of patients treated to conclusively know if that is the case.”

US key opinion leader

Despite risankizumab’s promising clinical performance to date and AbbVie’s extensive experience in the immunology space, Datamonitor Healthcare forecasts the IL-23 inhibitor to face several challenges once it enters the Crohn’s disease market. In particular, risankizumab’s relatively late market entry in 2021, increasing physician familiarity with Stelara, and the growing presence of anti-TNF biosimilars are likely to restrict risankizumab’s overall uptake.

Figure 8: Sales of risankizumab versus pipeline agents in the US, Japan, and five major EU markets, by drug, 2016–25

Source: Datamonitor Healthcare

GASTROENTEROLOGISTS ARE UNCONVINCED ABOUT OZANIMOD’S ROLE IN CROHN’S DISEASE

Datamonitor Healthcare believes that ozanimod’s prospects in Crohn’s disease are unfavorable. Ozanimod’s modest efficacy data to date and concerns around its side-effect profile will limit its uptake, should it be approved and launched. Gastroenterologists note that due to cardiac adverse events observed with sphingosine modulators, it is likely that cardiac monitoring will be required before initiating therapy with ozanimod, which will be highly inconvenient for both physicians and patients.

“The data so far in colitis that I have seen, ozanimod has very modest to weak efficacy, and it has some safety concerns in terms of cardiac effects at the higher doses, and there is also some uncertainty in my mind about its exact mechanism of action. So, I am not very enthusiastic at this stage about ozanimod when you compare it to other agents in the pipeline for Crohn’s disease.“

US key opinion leader

“So, in the Phase I studies I am aware there were some issues with slow heart beats and heart block, they mitigated that by using a lower dose in the Phase II studies, but in my understanding, to be in those clinical trials you have to first have a cardiac monitoring beforehand to prove that you have no bradycardia, and then be included in the trial. So, if that is on the label for ozanimod for Crohn’s or colitis that would be a challenge for gastroenterologists to be doing EKGs in the office on these patients before they start therapy.“

US key opinion leader

MARKET DEFINITION AND METHODOLOGY

MARKET DEFINITION FOR CROHN’S DISEASE

For the purposes of this patient-based forecast, Datamonitor Healthcare defines the Crohn’s disease market in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) as comprising the drug classes and brands shown below. These have been identified as the key brands and molecules in the market, based on country-specific primary market research with prescribing gastroenterologists, secondary research, and key opinion leader discussions.

SUMMARY OF KEY CLASSES, BRANDS, AND MOLECULES INCLUDED IN DATAMONITOR HEALTHCARE’S CROHN’S DISEASE PATIENT-BASED FORECAST

TNF-alpha inhibitors

• Cimzia (certolizumab pegol; UCB/Astellas)

• Humira (adalimumab; AbbVie/Eisai)

• Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe)

• Simponi (golimumab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe)

Aminosalicylic acid and similar agents

• generic mesalamine (multiple)

• generic sulfasalazine (multiple)

Calcineurin inhibitors

• generic cyclosporine (multiple)

Locally acting corticosteroids

• generic budesonide (multiple)

• generic hydrocortisone (multiple)

• generic prednisolone (multiple)

Interleukin (IL) inhibitors

• Stelara (ustekinumab; Johnson & Johnson; Mitsubishi Tanabe)

• risankizumab (AbbVie/Boehringer Ingelheim)

Other immunosuppressants

• azathioprine (multiple)

• methotrexate (multiple)

Purine analogs

• mercaptopurine (multiple)

Selective immunosuppressants

• Entyvio (vedolizumab; Takeda)

• etrolizumab (Roche)

• filgotinib (Galapagos/Gilead)

• ozanimod (Celgene)

• Tysabri (natalizumab; Biogen/Eisai)

• upadacitinib (AbbVie)

Stem cell therapies

• Alofisel (darvadstrocel; TiGenix/Takeda).

FORECAST METHODOLOGY AND ASSUMPTIONS

Datamonitor Healthcare’s Crohn’s disease forecast is based on primary research, discussions with key opinion leaders, and secondary sources. Datamonitor Healthcare’s primary research includes a survey of 240 gastroenterologists, which was carried out in April 2016 across the US, Japan, and five major EU markets.

Methodology flow

Datamonitor Healthcare’s methodology for this Crohn’s disease forecast is summarized in the following figure, which shows how forecasts of each included product were calculated.

Figure 9: Datamonitor Healthcare’s Crohn’s disease forecast methodology

Source: Datamonitor Healthcare

Epidemiology

The starting point for Datamonitor Healthcare’s patient-based Crohn’s disease forecast is estimated diagnosed prevalent cases of Crohn’s disease by country, as calculated by Datamonitor Healthcare’s epidemiology team. An in-depth discussion of the methodology used to calculate the estimated diagnosed patient population, as well as the age and gender splits, is available in Datamonitor Healthcare’s Epidemiology: Crohn’s Disease.

Percentage of patients treated by gastroenterologists

In this forecast, the country-specific percentage of patients whose treatment is managed by gastroenterologists is determined from the results of Datamonitor Healthcare’s 2016 primary market survey. This survey exclusively targeted gastroenterologists as Datamonitor Healthcare assumes that the types of treatment included in this forecast would require specialist care.

Pharmacological treatment

Datamonitor Healthcare’s 2016 primary market research survey asked gastroenterologists to indicate the percentage of their Crohn’s disease patients receiving pharmacological therapy, either alone or in combination with non-pharmacological therapy.

Brand penetration

For all marketed therapies included in this forecast, Datamonitor Healthcare applied a baseline brand penetration rate to patients treated with pharmacological therapy by line of therapy. This is estimated from Datamonitor Healthcare’s 2016 primary research results. Baseline penetration rates have been benchmarked against company-reported sales.

Market events

Datamonitor Healthcare applied events to the Crohn’s disease market by switching patients between products. Events in this forecast include new product launches and the impact of biosimilars. The selection of events and their impact is based on survey results, analyst insight, and judgment derived from interviews with key opinion leaders. Reviews of clinical trial data and conference materials are also incorporated. All events are applied by line of therapy and are country-specific. Different countries can have different launch dates and different rates of patient switching, both in terms of the percentage of patients switched and the speed of switching. Events by brand are discussed in detail in the individual brand sections and can be viewed in the Events tab of the accompanying Excel deliverable.

Compliance

Formulation-specific compliance rates for each country, obtained from the 2016 survey, are applied to Datamonitor Healthcare’s Crohn’s disease forecast. As part of the primary market survey, Datamonitor Healthcare asked leading gastroenterologists to indicate how compliant their Crohn’s disease patients are with six different types of formulation: oral tablets, oral solutions, liquid therapies, rectal therapies, subcutaneous therapies, and intravenous therapies. For example, if, on average, patients took half of their prescribed dose of oral tablets, this was defined as 50% compliance, while if, on average, patients attended three out of four of their intravenous therapy sessions, compliance was defined as 75%. The resulting percentages for all formulation types have been adjusted downward based on secondary sources, which highlight the high degree of non-compliance to inflammatory bowel disease

(IBD) therapies. Datamonitor Healthcare has accounted for patients not taking prescribed medicine at the prescribed frequency, as well as not persisting with maintenance treatment. Studies report that approximately a third of IBD patients are low adherers to medication, with younger age, medication cost, and low education levels considered some of the key risk factors for non-adherence. In addition, increased doubts about personal need for maintenance therapy and concerns about adverse effects associated with maintenance therapies are significant barriers to adherence to treatment in IBD (Cerveny et al., 2007; Ediger et al., 2007; D’Inca et al., 2008; Horne et al., 2009).

Price and dose assumptions

For this forecast, Datamonitor Healthcare calculates each product’s country-specific price per year by line of therapy. Datamonitor Healthcare starts by determining dose assumptions for each product based on prescribing information.

Datamonitor Healthcare uses national formularies to gather pricing information per product. As the prices presented in formularies can differ, showing prices at different stages in the supply chain, Datamonitor Healthcare uses backing-out formulas to adjust formulary prices in order to obtain estimates of ex-factory wholesale prices for each country. The following table outlines the sources and calculations used in the US and EU. For Japan, prices are taken from the National Health Insurance drug database. These prices are the retail price exclusive of consumption tax, and therefore it is important to note that the sales given for Japan may be inflated compared to other countries, depending on the extent of price markups at different stages in the supply chain. However, Datamonitor Healthcare has validated its patient-based sales estimates with company-reported sales in Japan where available, and believes the impact to be minimal.

Figure 10: Price sources and calculations, by country

Source: Datamonitor Healthcare; various (see above)

Using the calculated ex-factory wholesale price, the price per mg is calculated. This is multiplied by Datamonitor Healthcare’s annual dosing assumptions in order to obtain an annual price per patient. Four years of historical prices are used to trend forward prices over the forecast period. Datamonitor Healthcare assumes an overall price increase of 1.5% in the US, based on the current increase in prices after rebates and discounts have taken place. All prices are shown in US dollars, using the average 2016 exchange rate from Open Exchange Rates.

Table 1: Exchange rates used for calculating prices

Currency Local currency to USD

EUR 1.1067

GBP 1.3552

JPY 0.0092

Source: Open Exchange Rates, 2017

In the case of novel pipeline products, the prices are either the average market price or benchmarked to similar branded products, taking into account dosing discrepancies and any expected price premiums due to novelty or expected price discounts. Prices are calculated individually for each product in each country. To see specific price assumptions by brand, please refer to the individual brand sections.

Total annual sales per brand

In order to arrive at final sales per brand in each country, the number of patients on a product is multiplied by compliance and the cost per patient per year. Sales by line of therapy are then summed to provide the total values (US dollar sales) for each product in each country. These sales are then validated with company-reported data where available.

PRIMARY RESEARCH METHODOLOGY

PHYSICIAN RESEARCH

Datamonitor Healthcare conducted primary research with a sample of 240 gastroenterologists in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). The research was conducted in April 2016. The sample breakdown by country is shown in the table below, together with some key respondent metrics.

Table 2: Gastroenterologists surveyed for the Crohn’s disease primary research study, 2016

US Japan France Germany Italy Spain UK

Sample size 35 31 31 38 35 37 33

Mean number of years in specialty 13.4 20.3 15.9 15.9 18.3 17.2 12.0

Mean number of Crohn’s disease patients under 182 38 77 129 146 155 149 respondents’ care

Mean number of hours per day spent in clinical 9.2 9.0 8.7 8.5 8.3 8.1 8.2 practice

Source: Datamonitor Healthcare’s proprietary Crohn’s disease survey, April 2016

The primary research study was conducted online, with all the respondents self-completing a 30-minute questionnaire in their own language. The questionnaire was divided into three sections:

• screening questions

• main questionnaire

• demographic questions.

Datamonitor Healthcare’s questionnaire was carefully designed and included a number of screening questions to ensure the most appropriate targeting of respondents for this study. Respondents needed to have clinical responsibility for the treatment and management of a minimum number of Crohn’s disease patients to ensure that responses were broadly representative of current treatment practices. The participating physicians also had to be working in clinical practice daily, have three years’ experience in their specialty, and to not work directly for a pharmaceutical company, other than involvement in clinical trials. All these criteria aimed to ensure, as far as possible, that respondents were experienced, practicing specialists with unbiased views.

The objectives of the main questionnaire for this study were to gain an understanding and insight into the following:

• key epidemiological datasets (diagnosis and treatment rates), both in terms of the condition as a whole and for specific patient

segments including mild, moderate, and severe

• patient management pathways

• patient segmentation, by severity and by line of therapy

• prescribing behavior including the use of monotherapy and/or combination therapy, by line of therapy

• patient compliance

• prescribing influences

• product comparative performance and valued product attributes

• assessment of unmet treatment needs

• future trends and uptake of new therapies, and their impact on the market.

The demographic questions that were asked at the end of Datamonitor Healthcare's survey helped to ensure that the sample was broadly representative of the treating physician population in each country.

Pilot interviews (consisting of online self-completion of the questionnaire) and subsequent telephone interviews with a Datamonitor Healthcare analyst were conducted with a small number of physicians in the US and UK. The purpose of piloting was to determine if the questionnaire:

• was “fit-for-purpose” and able to gather data that answered the research objectives

• was straightforward for the respondents to complete in the allocated time period

• covered all relevant aspects of treatment and management for Crohn’s disease.

After the mainstage fieldwork was completed, the raw data at the respondent level were carefully reviewed and quality-checked by the research team prior to data processing and analysis.

KEY OPINION LEADER RESEARCH

Contributing experts

Datamonitor Healthcare conducted telephone interviews with four key opinion leaders in the US and Italy as part of the primary research undertaken for Crohn’s disease. Each interview lasted 45 minutes.

With the aid of a detailed discussion guide, the objectives of each interview were to gain an understanding and insight into the following:

• patient management

• influences on current prescribing practice

• opinion on current therapies, including therapy comparisons and prescribing preferences

• opinion on pipeline drugs, including likely approval/uptake/impact on current therapies, likely target patient populations, required trial endpoints, and key opportunities and threats

• treatment challenges and unmet needs.

All key opinion leaders interviewed wished to remain anonymous.

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D'Inca R, Bertomoro P, Mazzocco K, Vettorato MG, Rumiati R, et al. (2008) Risk Factors for Non-Adherence to Medication in Inflammatory Bowel Disease Patients. Alimentary Pharmacology and Therapeutics, 27(2), 166–72.

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Panes J, Garcia-Olmo D, Van Assche GA, Colombel JF, Reinisch W, et al. (2017) CX601, ALLOGENEIC EXPANDED ADIPOSE-DERIVED MESENCHYMAL STEM CELLS (EASC), FOR COMPLEX PERIANAL FISTULAS IN CROHN'S DISEASE: LONG-TERM RESULTS FROM A PHASE III RANDOMIZED CONTROLLED TRIAL. Presented at the 2017 Digestive Disease Week annual meeting, 6–9 May 2017, Chicago, Illinois, US; Abstract 985.

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TiGenix (2018) TiGenix and Takeda announce Alofisel® (darvadstrocel) receives approval to treat complex perianal fistulas in Crohn’s disease in Europe. Available from: http://tigenix.com/wp-content/uploads/2018/03/20180323-TiGenix-Takeda-EC-approval-PR-ENG- FINAL-clean.pdf [Accessed 26 March 2018].

PRODUCT PROFILE: ALOFISEL

PRODUCT PROFILE

ANALYST OUTLOOK

TiGenix and Takeda’s stem cell therapy Alofisel (darvadstrocel) will be used as an add-on to late-line therapies, thereby avoiding direct competition with Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) or its biosimilar versions, the current standard of care for fistulizing Crohn’s disease. Alofisel’s novelty and the fact that it is the first therapy demonstrating efficacy in patients with perianal fistulas who have failed tumor necrosis factor (TNF) therapy counteract its modest efficacy profile. While Alofisel has the potential to address a key unmet need in the treatment of perianal fistulizing Crohn’s disease, it will face several barriers upon launch. Its limited target patient population, anticipated high cost, and inconvenient administration method will restrict its overall patient share.

DRUG OVERVIEW

Alofisel is a suspension of allogeneic expanded adipose-derived stem cells via intralesional injection. The therapy is being developed in Crohn’s disease for the treatment of complex perianal fistulas which show an inadequate response to at least one conventional or biologic therapy, including antibiotics, immunosuppressants, or anti-TNF agents.

Table 3: Alofisel drug profile

Molecule darvadstrocel

Mechanism of action Stem cell therapy; anti-inflammatory and tissue regenerative properties

Originator Cellerix (now TiGenix)

Marketing company TiGenix/Takeda

Formulation Intralesional injection

Alternative names Cx601

Source: Biomedtracker; Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

Cellerix developed Alofisel using its proprietary fat-derived adult stem cell platform. In February 2011, TiGenix and Cellerix entered into a contribution agreement to combine their operations by means of a share for share exchange (Ventech, 2011). Then, in July 2016, TiGenix entered into a licensing agreement with Takeda, whereby Takeda acquired an exclusive right to develop and commercialize Alofisel for complex perianal fistulas in Crohn’s disease patients outside of the US (Takeda, 2016).

In March 2018, Alofisel was approved by the European Medicines Agency (EMA) for the treatment of complex perianal fistulas in Crohn’s disease (TiGenix, 2018). The approval was supported by positive data from the pivotal Phase III ADMIRE-CD study (ClinicalTrials.gov identifier: NCT01541579).

In 2009, the European Commission granted Alofisel orphan designation for the treatment of anal fistulas (EMA, 2009).

In June 2017, TiGenix hosted an investigator meeting where it formally launched the global pivotal Phase III clinical trial for Alofisel in Crohn’s disease. The global trial will support a future filing with the US Food and Drug Administration (FDA). The trial design is similar to that of the European ADMIRE-CD trial, with an identical primary endpoint (TiGenix, 2017a). In January 2017, the FDA confirmed that a future US filing could be made based on efficacy and safety data at week 24, instead of week 52, which was the FDA’s initial recommendation. In addition, the FDA agreed to accept fewer patients in the study than originally planned, and endorsed a broader patient population, which will facilitate the recruitment process (TiGenix, 2017b). In October 2017, TiGenix was granted orphan drug designation for Alofisel (TiGenix, 2017c).

PIVOTAL TRIAL DATA

The European Phase III ADMIRE-CD study is summarized in the table below. Details of Alofisel’s global pivotal Phase III study in Crohn’s disease are yet to be announced.

Table 4: Alofisel Phase III data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

ADMIRE-CD 278 Adults with perianal Randomized, double-blind, parallel- Alofisel (120 million cells Combined remission rates* Biomedtracker; (NCT01541579) fistulizing Crohn’s disease group, placebo-controlled, administered by a single intralesional in ITT population at week Trialtrove; Panes et (Phase III) refractory to at least one multicenter injection); placebo 24: 49.5% Alofisel versus al., 2016; 2017 of the following 34.3% placebo (p<0.024); treatments: antibiotics, Combined remission rates* immunosuppressants, or in mITT population at week anti-TNF biologics 24: 51.5% Alofisel versus 35.6% placebo (p=0.021); Combined remission rates* in ITT population at week 52: 54.2% Alofisel versus 37.1% placebo (p=0.012); Combined remission rates* in mITT population at week 52: 56.3% Alofisel versus 38.6% placebo (p=0.010); Clinical remission** (mITT population) at week 24: 55.3% Alofisel versus 42.6% placebo (p=0.057); Clinical remission** (mITT population) at week 52: 59.2% Alofisel versus 41.6% placebo (p=0.013) Disease Coverage | Forecast: Crohn’s Disease 48

Table 4: Alofisel Phase III data in Crohn’s disease

*Combined remission rates of perianal fistulizing Crohn’s disease = clinical assessment of closure of all treated external openings that were draining at baseline despite gentle finger compression at week 24/52, and absence of collections >2cm of the treated perianal fistulas confirmed by centrally blinded MRI assessment by week 24/52.

**Clinical remission = closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed.

ITT = intent-to-treat; mITT = modified intent-to-treat; MRI = magnetic resonance imaging; TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Forecast: Crohn’s Disease 49

The table below summarizes the design of the international Phase III study.

Table 5: Alofisel Phase III trial in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Primary endpoints Start date/primary completion date

ADMIRE-CD-II 326 Adult Crohn’s disease Randomized, Arm 1: Alofisel 120 million cells Combined remission of September 2017/October (NCT03279081) patients with perianal double-blind, administered by intralesional complex perianal fistula(s) 2021 (Phase III) fistula(s) who are placebo-controlled administration at week 24 intolerant to/have an Arm 2: Placebo inadequate response to conventional immunosuppressive agents or biologics (anti-TNF, Entyvio, Stelara)

TNF = tumor necrosis factor

Source: Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 51

OTHER TRIALS

Phase I/II efficacy data for Alofisel in Crohn’s disease are summarized in the table below.

Table 6: Alofisel Phase I/II data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

NCT01372969 24 Adult patients with Multicenter, open-label, single- Single treatment of intralesional 69.2% of patients had a de la Portilla et al., 2012 (Phase I/II) Crohn’s disease and group assessment Alofisel 20 million cells in one reduction in the number complex perianal fistulas draining fistula tract; if fistula of draining fistulas at week with three or fewer closure incomplete at week 12, an 24, 56.3% of the patients fistulous tracts additional treatment of intralesional achieved complete closure determined by MRI scan Alofisel 40 million cells was of the treated fistula at performed week 24, complete closure of all fistula tracts occurred in 30% of patients at week 24; Treatment-related adverse events did not indicate any clinical safety concerns after six months of follow- up

MRI = magnetic resonance imaging

Source: see above Disease Coverage | Forecast: Crohn’s Disease 53

SWOT ANALYSIS Figure 11: Alofisel for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of Alofisel’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the comparator drug Remicade and all of the other key marketed and pipeline drugs profiled.

Figure 12: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

Source: Datamonitor Healthcare

Figure 13: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Alofisel compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Alofisel for Crohn’s disease:

REGULATORY

• Alofisel was approved by the EMA for the treatment of complex perianal fistulas in Crohn’s disease in March 2018 (TiGenix, 2018). The approval was supported by positive data from the pivotal Phase III ADMIRE-CD study (ClinicalTrials.gov identifier: NCT01541579).

• Datamonitor Healthcare anticipates launch in Germany and the UK in Q2 2018. This is expected to be followed by launch a year later in France, Italy, and Spain (in Q2 2019), following the conclusion of reimbursement negotiations. The relative launch timings are based on historical development and launch timelines in autoimmune indications.

• Datamonitor Healthcare forecasts Alofisel to launch in the US in Q1 2022. In June 2017, TiGenix launched a pivotal Phase III trial that will support a future Biologics License Application for Alofisel in the US (TiGenix, 2017a). The protocol for this trial has been agreed with the FDA, and is similar to the European ADMIRE-CD study (Biomedtracker, 2018; TiGenix, 2017b). Based on the

timeline of Alofisel’s ADMIRE-CD trial, Datamonitor Healthcare assumes TiGenix will file for FDA approval by Q4 2020, provided the US trial generates positive data. Assuming a positive FDA decision, Datamonitor Healthcare anticipates launch in the US in Q1 2022.

• Datamonitor Healthcare does not forecast Alofisel to launch in Japan as no evidence of the drug’s clinical development in Japanese Crohn’s disease patients has been found.

COMPETITION

• While Alofisel has the potential to address a high burden in the treatment of perianal Crohn’s disease, its overall use will be limited. Alofisel will only be used in patients who have complex perianal fistulas, which is a very small subpopulation of Crohn’s disease.

“Alofisel is specifically for fistulizing disease and will be administered by a colorectal surgeon at the time of an exam under anesthesia. It will be injected into the fistula tracks. It is a niche drug, it is not going to be for most Crohn’s disease patients, but only for those with active fistulas […] At any given point in time, the percentage of patients with active fistulas, where fistulas are the major driver of symptoms, is less than 10%, so it is a clear subpopulation of the entire Crohn’s disease population.”

US key opinion leader

“Alofisel is going to fill a huge unmet medical need in the treatment of perianal Crohn’s disease. Fistulas are very distressing, they cause a lot of pain and can often turn into abscesses. Bad fistulizing perianal Crohn’s disease is one of the reasons why patients have to have proctectomy or have their rectum removed. Patients can often deal with the stool frequency and the urgency, but it is the fistula pain and the abscesses that are very bothersome and that might drive them to have their rectum removed. Having your rectum removed means you will have a permanent ostomy. So a therapy that can heal the fistulas could theoretically prevent these patients from having a really big, life-changing surgery, and even though we are talking about a very small percentage of patients, these patients will really appreciate having the possibility to try a therapy like this.”

US key opinion leader

• Alofisel demonstrated modest efficacy in its Phase III trial; however, key opinion leaders stress that patients with perianal Crohn’s disease will appreciate having another therapy option that could potentially help them avoid surgery (Panes et al., 2017).

“Looking at the one-year trial data that were presented at ECCO [European Crohn’s and Colitis Organisation], combined remission at week 52 was 56% for Alofisel versus 39% for placebo, so it is not as big of a delta as I would like, but it is still a delta. Alofisel is going to be modestly effective. It is not a SONIC-type result. Like I said, the patients who are in that niche are going to appreciate having the possibility of trying this, but this is definitely not going to take over the market.”

US key opinion leader

• Alofisel is expected to be used as an add-on to therapies at third line and later. Datamonitor Healthcare forecasts up to 2% of patients at third line, and up to 7% of patients at fourth line and later to receive the drug.

“Alofisel will be used as needed to help heal the fistula tracks, but patients will continue whatever therapies they were on for their luminal Crohn’s disease.”

US key opinion leader

“Patients that will receive Alofisel therapy will likely be refractory, so they will have already tried a few biologics. Alofisel will be used in combination with the therapy they are receiving at that time.”

EU key opinion leader

• Key opinion leaders interviewed by Datamonitor Healthcare stress that Alofisel’s inconvenient administration method will also restrict its use. Alofisel will be administered by a colorectal surgeon at the time of an examination, while under anesthesia. In addition, Alofisel can only be administered if the rectum is not inflamed, which is often not the case in patients who are refractory to anti-TNFs.

“I am not 100% sure regarding its practical implications, because it is not easy to use. This treatment will be reserved to referral centers, because you need a surgeon to inject the cells into the fistula tracks, under anesthesia, so it is not something that can be done by all gastroenterologists. It is a promising therapy because it is the first treatment showing efficacy for perianal Crohn’s disease beyond anti-TNFs, but there is a gap between this data and the clinical practice. On top of that, there is a limitation to the use of this technique, which is that the drug works only if the rectum is not inflamed, and in clinical practice when we have this fistula very often the patient is refractory, and the rectum may be inflamed; so this will also limit the number of patients that can receive Alofisel.”

US key opinion leader

DOSING

• Datamonitor Healthcare has assumed dosing of 120 million cells administered by a single intralesional injection, as described in the prescribing information (EMA, 2018).

PRICING

• Due to the drug’s novelty, its potential to address a high unmet need in the treatment of perianal Crohn’s disease, and the cost of bringing this stem cell therapy to market, Datamonitor Healthcare assumes Alofisel will be priced at a 40% premium to the average annual treatment cost of the marketed biologics Humira (adalimumab; AbbVie/Eisai), Remicade, Cimzia (certolizumab pegol; UCB/Astellas), Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe), and Entyvio (vedolizumab; Takeda).

• Datamonitor Healthcare uses national formularies to gather pricing information per product and applies backing-out formulas to adjust formulary prices in order to obtain estimates of ex-factory wholesale prices for each country.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

ALOFISEL FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Alofisel in Crohn’s disease, by country, over 2016–25.

Figure 14: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 7: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US ------26.6 61.9 120.6 177.8

France - - - 1.3 4.0 8.9 13.7 18.3 23.0 27.0

Germany - - 2.6 8.2 18.3 27.9 37.2 46.4 54.1 59.7

Italy - - - 0.7 2.1 4.7 7.2 9.7 12.2 14.3

Spain - - - 0.6 2.0 4.6 7.1 9.5 12.0 14.2

UK - - 0.5 1.5 3.3 5.1 6.8 8.6 10.2 11.3

Total - - 3.1 12.2 29.6 51.1 98.6 154.4 232.0 304.3

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 60

BIBLIOGRAPHY de la Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, et al. (2012) Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical trial. International Journal of Colorectal Disease, 28(3), 313–23.

EMA (2009) Public summary of opinion on orphan designation. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006230.pdf [Accessed 12 June 2017].

EMA (2018) Alofisel prescribing information. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/004258/WC500246474.pdf [Accessed 25 April 2018].

Panes J, Garcia-Olmo D, Van Assche GA, Colombel JF, Reinisch W, et al. (2016) Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet, 388(10051), 1281–90.

Panes J, Garcia-Olmo D, Van Assche GA, Colombel JF, Reinisch W, et al. (2017) CX601, ALLOGENEIC EXPANDED ADIPOSE-DERIVED MESENCHYMAL STEM CELLS (EASC), FOR COMPLEX PERIANAL FISTULAS IN CROHN'S DISEASE: LONG-TERM RESULTS FROM A PHASE III RANDOMIZED CONTROLLED TRIAL. Presented at the 2017 Digestive Disease Week Annual Meeting, 6–9 May 2017, Chicago, Illinois, US; Abstract 985.

Takeda (2016) Takeda and TiGenix Enter into Licensing Agreement for Ex-U.S. Rights to Cx601 for the Treatment of Complex Perianal Fistulas in Patients with Crohn's Disease. Available from: https://www.takeda.com/newsroom/newsreleases/2016/takeda-and-tigenix- enter-into-licensing-agreement-for-ex-u.s.-rights-to-Cx601-for-the-treatment-of-complex-perianal-fistulas-in-patients-with-crohns- disease/ [Accessed 12 June 2017].

TiGenix (2017a) TiGenix Launches Global Phase III Trial for Cx601. Available from: http://tigenix.com/wp- content/uploads/2017/06/170613-TiGenix-Launches-Global-Phase-III-trial-EN-final-1-1.pdf [Accessed 12 June 2017].

TiGenix (2017b) TiGenix Receives Positive Feedback from the FDA on Cx601 Global Phase III Trial Protocol. Available from: http://tigenix.com/wp-content/uploads/2017/03/07032017-Cx601-endorsement-FDA_EN.pdf [Accessed 12 June 2017].

TiGenix (2017c) TiGenix granted Orphan Drug Designation from the U.S. FDA for Cx601. Available from: http://tigenix.com/wp- content/uploads/2017/10/171023-ODD-decision-FINAL-EN.pdf [Accessed 7 February 2018].

Ventech (2011) CELLERIX: TIGENIX ANNOUNCES THE ACQUISITION OF CELLERIX IN A STOCK DEAL. Available from: http://www.ventechvc.com/autres/cellerix-tigenix-announces-the-acquisition-of-cellerix-in-a-stock-deal/ [Accessed 12 June 2017].

PRODUCT PROFILE: CIMZIA

PRODUCT PROFILE

ANALYST OUTLOOK

Cimzia (certolizumab pegol; UCB/Astellas) was the third anti-tumor necrosis factor (TNF) biologic to enter the Crohn’s disease market, and it has struggled to replicate the commercial successes of incumbents Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and Humira (adalimumab; AbbVie/Eisai). An indirect comparison of pivotal trial data for the three anti-TNFs ranks Cimzia as having the lowest efficacy in Crohn’s disease. Cimzia’s approval solely in the US also limits patient numbers and commercial potential. Datamonitor Healthcare anticipates that the increasing availability of anti-TNF biosimilars and growing physician familiarity with the marketed non-TNF biologics Entyvio (vedolizumab; Takeda) and Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) will negatively impact Cimzia’s patient share in the near term.

DRUG OVERVIEW

Cimzia is a PEGylated humanized monoclonal antibody fragment indicated for the treatment of moderately to severely active Crohn’s disease. It binds to TNF-alpha, preventing the binding of TNF-alpha to its receptors and inhibiting its biological activity.

Table 8: Cimzia drug profile

Molecule certolizumab pegol

Mechanism of action TNF inhibitor

Originator Celltech (now UCB)

Marketing company UCB, Astellas

Formulation SC

Alternative names n/a

SC = subcutaneous; TNF = tumor necrosis factor

Source: Biomedtracker; Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

Cimzia was approved and launched in the US for the treatment of Crohn’s disease in April 2008 (FDA, 2008). Datamonitor Healthcare does not expect Cimzia to be approved for Crohn’s disease in the EU, following two negative opinions from the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP). In November 2007, the CHMP adopted a negative

opinion for the use of Cimzia in Crohn’s disease, stating that the benefits of Cimzia did not outweigh the risk to patients. UCB appealed this decision, but was subsequently informed by the EMA in March 2008 that the CHMP had adopted a second negative opinion. This was due to a general concern over Cimzia’s safety and that it showed only marginal effectiveness, and that therefore the benefits did not outweigh the risks to patients (EMA, 2008).

Datamonitor Healthcare does not expect Cimzia to be approved for the treatment of Crohn’s disease in Japan. UCB previously partnered with Otsuka to develop and market Cimzia for Crohn’s disease and rheumatoid arthritis (RA) in Japan, but this partnership was terminated in January 2012 (Otsuka, 2012). In January 2012, UCB entered into an agreement with Astellas to develop and commercialize Cimzia for RA in Japan, but did not outline plans for development of the drug for Crohn’s disease (Astellas, 2012).

PIVOTAL TRIAL DATA

Pivotal Phase III trial data that supported the approval of Cimzia in the US are summarized in the table below.

Table 9: Cimzia pivotal trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

PRECiSE 1 662 Adults with moderately to Multinational, Cimzia 400mg (weeks 0, 2, and 4, then every four Clinical response*: week 6 FDA, 2017; Sandborn (NCT00152490) severely active Crohn’s multicenter, double- weeks to week 24) versus placebo = 35% Cimzia versus 27% et al., 2007 (Phase III) disease blind, placebo- placebo; week 26 = 37% controlled, parallel- Cimzia versus 27% placebo; group, 26-week study Clinical remission**: week 6 = 22% Cimzia versus 17% placebo; week 26 = 29% Cimzia versus 18% placebo; Cimzia treatment conferred significant improvement in response rates over placebo, but no significant differences in remission rates between arms

PRECiSE 2 428 Adults with moderately to Multinational, Cimzia 400mg (weeks 0, 2, and 4), then responders Clinical response*: week 26 FDA, 2017 (NCT00152425) severely active Crohn’s multicenter, double- randomized to receive Cimzia 400mg every four = 63% Cimzia versus 36% (Phase III) disease blind, placebo- weeks to week 24 or placebo placebo; controlled, parallel- Clinical remission**: week group, 26-week study 26 = 48% Cimzia versus 29% placebo; Significantly higher rate of remission in Cimzia group versus placebo

*Clinical response = ≥100-point decrease in CDAI score from baseline. Disease Coverage | Forecast: Crohn’s Disease 64

Table 9: Cimzia pivotal trial data in Crohn’s disease

**Clinical remission = CDAI score ≤150 points.

CDAI = Crohn’s Disease Activity Index

Source: various (see above) Disease Coverage | Forecast: Crohn’s Disease 65

OTHER LATE-PHASE TRIALS

Additional late-phase trial data for Cimzia in Crohn’s disease are summarized in the table below.

Table 10: Cimzia late-phase trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

PRECiSE 3 596 Crohn’s disease patients Multinational, multicenter, open-label Cimzia 400mg, every four weeks until Clinical remission* (year Sandborn et al., (PRECiSE 1 and 2 who completed the study week 362 seven) = 76%; mean 2014 extension) PRECiSE 1 or PRECiSE 2 duration of remission* (NCT00160524) studies (see table above) prior to TNF exposure = 1.5 (Phase III) years; mean duration of remission* in TNF-naïve patients = 2.3 years; mean duration of treatment response prior to TNF exposure = 2.5 years; mean duration of treatment response in TNF-naïve patients = 3.14 years

PRECiSE 4 310 Crohn’s disease patients Multinational, multicenter, open-label Patients from treatment arm of Clinical remission* (year Sandborn et al., (PRECiSE 1 and 2 withdrawn from the study PRECiSE 2: Cimzia 400mg at week 2, four) = 50% Remicade- 2010 extension) PRECiSE 1 and 2 studies then every four weeks thereafter experienced patients (NCT00160706) due to a Crohn’s disease Patients from placebo arm of versus 62.5% Remicade- (Phase III) exacerbation (see table PRECiSE 2: Cimzia 400mg (weeks 0, 2, naïve patients; above) and 4, then every four weeks Patients who are losing thereafter) response to or interrupt Cimzia therapy can be recaptured with one additional dose

*Clinical remission calculated using the Harvey-Bradshaw index. Disease Coverage | Forecast: Crohn’s Disease 67

Table 10: Cimzia late-phase trial data in Crohn’s disease

TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Forecast: Crohn’s Disease 68

SWOT ANALYSIS Figure 15: Cimzia for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of Cimzia’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the biologic comparator drug Remicade and all of the other key marketed and pipeline drugs profiled.

Figure 16: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

Source: Datamonitor Healthcare

Figure 17: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

Source: Datamonitor Healthcare

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Cimzia in Crohn’s disease:

REGULATORY

• Cimzia was approved and launched in the US for the treatment of Crohn’s disease in April 2008 (FDA, 2008).

• Datamonitor Healthcare does not expect Cimzia to be approved for the treatment of Crohn’s disease in Japan or the five major EU markets (France, Germany, Italy, Spain, and the UK) during the forecast period. There is no evidence of clinical development of Cimzia in Crohn’s disease in Japan; a previous co-development and co-commercialization agreement between UCB and Otsuka for Cimzia in Crohn’s disease was terminated in 2012 (Otsuka, 2012). In the EU, UCB’s Marketing Authorization Application for Cimzia in Crohn’s disease was rejected following two negative CHMP opinions, based on concerns that the drug’s benefits did not outweigh its risks (EMA, 2008).

COMPETITION

• Datamonitor Healthcare’s 2016 survey indicates that there is a small amount of off-label prescribing of Cimzia in Japan and

Spain.

• In the US and Spain, Cimzia is forecast to continue to lose patient share to the anti-integrin therapy Entyvio. Entyvio launched in the US and EU in June and July 2014, respectively (FDA, 2014; Takeda, 2014; Biomedtracker, 2018). Cimzia is set to lose up to a further 5% of its patient share at first and second line, and up to a further 12% of its patient share at third line and later to Entyvio. Loss of patient share will be lower at first and second lines as anti-TNFs – either the reference brands or their biosimilar versions – are anticipated to remain the preferred first-line biologic agents based on their proven efficacy and preferential formulary placement. Leading gastroenterologists highlight that Entyvio is primarily used late in the Crohn’s disease treatment algorithm.

“Entyvio is mostly used in later lines in patients who are refractory to anti-TNFs, and only in a few biologic-naïve patients.”

EU key opinion leader

• In Japan, Datamonitor Healthcare forecasts Cimzia to lose up to 8% of its patient share at first and second line, and up to 12% of its patient share at third line and later to Entyvio. Datamonitor Healthcare anticipates Entyvio to launch in Japan in Q4 2020 (Takeda, 2017).

• Datamonitor Healthcare forecasts Cimzia to lose patient share to the interleukin (IL)-12/23 inhibitor Stelara, which was approved for use in Crohn’s disease in the US in September 2016, in Europe in November 2016, and in Japan in March 2017 (Janssen, 2016; Johnson & Johnson, 2016; Mitsubishi Tanabe Pharma, 2017). Cimzia is set to lose up to 15% of its first- and second-line patient share, and up to 20% of its third-line or later patient share to Stelara. Among the forecast markets, erosion will be greatest in Japan, where Stelara is the first non-TNF biologic approved for use in Crohn’s disease.

• Datamonitor Healthcare forecasts Cimzia to lose patient share to the two pipeline oral Janus kinase (JAK)-1 inhibitors, filgotinib (Galapagos/Gilead) and upadacitinib (AbbVie), which are anticipated to launch from 2021. Cimzia is forecast to lose up to 4% of its first-line patient share, and up to 6% of its second-line or later patient share to filgotinib. Similarly, Cimzia is expected to lose up to 5% of its first-line patient share, and up to 9% of its second-line or later patient share to upadacitinib. Loss of patient share will be lower at first line as concerns remain around the safety profile of JAK inhibitors.

• Cimzia is expected to face minimal competition from the late-phase anti-integrin antibody etrolizumab (Roche), which is forecast to launch from 2021. Cimzia is set to lose 6–8% of its patient share to etrolizumab at third line and later in the US and Spain.

• Cimzia is forecast to lose patient share to the IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim), which is anticipated to launch from 2021. Cimzia is set to lose up to 3% of its first- and second-line patient share, and up to 8% of its third-line or later patient share to risankizumab.

• Cimzia is forecast to lose up to 3% of its first-line patient share, and up to 6% of its second-line and later patient share to the oral sphingosine-1-phosphate (S1P) modulator ozanimod (Celgene), which is forecast to launch from Q1 2023.

DOSING

• Datamonitor Healthcare has assumed dosing of 400mg every four weeks, as described in Cimzia’s prescribing information (FDA, 2017).

PRICING

• Based on discussions with key opinion leaders, Datamonitor Healthcare assumes that Cimzia’s net price in the US is 30% lower than the list price due to discounts and rebates.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

CIMZIA FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Cimzia in Crohn’s disease, by country, over 2016–25.

Figure 18: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country, 2016–25

Source: Datamonitor Healthcare

Table 11: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 334.0 345.7 352.5 360.7 372.9 389.4 405.1 418.8 432.0 443.6

Japan 2.0 2.0 1.9 1.8 1.7 1.7 1.6 1.5 1.5 1.4

Spain 6.6 6.6 6.4 6.2 6.1 6.0 6.0 5.9 5.8 5.6

Total 342.6 354.3 360.8 368.7 380.7 397.1 412.6 426.2 439.3 450.6

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 74

BIBLIOGRAPHY

Astellas (2012) UCB and Astellas announce agreement to jointly develop and commercialize Cimzia® (certolizumab pegol) in Japan. Available from: https://www.astellas.com/en/corporate/news/detail/ucb-and-astellas-announce-agre.html [Accessed 12 June 2017].

EMA (2008) QUESTIONS AND ANSWERS ON RECOMMENDATION FOR THE REFUSAL OF THE MARKETING AUTHORISATION FOR CIMZIA. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/11/WC500015246.pdf [Accessed 12 June 2017].

FDA (2008) Cimzia’s approval. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/125160s000ltr.pdf [Accessed 12 June 2017].

FDA (2014) FDA approves Entyvio to treat ulcerative colitis and Crohn's disease. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398065.htm [Accessed 12 June 2017].

FDA (2017) Cimzia prescribing information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125160s270lbl.pdf [Accessed 23 March 2018].

Janssen (2016) EUROPEAN COMMISSION APPROVES STELARA® (USTEKINUMAB) FOR TREATMENT OF ADULTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE. Available from: http://www.janssen.com/european-commission-approves-stelara-ustekinumab- treatment-adults-moderately-severely-active-crohn-s-disease [Accessed 12 June 2017].

Johnson & Johnson (2016) FDA Approves STELARA® (Ustekinumab) for Treatment of Adults With Moderately to Severely Active Crohn’s Disease. Available from: https://www.jnj.com/media-center/press-releases/fda-approves-stelara-ustekinumab-for-treatment- of-adults-with-moderately-to-severely-active-crohns-disease [Accessed 12 June 2017].

Mitsubishi Tanabe Pharma (2017) Notice regarding approval of indication of ulcerative colitis and additional formulation for Simponi subcutaneous injection 50mg syringe (generic name: golimumab), a human monoclonal antibody specific for human TNF a. Available from: http://www.mt-pharma.co.jp/e/release/nr/2017/pdf/e_MTPC170330.pdf [Accessed 12 June 2017].

Otsuka (2012) Otsuka Pharmaceutical and UCB focus collaboration in the area of Central Nervous System (CNS) disorders. Available from: https://www.otsuka.co.jp/en/company/newsreleases/2012/20120113_1.html [Accessed 12 June 2017].

Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, et al. (2007) Certolizumab pegol for the treatment of Crohn's disease. The New England Journal of Medicine, 357(3), 228–38.

Sandborn WJ, Schreiber S, Hanauer SB, Colombel JF, Bloomfield R, et al. (2010) Reinduction with certolizumab pegol in patients with relapsed Crohn's disease: results from the PRECiSE 4 Study. Clinical Gastroenterology and Hepatology, 8(8), 696–702.

Sandborn WJ, Lee SD, Randall C, Gutierrez A, Schwartz DA, et al. (2014) Long-term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7-year results from the PRECiSE 3 study. Alimentary Pharmacology and Therapeutics, 40(8), 903–16.

Takeda (2014) Takeda Receives European Commission Marketing Authorisation for Entyvio® (vedolizumab) for the Treatment of Ulcerative Colitis and Crohn’s Disease. Available from: http://www.takeda.com/news/files/20140528_02_en.pdf [Accessed 12 June 2017].

Takeda (2017) Results for FY2016: DATA BOOK. Available from: http://infopub.sgx.com/FileOpen/qr2016_q4_d_en.ashx?App=Announcement&FileID=452899 [Accessed 12 June 2017].

PRODUCT PROFILE: ENTYVIO

PRODUCT PROFILE

ANALYST OUTLOOK

Entyvio (vedolizumab; Takeda) has seen high use in Crohn’s disease since its launch in 2014, despite its modest efficacy in patients who are refractory to tumor necrosis factor (TNF) inhibition and its slower onset of action compared to other marketed biologics. Its high use is largely due to its favorable safety profile, with no black box warnings, and the overall lack of novel biologic therapies suitable for TNF-refractory patients, or patients with contraindications to TNF inhibition. Up until Stelara’s (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) approval in late 2016, Entyvio and Tysabri (natalizumab; Biogen) were the only non-TNF biologics in Crohn’s disease. Tysabri is approved for use in Crohn’s disease only in the US, and its use has been limited due to the associated increased risk of progressive multifocal leukoencephalopathy (PML). Datamonitor Healthcare forecasts Entyvio to face significant competition from Stelara, which has a faster onset of action and a comparable safety profile.

DRUG OVERVIEW

Entyvio is a monoclonal antibody (MAb) approved for the treatment of Crohn’s disease. It inhibits the alpha-4-beta-7 integrin receptor, preventing the migration of T cells to the gut. T cells have been shown to play a role in mediating the inflammatory process in Crohn’s disease (Gledhill and Bodger, 2013).

Table 12: Entyvio drug profile

Molecule vedolizumab

Mechanism of action MAb against alpha-4-beta-7 integrin receptor

Originator Millennium Pharmaceuticals (now Takeda Oncology)

Marketing company Takeda

Formulation IV

Alternative names n/a

IV = intravenous; MAb = monoclonal antibody

Source: Biomedtracker; Medtrack; Pharmaprojects; Entyvio prescribing information, 2018

DEVELOPMENT OVERVIEW

Entyvio was originally developed by Millennium Pharmaceuticals, which became a wholly owned subsidiary of Takeda in 2008. Takeda is now responsible for the development and commercialization of Entyvio (Takeda, 2008).

Intravenous (IV) Entyvio was approved for the treatment of moderately to severely active Crohn’s disease by the US Food and Drug Administration (FDA) and European Medicines Agency in May 2014. It launched in the US in June 2014, and in Europe in July 2014 (FDA, 2014; Takeda, 2014a/b).

In January 2014, Takeda initiated a Phase III program for IV Entyvio in Crohn’s disease in Japan (Biomedtracker, 2017).

A subcutaneous (SC) formulation of Entyvio is also being assessed in a Phase III program, and is forecast to launch in the US, Japan, and Europe from 2021 (Takeda, 2017).

PIVOTAL TRIAL DATA

Pivotal Phase III trial data that supported approvals of Entyvio in the US and EU are summarized in the table below.

Table 13: Entyvio pivotal trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and Results Reference duration

GEMINI II 1,116 Patients with moderately Randomized, placebo-controlled, IV Entyvio 300mg Induction phase (368 patients, 48% Entyvio prescribing (NCT00783692) to severely active Crohn’s blinded, multicenter study administered at weeks 0, 2, experienced TNF inhibitor failure): information, 2018 (Phase III) disease, who and 6, then at four- or eight- clinical remission** at week 6 = demonstrated an week intervals for up to one 15% Entyvio versus 7% placebo; inadequate response to, year versus placebo Maintenance phase (461 patients, loss of response to, or 51% experienced TNF inhibitor intolerance to failure): clinical response*** at conventional therapies week 52 = 44% Entyvio versus 30% placebo; clinical remission** at week 52 = 39% Entyvio versus 22% placebo; corticosteroid-free remission* = 32% Entyvio versus 16% placebo

GEMINI III 416 Patients with moderately Randomized, placebo-controlled, IV Entyvio 300mg In TNF inhibitor-failure population Entyvio prescribing (NCT01224171) to severely active Crohn’s blinded, multicenter study administered at weeks 0, 2, (315 patients): clinical remission** information, 2018 (Phase III) disease, who and 6 versus placebo at week 6 = 15% Entyvio versus 12% demonstrated an placebo; inadequate response to, Treatment with Entyvio did not loss of response to, or result in a statistically significant intolerance to improvement in clinical remission conventional therapies; over placebo; secondary endpoints, 76% of patients including week 10 clinical remission, experienced TNF inhibitor were not tested failure Disease Coverage | Forecast: Crohn’s Disease 78

Table 13: Entyvio pivotal trial data in Crohn’s disease

*Corticosteroid-free remission = proportion of patients that discontinued corticosteroids and were in clinical remission.

**Clinical remission = CDAI score ≤150.

***Clinical response = decrease of ≥70 points in CDAI score from baseline.

CDAI = Crohn’s Disease Activity Index; IV = intravenous; TNF = tumor necrosis factor

Source: see above Disease Coverage | Forecast: Crohn’s Disease 79

Post-hoc analyses of the efficacy data for 516 TNF inhibitor-naïve and 960 TNF inhibitor-failure patients from the GEMINI II and III studies showed that Entyvio achieved higher efficacy compared with placebo in patients, irrespective of anti-TNF treatment history. In addition, higher response and remission rates were observed in patients receiving Entyvio as a first biologic than in patients who had experienced TNF failure. Among the patients who responded to Entyvio induction at week 6, 48.9% of TNF inhibitor-naïve and 27.7% of TNF inhibitor-failure patients were in remission with Entyvio at week 52, compared to 26.8% and 12.8% with placebo. Overall, comparable efficacy was observed between the different types of TNF inhibitor failure or the number of prior TNF inhibitors failed (Sands et al., 2017).

Combined safety data from the GEMINI I, II, and III studies demonstrate that Entyvio is well tolerated. The combined safety population of the three GEMINI studies was derived from 769 ulcerative colitis patients and 962 Crohn’s disease patients. Of these patients, 1,434 received Entyvio and 297 received placebo. Adverse events (AEs) were reported in 52% of Entyvio patients and 45% of placebo patients, and serious AEs were reported in 7% of Entyvio patients and 4% of placebo patients. The most common AEs in patients treated with Entyvio were nasopharyngitis (13% versus 7% placebo), headache (12% versus 11% placebo), arthralgia (12% versus 10% placebo), nausea (9% versus 8% placebo), pyrexia (9% versus 7% placebo), and upper respiratory tract infection (7% versus 6% placebo). Bacterial sepsis including septic shock was reported in four Entyvio patients (0.7%) and two placebo patients (1%). Two Crohn’s disease patients treated with Entyvio died due to reported sepsis or septic shock; however, these patients had significant co- morbidities and a complicated hospital course, and it was unclear if Entyvio contributed toward their deaths. The rate of sepsis in patients with ulcerative colitis or Crohn’s disease receiving Entyvio was two per 1,000 patient-years (Entyvio prescribing information, 2018).

ONGOING LATE-PHASE TRIALS

Ongoing late-phase trials for Entyvio in Crohn’s disease are summarized in the table below.

Table 14: Entyvio ongoing late-phase trials in Crohn’s disease

Trial Sample size Target patients Study design Dosing Primary Study start/primary endpoints/results completion date

GEMINI LTS 2,243 Patients with Crohn’s Multicenter, open-label IV Entyvio 300mg every Among patients who May 2009/July 2017 (still (NCT00790933) disease and ulcerative study four weeks, starting at responded to Entyvio at ongoing) (Phase III) colitis previously treated week 0 for up to 46 week 6 in GEMINI II, 83% in GEMINI I, II, III, and months and 89% of patients were NCT00619489 in remission at weeks 104 and 152, respectively; Increased dosing frequency from every eight weeks in GEMINI II to every four weeks in GEMINI LTS improved outcomes in patients who had withdrawn early from GEMINI II; 47% of these patients experienced clinical response and 32% were in remission at week 52 vs 39% and 4% before the dose increase Disease Coverage | Forecast: Crohn’s Disease 81

Table 14: Entyvio ongoing late-phase trials in Crohn’s disease

NCT02038920 157 Japanese adults with Multicenter, randomized, IV Entyvio 300mg Induction phase: CDAI March 2014/February (Phase III) moderately or severely double-blind, placebo- administered at weeks 0, 100 response at week 10 2019 active Crohn’s disease controlled, parallel-group 2, and 6, and every eight Maintenance phase: study weeks thereafter Clinical remission* at week 60; Adverse events, body weight, vital signs, ECG, clinical laboratory test from baseline to 16 weeks after the last dose of study drug Disease Coverage | Forecast: Crohn’s Disease 82

Table 14: Entyvio ongoing late-phase trials in Crohn’s disease

NCT02611817 824 Patients with moderately Randomized, double- Entyvio SC 108mg Clinical remission* at January 2016/June 2019 (Phase III) to severely active Crohn’s blind, placebo-controlled maintenance arm: Open- week 52 disease who achieved study label induction: IV Entyvio clinical response following 300mg, infusion at weeks administration of Entyvio 0 and 2 IV induction therapy Double-blind maintenance: SC Entyvio 108mg every two weeks starting at week 6 up to week 50 Placebo maintenance arm: Open-label induction: IV Entyvio 300mg, infusion at weeks 0 and 2 Double-blind maintenance: Matching placebo to SC Entyvio every two weeks, starting at week 6 up to week 50

*Clinical remission = CDAI score ≤150.

CDAI = Crohn's Disease Activity Index; ECG = electrocardiogram; IV = intravenous; SC = subcutaneous

Source: : Biomedtracker; Trialtrove; ClinicalTrials.gov; Vermeire et al., 2017 Disease Coverage | Forecast: Crohn’s Disease 83

SWOT ANALYSIS Figure 19: Entyvio for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of Entyvio’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the biologic comparator drug Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and all of the other key marketed and pipeline drugs profiled.

Figure 20: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

Source: Datamonitor Healthcare

Figure 21: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Entyvio compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Entyvio for Crohn’s disease:

REGULATORY

• Entyvio launched in the US and Europe in June and July 2014, respectively (Takeda, 2014; Biomedtracker, 2017).

• Datamonitor Healthcare forecasts Entyvio to launch in Japan in Q4 2020 (Takeda, 2017). ClinicalTrials.gov lists one ongoing Phase III study examining Entyvio’s efficacy, safety, and pharmacokinetics in induction and maintenance therapy in Japanese patients with moderately or severely active Crohn’s disease (ClinicalTrials.gov identifier: NCT02038920). Based on the primary completion date of February 2019 for this Phase III study, Datamonitor Healthcare assumes Takeda will file for Japanese regulatory approval by Q3 2019, provided that the study generates positive data. Assuming a positive decision from regulators in Q3 2020, Datamonitor Healthcare anticipates launch in Japan in Q4 2020.

• Datamonitor Healthcare forecasts an SC formulation of Entyvio to launch in Q2 2023 in the US, and from Q1 2021 in Japan and select EU markets. ClinicalTrials.gov lists two Phase III trials that are examining the efficacy and safety of SC Entyvio in patients

with Crohn’s disease (ClinicalTrials.gov identifiers: NCT02620046, NCT02611817). The estimated primary completion date of the trial being conducted in US sites (NCT02620046) is August 2021. Based on this, Datamonitor Healthcare assumes Takeda will file for US approval by Q1 2022, provided that the study generates positive data. Assuming a positive decision from the FDA in Q1 2023, Datamonitor Healthcare anticipates launch in the US in Q2 2023. The estimated primary completion date of the trial being conducted in EU and Japanese sites (NCT02611817) is June 2019. Based on this, Datamonitor Healthcare assumes Takeda will file for approval with European and Japanese regulatory agencies by Q4 2019. Assuming a positive decision from regulators, Datamonitor Healthcare forecasts SC Entyvio to launch in Japan, Germany, and the UK in Q1 2021. This is expected to be followed by launch in France, Italy, and Spain a year later (in Q1 2022), following the conclusion of reimbursement negotiations. The relative launch timings are based on historical development and launch timelines in autoimmune indications.

COMPETITION

• In the US and five major EU markets (France, Germany, Italy, Spain, and the UK), Entyvio is forecast to capture up to an additional 8% of first-line patient share from commonly prescribed immunomodulators, including azathioprine, mercaptopurine, cyclosporine, and methotrexate. Gastroenterologists interviewed by Datamonitor Healthcare note that Entyvio is used as a first-line biologic in unique cases, such as patients at high risk for infections, elderly patients with co-morbidities, or patients with a personal history of malignancy.

“Anti-TNFs are still, in most cases, the first-line biologics, but there are special cases where we do not prescribe an anti-TNF first. These cases include older patients starting biologic therapy, patients at high risk for infections, patients with a personal history of malignancy, and patients who are worried about the side effects of anti-TNFs. These are the cases where I have prescribed Entyvio first…”

US key opinion leader

“The safety profile of vedolizumab (Entyvio) is very good, and I think it is better than the safety profile of anti-TNFs. Entyvio doesn’t have a black box warning.”

US key opinion leader

• In Japan, Entyvio is forecast to capture 5% of first-line patient share from immunomodulators.

• In the US and five major EU markets, Datamonitor Healthcare forecasts Entyvio to capture up to an additional 5% of first- and second-line patient share, and up to an additional 12% of third-line and later patient share from anti-TNF biologics Humira (adalimumab; AbbVie/Eisai), Remicade, and Cimzia (certolizumab pegol; UCB/Astellas). Erosion will be lower at first and second lines as anti-TNFs – either the reference brands or their biosimilar versions – are anticipated to remain the preferred first-line biologic agents, based on their proven efficacy and preferential formulary placement. Leading gastroenterologists highlight that Entyvio is primarily used late in the Crohn’s disease treatment algorithm.

“Entyvio is mostly used in later lines in patients who are refractory to anti-TNFs, and only in a few biologic-naïve patients.”

EU key opinion leader

• In Japan, Entyvio is forecast to capture 8% of Humira, Remicade, and Cimzia’s first- and second-line patient shares, and 12% of

their third-line and later patient shares.

• In the US, Entyvio is forecast to capture up to an additional 8% of patient share from Tysabri, across all lines of therapy.

“To begin with, there were very few patients on Tysabri because of the PML [progressive multifocal leukoencephalopathy] risk. When Entyvio came out we started prescribing Tysabri even less….”

US key opinion leader

• Across the US and five major EU markets, Datamonitor Healthcare forecasts up to 10% of Entyvio’s patient share to shift to Stelara, across all lines of therapy. Leading gastroenterologists stress that Stelara has a faster onset of action than Entyvio, and a comparable safety profile.

“Entyvio is going to take a hit now that Stelara is approved. Stelara has a faster onset of action than Entyvio in Crohn’s disease, and it has a good safety profile, with no black box warnings, similar to Entyvio. Personally, I will be prescribing Stelara in cases where I would have typically prescribed Entyvio in the past. Stelara will become the alternative to Humira and Remicade. Entyvio is definitely feeling a little pressure now.”

US key opinion leader

“Entyvio takes longer to work in Crohn’s disease than an anti-TNF and Stelara. So, in cases where I offered Entyvio, I made sure to manage patients’ expectations. I’d tell patients to be patient with Entyvio and that they would need at least four or five infusions before deciding whether they would continue treatment […] Stelara has a faster onset of action and, anecdotally, based on prescribing Stelara off-label and the data from clinical trials, I think Stelara is more durable, so patients are more likely to stay on it than Entyvio.”

US key opinion leader

“I believe Entyvio is a little bit less effective than an anti-TNF and Stelara. The speed of action and the effect rates are a bit lower, but in the long term the effects are superimposable.”

EU key opinion leader

• In Japan, where Entyvio is forecast to launch after Stelara (and before SC Entyvio), it is forecast to capture 5% of Stelara’s patient share, across all lines of therapy. Datamonitor Healthcare believes that Entyvio will be prescribed over Stelara in cases where there is a preference for IV administration, despite its slower onset of action compared to Stelara.

• In all markets, Datamonitor Healthcare forecasts Entyvio to lose patient share to SC Entyvio, which will launch from Q1 2021. Entyvio is forecast to lose up to 65% of its patient share across all lines of therapy to SC Entyvio.

• Datamonitor Healthcare forecasts Entyvio to lose patient share to the two pipeline oral Janus kinase (JAK)-1 inhibitors, filgotinib (Galapagos/Gilead) and upadacitinib (AbbVie), which are anticipated to launch from 2021. Entyvio is forecast to lose up to 4% of its first-line patient share, and 6% of its second-line or later patient share to filgotinib. Similarly, Entyvio is expected to lose up to 5% of its first-line patient share, and up to 9% of its second-line or later patient share to upadacitinib. Loss of patient share will be lower at first line as concerns remain around the safety profile of JAK inhibitors.

• Entyvio is expected to face direct competition from the late-phase anti-integrin antibody etrolizumab (Roche), which is forecast to launch from 2021. Entyvio is set to lose 10–12% of its first-line patient share, and 13–15% of its second-line and later patient

share to etrolizumab. Loss of patient share will be higher at the second line and later as gastroenterologists will be reluctant to prescribe a new, undifferentiated agent such as etrolizumab early in the Crohn’s disease treatment algorithm.

• Entyvio is forecast to lose up to 7% of its patient share to the IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim) across all lines of therapy following its anticipated launch in 2021.

• Entyvio is forecast to lose up to 3% of its first-line patient share, and up to 6% of its second-line and later patient share to the oral sphingosine-1-phosphate (S1P) modulator ozanimod (Celgene), which is forecast to launch in Q1 2023.

DOSING

• Datamonitor Healthcare has assumed dosing of 300mg every eight weeks, as described in Entyvio’s prescribing information (FDA, 2018; EMA, 2018).

PRICING

• Datamonitor Healthcare assumes that SC Entyvio will be priced at the average annual cost per patient of available biologic therapies in Crohn’s disease.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

ENTYVIO FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Entyvio in Crohn’s disease, by country, over 2016–25.

Figure 22: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 15: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 422.9 527.2 656.9 769.0 827.5 847.3 852.9 848.4 838.1 820.8

Japan - - - - <0.1 0.8 3.1 5.6 8.3 11.3

France 29.2 37.5 48.7 57.8 61.6 62.1 61.8 60.3 58.7 57.2

Germany 45.5 52.6 61.5 67.4 69.2 69.6 69.7 69.7 69.5 69.5

Italy 11.0 13.9 17.6 20.7 22.2 22.5 22.6 22.4 22.2 22.1

Spain 14.9 20.9 28.9 35.7 39.0 39.7 39.5 38.0 36.2 34.6

UK 11.3 16.1 22.6 28.0 30.5 30.9 30.4 29.6 28.9 28.2

Total 534.8 668.3 836.2 978.6 1,049.9 1,072.9 1,080.0 1,073.9 1,061.9 1,043.7

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 91

BIBLIOGRAPHY

EMA (2018) Entyvio’s prescribing information. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/002782/WC500168528.pdf [Accessed 26 March 2018].

Entyvio prescribing information (2018) Available from: https://general.takedapharm.com/entyviopi/ [Accessed 26 March 2018].

FDA (2014) FDA approves Entyvio to treat ulcerative colitis and Crohn's disease. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398065.htm [Accessed 12 June 2017].

FDA (2018) Entyvio’s prescribing information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125476s022lbl.pdf [Accessed 23 March 2018].

Gledhill T, Bodger K (2013) New and emerging treatments for ulcerative colitis: a focus on vedolizumab. Biologics, 7, 123–30.

Sands BE, Sandborn WJ, Van Assche G, Lukas M, Xu J, et al. (2017) Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflammatory Bowel Diseases, 23(1), 97–106.

Takeda (2008) Takeda Completes Acquisition of Millennium. Available from: http://www.takeda.com/news/2008/20080515_3619.html [Accessed 12 June 2017].

Takeda (2014a) Takeda Receives European Commission Marketing Authorisation for Entyvio® (vedolizumab) for the Treatment of Ulcerative Colitis and Crohn’s Disease. Available from: http://www.takeda.com/news/files/20140528_02_en.pdf [Accessed 12 June 2017].

Takeda (2014b) Summary of Financial Statements for the Three Month Period Ended June 30, 2014. Available from: http://www.takeda.com/investor-information/files/qr2014_q1_f_en.pdf [Accessed 12 June 2017].

Takeda (2017) Key Products and Pipeline. Available from: https://www.takeda.com/what-we-do/research-and-development/our- pipeline/ [Accessed 12 June 2017]

Vermeire S, Loftus EV Jr, Colombel JF, Feagan BG, Sandborn WJ, et al. (2017) Long-term Efficacy of Vedolizumab for Crohn’s Disease. Journal of Crohn’s and Colitis, 11(4), 412–24.

PRODUCT PROFILE: HUMIRA

PRODUCT PROFILE

ANALYST OUTLOOK

Humira (adalimumab; AbbVie/Eisai) has managed to successfully penetrate the first-line biologic setting in Crohn’s disease, sharing this position with Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe). While Humira is perceived to have an overall comparable efficacy profile to Remicade, and benefits from a more convenient formulation, key opinion leaders note that Remicade remains the preferred anti-tumor necrosis factor (TNF) biologic in patients with more advanced or complicated Crohn’s disease. This is because Remicade benefits from a flexible dosing regimen, and is perceived to have a faster onset of action compared to subcutaneously administered biologics. Humira will face significant competition from cheaper adalimumab biosimilars, which are expected to launch from Q4 2018 in the five major EU markets (France, Germany, Italy, Spain, and the UK). Nonetheless, Humira is forecast to remain among the preferred biologic brands for Crohn’s disease for the foreseeable future.

DRUG OVERVIEW

Humira is a recombinant human immunoglobulin G1 monoclonal antibody that acts as a TNF inhibitor. It is approved for use in several autoimmune indications, including Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, and ankylosing spondylitis.

Table 16: Humira drug profile

Molecule adalimumab

Mechanism of action TNF inhibitor

Originator AbbVie

Marketing company AbbVie (US/EU/Japan), Eisai (Japan)

Formulation SC

Alternative names n/a

SC = subcutaneous; TNF = tumor necrosis factor

Source: Datamonitor Healthcare; Biomedtracker; Pharmaprojects

DEVELOPMENT OVERVIEW

Humira was originally developed by Cambridge Antibody Technologies, and was subsequently licensed to Abbott (now AbbVie). Cambridge Antibodies was acquired by AstraZeneca in 2006, and AstraZeneca sold its inherited Humira royalty scheme to Royalty

Pharma in the same year for $700m (Royalty Pharma, 2006). AbbVie is Humira’s majority stakeholder, and is responsible for marketing and development of the drug in Europe and the US. In Japan, Humira is co-marketed by Abbott Japan and Eisai (Eisai, 2010).

In February 2007, the US Food and Drug Administration (FDA) approved Humira for reducing the signs and symptoms, and inducing and maintaining clinical remission in adults with moderately to severely active Crohn's disease, who have had an inadequate response to conventional therapy (FDA, 2007). In September 2014, the FDA approved Humira for the treatment of pediatric Crohn’s disease patients aged six years and older (AbbVie, 2014; FDA, 2014).

The European Medicines Agency (EMA) initially approved Humira for the treatment of severely active Crohn’s disease in adults in June 2007, and subsequently approved its use in adults with the moderately active form of the disease in August 2012 (Abbott, 2012). In November 2012, Humira was approved in the EU for the treatment of pediatric patients (aged 6–17 years) with severe active Crohn’s disease. In May 2016, the EMA approved Humira for use in pediatric patients with moderately active Crohn’s disease (EMA, 2018).

In Japan, Humira was approved for the treatment of moderately to severely active Crohn’s disease in October 2010 (Biomedtracker, 2018). In June 2016, a new dosing regimen for Humira in Crohn’s disease was approved in Japan; based on this, patients with moderate to severe Crohn’s disease who become less responsive to treatment with 40mg every two weeks can double the dose to 80mg every two weeks (Eisai, 2016).

PIVOTAL TRIAL DATA

Pivotal trial data that supported approvals of Humira for the treatment of moderately to severely active Crohn’s disease in adult patients in the US, Japan, and EU are summarized in the table below.

Table 17: Humira pivotal trial data in adult Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

CLASSIC 1 299 Adults with moderately to Randomized, double-blind, placebo- Arm 1: Humira 160mg week 0 then Clinical remission* at week Hanauer et al., 2006 (Phase III) severely active Crohn’s controlled, multicenter study Humira 80mg week 2 4: disease with CDAI ≥220 Arm 2: Humira 80mg week 0 then Arm 1: 36% and ≤400, TNF inhibitor- Humira 40mg week 2 Arm 2: 24% naïve Arm 3: Humira 40mg week 0 then Arm 3: 18% Humira 20mg week 2 Arm 4: 12%; Arm 4: Placebo weeks 0 and 2 Humira superior to placebo; optimum dosing 160mg/80mg; Humira well tolerated

GAIN 325 Adults with moderately to Randomized, double-blind, placebo- Arm 1: Humira 160mg week 0 then Clinical remission* at week Sandborn et al., (NCT00105300) severely active Crohn’s controlled, multicenter study Humira 80mg week 2 4: 2007 (Phase III) disease with CDAI ≥220 Arm 2: Placebo weeks 0 and 2 Arm 1: 21% and ≤400, lost Arm 2: 7%; response/become Clinical response** at week intolerant to Remicade 4: Arm 1: 52% Arm 2: 34%; Humira superior to placebo in patients previously treated with Remicade Disease Coverage | Forecast: Crohn’s Disease 95

Table 17: Humira pivotal trial data in adult Crohn’s disease

CHARM 499 Adults with moderately to Randomized, double-blind, placebo- Arm 1: Humira 80mg week 0 then Clinical remission*at week Colombel et al., 2007 (NCT00077779) severely active Crohn’s controlled, multicenter study Humira 40mg week 2 then Humira 26: (Phase III) disease with CDAI ≥220 40mg week 4 and then every other Arm 1: 40% and ≤400 week until week 56 Arm 2: 47% Arm 2: Humira 80mg week 0 then Arm 3: 17%; Humira 40mg week 2 then Humira Clinical remission*at week 40mg week 4 and then weekly until 56: week 56 Arm 1: 36% Arm 3: Humira 80mg week 0 then Arm 2: 41% Humira 40mg week 2 then placebo Arm 3: 1%; Clinical response** at week 26: Arm 1: 52% Arm 2: 52% Arm 3: 28%; Clinical response** at week 56: Arm 1: 41% Arm 2: 47% Arm 3: 17%; Humira weekly or every other week superior to placebo at maintaining remission of moderate to severe Crohn’s disease

*Clinical remission = CDAI score <150 points. Disease Coverage | Forecast: Crohn’s Disease 96

Table 17: Humira pivotal trial data in adult Crohn’s disease

**Clinical response = ≥70-point decrease in CDAI score from baseline.

CDAI = Crohn’s Disease Activity Index; TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Forecast: Crohn’s Disease 97

Pivotal trial data that supported Humira’s approvals for the treatment of pediatric Crohn’s disease in the US and EU are summarized in the table below.

Table 18: Humira pivotal trial data in pediatric Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

IMAGINE 1 192 Pediatric patients aged Randomized, double-blind, parallel- Arm 1: >40kg: Humira 160mg week 0 Clinical remission* at week EMA, 2018; FDA, (NCT00409682) 6–17 years with group, multicenter study then Humira 80mg week 2 then 26: 2017b Phase III) moderately to severely 20mg every other week until week 52 Arm 1: 39% active Crohn’s disease <40kg: Humira 80mg week 0 then Arm 2: 28%; with PCDAI >30 on Humira 40mg week 2 then 10mg Clinical remission* at week current treatment every other week until week 52 52: Arm 2: >40kg: Humira 160mg week 0 Arm 1: 33% then Humira 80mg week 2 then Arm 2: 23%; 40mg every other week until week 52 Clinical response** at week <40kg: Humira 80mg week 0 then 26: Humira 40mg week 2 then 20mg Arm 1: 59% every other week until week 52 Arm 2: 48%; Clinical response** at week 52: Arm 1: 42% Arm 2: 28%; Improved BMI and height velocity from baseline to week 26 and week 52 in both groups; improvement in quality of life parameters from baseline to week 26 and week 52 in both groups

*Clinical remission = PCDAI score <10 points. Disease Coverage | Forecast: Crohn’s Disease 99

Table 18: Humira pivotal trial data in pediatric Crohn’s disease

**Clinical response = ≥15-point decrease in PCDAI score from baseline.

BMI = body mass index; PCDAI = Pediatric Crohn’s Disease Activity Index

Source: various (see above) Disease Coverage | Forecast: Crohn’s Disease 100

ONGOING LATE-PHASE TRIALS

Ongoing late-phase trials for Humira in Crohn’s disease are summarized in the table below.

Table 19: Humira ongoing trials in Crohn’s disease

Trial Sample Target patients Study design Dosing Primary endpoints Study start/primary size completion date

NCT02065570 600 Adult patients with Multicenter, randomized, double- Induction: Proportion of patients who April 2014/March 2019 (Phase III) moderately to severely blind Arm 1: Patients are randomized to achieve clinical remission as active Crohn’s disease receive a higher induction regimen of measured by CDAI; and evidence of Humira; patients then receive blinded proportion of patients who mucosal ulceration Humira until week 12 achieve endoscopic Arm 2: Patients are randomized to improvement receive a standard induction regimen of Humira; patients then receive blinded Humira until week 12 Maintenance: Arm 1: Patients are re-randomized at week 14 to a clinically adjusted regimen Arm 2: Patients are re-randomized at week 14 to the therapeutic drug monitoring regimen

CDAI = Crohn’s Disease Activity Index

Source: Biomedtracker; Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 102

SWOT ANALYSIS Figure 23: Humira for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of Humira’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the biologic comparator drug Remicade and all of the other key marketed and pipeline drugs profiled.

Figure 24: Datamonitor Healthcare’s drug assessment summary of Humira in Crohn’s disease

Source: Datamonitor Healthcare

Figure 25: Datamonitor Healthcare’s drug assessment summary of Humira in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Humira compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Humira for Crohn’s disease:

REGULATORY

• In February 2007, the FDA approved Humira for reducing the signs and symptoms, and inducing and maintaining clinical remission in adults with moderately to severely active Crohn's disease, who have had an inadequate response to conventional therapy (FDA, 2007).

• The EMA initially approved Humira for the treatment of severely active Crohn’s disease in adults in June 2007, and subsequently approved its use in adults with the moderately active form of the disease in August 2012 (Abbott, 2012).

• In November 2012, Humira was approved in the EU for the treatment of pediatric patients (aged 6–17 years) with severe active Crohn’s disease. In Japan, Humira was approved for the treatment of moderately to severely active Crohn’s disease in October 2010 (Biomedtracker, 2018).

COMPETITION

• Datamonitor Healthcare expects biosimilar adalimumab to be the first biosimilar of a subcutaneous anti-TNF factor biologic to enter the US Crohn’s disease market, in Q1 2023. In September 2016, the FDA approved Amgen’s biosimilar adalimumab, Amjevita, for all of Humira’s indications excluding those for which Humira has outstanding orphan exclusivity (FDA, 2016). Further competition comes from Boehringer Ingelheim’s biosimilar adalimumab, Cyltezo, which was approved by the FDA in August 2017 (FDA, 2017a). However, the launch of any adalimumab biosimilar in the US is dependent on successful litigation relating to multiple patents held by AbbVie for Humira. In September 2017, AbbVie announced a global resolution of all intellectual property-related litigation with Amgen, which will delay the launch of Amjevita in the US until January 2023 (AbbVie, 2017). While this does not preclude other biosimilar developers from undertaking an at-risk launch, successfully challenging patents held by AbbVie, or designing around patents and using their own patent estate to support a biosimilar launch, Datamonitor Healthcare believes that a biosimilar adalimumab launch in the US is unlikely prior to 2023.

• Biosimilar adalimumab is expected to reach the Crohn’s disease market in Japan in Q1 2021, following the expiry of key patent protection (Medtrack, 2017). Datamonitor Healthcare forecasts biosimilar adalimumab to enter the EU Crohn’s disease market in Q4 2018, following the expiry of residual patent protection in the five major EU markets (Medtrack, 2017). Amgen won EMA approval for Amjevita in March 2017 (EMA, 2017). Datamonitor Healthcare forecasts further biosimilar competition in Europe from Samsung Bioepis’s biosimilar adalimumab candidate, Imraldi/SB5, which was approved by the EMA in August 2017 (Biogen, 2017).

• Datamonitor Healthcare forecasts biosimilar adalimumab to be priced at 20% below the annual cost of Humira. The first biosimilar approved in the US, Zarxio (filgrastim; Sandoz/Novartis), was priced at a 15% discount of its reference product, Neupogen (filgrastim; Amgen/Kyowa Hakko Kirin/Roche). Celltrion’s biosimilar infliximab, Inflectra, also launched in the US with a 15% discount to the reference brand. Datamonitor Healthcare assumes a marginally greater discount for biosimilar adalimumab based on the fact that several adalimumab biosimilars will be ready to launch from Q4 2018 onwards (Novartis, 2015; FDA News, 2015).

• In Japan, Datamonitor Healthcare forecasts biosimilar adalimumab to be priced at a 30% discount to the annual cost of Humira, based on Japanese pricing regulations, which state that biosimilar therapies will be initially priced at 70% of the reference product’s price (The Japan Times, 2015).

• Based on biosimilar pricing policies and trends in Europe, Datamonitor Healthcare forecasts biosimilar adalimumab to be priced up to 25% below the annual cost of Humira in the five major EU markets. In France and Italy, biosimilars are required to launch at a price which is 25–35% and 20% less than the originator drug, respectively. While Germany, Spain, and the UK have free pharmaceutical pricing, biosimilars will need to have a cost advantage to the originator in order to achieve penetration (Foxon et al., 2015).

• Datamonitor Healthcare expects the price of biosimilar adalimumab in all markets to decrease by approximately 30% over the forecast period, as additional biosimilar adalimumab entrants launch.

• Following the launch of biosimilar adalimumab, Datamonitor Healthcare assumes the price of Humira will decrease by approximately 30% across all markets, in order to maintain a constant price differential from the average price of biosimilar adalimumab.

• Datamonitor Healthcare forecasts Humira to lose up to 55% of its patient share to biosimilar adalimumab over the forecast period, across all markets. Datamonitor Healthcare expects that gastroenterologists’ initial caution with biosimilars will translate into relatively slow uptake of biosimilar adalimumab, with use primarily limited to new patients. In the long term, growing confidence in biosimilars driven by increasing familiarity and post-marketing data, alongside further reductions in the cost of

biosimilar adalimumab, will lead to greater erosion of Humira’s patient share to biosimilar adalimumab.

• In the US and five major EU markets, Humira is forecast to continue to lose patient share to the anti-integrin therapy Entyvio (vedolizumab; Takeda). Entyvio launched in the US and Europe in June and July 2014, respectively (Takeda, 2014; Biomedtracker, 2018). Humira is set to lose up to a further 5% of its patient share at first and second line, and up to a further 12% of its patient share at third line and later to Entyvio. Loss of patient share will be lower at first and second lines as anti-TNFs – either the reference brands or their biosimilar versions – are anticipated to remain the preferred first-line biologic agents based on their proven efficacy and preferential formulary placement. Leading gastroenterologists highlight that Entyvio is primarily used in patients who are refractory to TNF inhibition.

“Entyvio is mostly used in later lines in patients who are refractory to anti-TNFs, and only in a few biologic-naïve patients.”

EU key opinion leader

• In Japan, Datamonitor Healthcare forecasts Humira to lose up to 8% of its patient share at first and second line, and up to 12% of its patient share at third line and later to Entyvio. Datamonitor Healthcare anticipates Entyvio to launch in Japan in Q4 2020 (Takeda, 2017).

• Datamonitor Healthcare forecasts Humira to lose patient share to the interleukin (IL)-12/23 inhibitor Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe), which was approved for use in Crohn’s disease in the US in September 2016, in Europe in November 2016, and in Japan in February 2017 (Janssen, 2016; Johnson & Johnson, 2016; Mitsubishi Tanabe Pharma, 2017). Humira is set to lose up to 15% of its first- and second-line patient share, and up to 20% of its third-line or later patient share to Stelara. Datamonitor Healthcare anticipates that Stelara will struggle to displace the anti-TNFs from their preferred status as first-line biologics based on established treatment pathways and formulary placement, therefore erosion will be greatest at third line or later. Among the forecast markets, erosion will be greatest in Japan, where Stelara is the first non-TNF biologic approved for use in Crohn’s disease.

• Datamonitor Healthcare forecasts Humira to lose patient share to the two Phase III oral Janus kinase (JAK)-1 inhibitors, filgotinib (Galapagos/Gilead) and upadacitinib (AbbVie), which are anticipated to launch from 2021. Humira is forecast to lose up to 4% of its first-line patient share, and up to 6% of its second-line or later patient share to filgotinib. Similarly, Humira is expected to lose up to 5% of its first-line patient share, and up to 9% of its second-line or later patient share to upadacitinib. Loss of patient share will be lower at first line as concerns remain around the safety profile of JAK inhibitors.

• Humira is expected to face minimal competition from the late-phase anti-integrin antibody etrolizumab (Roche), which is forecast to launch from 2021. Humira is set to lose 6–8% of its patient share to etrolizumab at third line and later in all markets.

• Humira is forecast to lose patient share to the IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim), which is anticipated to launch from 2021. Humira is set to lose up to 3% of its first- and second-line patient share, and up to 8% of its third-line or later patient share to risankizumab.

• Humira is forecast to lose up to 3% of its first-line patient share, and up to 6% of its second-line and later patient share to the oral sphingosine-1-phosphate (S1P) modulator ozanimod (Celgene), which is forecast to launch from Q1 2023.

DOSING

• Datamonitor Healthcare has assumed dosing of 40mg every other week, as described in Humira’s prescribing information (EMA, 2018; FDA, 2017b).

PRICING

• Based on discussions with US payers, Datamonitor Healthcare assumes Humira’s net price in the US is 40% lower than the list price due to discounts and rebates.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

HUMIRA FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Humira in Crohn’s disease, by country, over 2016–25.

Figure 26: Humira sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 20: Humira sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 1,558.4 1,792.7 1,836.1 1,886.3 1,956.3 2,046.5 2,134.3 2,072.4 1,852.1 1,610.3

Japan 80.0 79.0 71.6 66.4 62.2 57.7 50.8 43.5 36.3 29.5

France 160.0 130.1 124.1 113.7 100.8 89.0 77.0 64.9 53.8 44.9

Germany 222.0 217.5 206.9 188.6 167.5 148.1 128.4 108.3 89.6 74.7

Italy 79.5 78.7 73.4 67.8 60.9 54.4 47.7 40.6 34.0 28.6

Spain 75.1 74.5 71.8 66.4 59.8 53.6 47.1 40.2 33.7 28.5

UK 77.7 76.7 73.5 67.7 60.7 54.3 47.6 40.7 34.3 29.1

Total 2,252.6 2,449.2 2,457.4 2,456.8 2,468.3 2,503.6 2,532.9 2,410.7 2,133.8 1,845.6

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 110

BIBLIOGRAPHY

Abbott (2012) Abbott's HUMIRA® (Adalimumab) Approved in Europe for Expanded Treatment of Crohn’s Disease (CD). Available from: http://www.abbott.com/news-media/press-releases/abbotts-humira-adalimumab-approved-in-europe-for-expanded-treatment-of- crohns-disease-cd.htm [Accessed 12 June 2017].

AbbVie (2014) AbbVie's Humira® (adalimumab) receives U.S. FDA approval for the treatment of pediatric patients with moderately to severely active Crohn's disease. Available from: http://abbvie.mediaroom.com/2014-09-25-AbbVies-HUMIRA-adalimumab-Receives-U- S-FDA-Approval-for-the-Treatment-of-Pediatric-Patients-with-Moderately-to-Severely-Active-Crohns-Disease [Accessed 12 June 2017].

Biogen (2017) IMRALDI®, Biogen’s Adalimumab Biosimilar Referencing Humira®, is Approved in the European Union. Available from: http://media.biogen.com/press-release/biosimilars/imraldi-biogens-adalimumab-biosimilar-referencing-humira-approved-european [Accessed 2 December 2017].

Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, et al. (2007) Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology, 132(1), 52–65.

Eisai (2010) Abbott Japan and Eisai Receive Approval for Additional Indications of Humira®, a Fully Human Anti-TNFα Monoclonal Antibody, for the Treatment of Crohn's Disease and Ankylosing Spondylitis. Available from: http://www.eisai.com/news/news201059.html [Accessed 12 June 2017].

Eisai (2016) AbbVie, Eisai, and EA Pharma Obtain Additional Approval for New Dosing Regimen of Fully Human AntiTNFα Monoclonal Antibody Humira® in Patients with Crohn’s Disease. Available from: http://www.eisai.com/news/enews201645pdf.pdf [Accessed 20 June 2017].

EMA (2017) Amgevita EPAR. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004212/human_med_002081.jsp&mid=WC0b01a c058001d124 [Accessed 23 May 2017].

EMA (2018) EPAR summary for the public. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000481/WC500050870.pdf [Accessed 26 March 2018].

FDA (2007) Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/125057s089Ltr.pdf [Accessed 12 June 2017].

FDA (2014) Supplemental Approval. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/125057Orig1s356ltr.pdf [Accessed 12 June 2017].

FDA (2016) FDA approves Amjevita, a biosimilar to Humira. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm [Accessed 23 May 2017].

FDA (2017a) Approval letter for Cyltezo. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761058Orig1s000ltr.pdf [Accessed 2 December 2017].

FDA (2017b) Humira prescribing information. Available from:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125057s403lbl.pdf [Accessed 26 March 2018].

FDA News (2015) Sandoz Launches Zarxio at 15 Percent Lower Price Than Neupogen. Available from: http://www.fdanews.com/articles/173036-sandoz-launches-zarxio-at-15-percent-lower-price-than-neupogen [Accessed 23 May 2017].

Foxon G, Fox G, Craddy P (2015) Are EU Payers Adapting Biosimilar Pricing and Reimbursement Approval Processes to Optimize Healthcare Savings? Presented at the ISPOR 20th Annual International Meeting, 16–20 May 2015, Philadelphia, US; Poster PHP106.

Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, et al. (2006) Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology, 130(2), 323–33.

Mitsubishi Tanabe Pharma (2017) Mitsubishi Tanabe Pharma Corporation Strategically Strengthens Its Foundation in the Field of Inflammatory Bowel Disease. Available from: http://www.mt-pharma.co.jp/e/release/nr/2017/pdf/e_MTPC170203.pdf [Accessed 23 May 2017].

Novartis (2015) Sandoz launches Zarxio (filgrastim-sndz), the first biosimilar in the United States. Available from: https://www.novartis.com/news/media-releases/sandoz-launches-zarxiotm-filgrastim-sndz-first-biosimilar-united-states [Accessed 23 May 2017].

Royalty Pharma (2006) Royalty Pharma Announces Agreement Regarding the Purchase of the Rights to a Pre-Existing Royalty Interest in HUMIRA® from AstraZeneca and CAT. Available from: http://www.royaltypharma.com/index.php?option=com_content&view=article&id=109:royalty-pharma-announces-agreement- regarding-the-purchase-of-the-rights-to-a-pre-existing-royalty-interest-in-humirar-from-astrazeneca-and-cat&catid=:press-releases- products&Itemid=21 [Accessed 12 June 2017].

Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, et al. (2007) Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Annals of Internal Medicine, 146(12), 829–38.

Takeda (2014) ENTYVIO™ (vedolizumab) Now Available in the United States for the Treatment of Adults with UC or CD. Available from: http://www.takeda.us/newsroom/press_release_detail.aspx?year=2014&id=311 [Accessed 23 May 2017].

Takeda (2017) Our Pipeline: Focus on our Therapeutic Areas. Available from: https://www.takeda.com/what-we-do/research-and- development/our-pipeline/ [Accessed 23 May 2017].

The Japan Times (2015) Generic drugs to be priced at 10% less from April. Available from: http://www.japantimes.co.jp/news/2015/12/02/national/science-health/generic-drugs-to-be-priced-at-10-less-from- april/#.WC8kx7KLTIU [Accessed 23 May 2017].

PRODUCT PROFILE: REMICADE

PRODUCT PROFILE

ANALYST OUTLOOK

Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) has managed to maintain its status as a preferred biologic for patients who fail conventional therapy, but is now sharing the position with Humira (adalimumab; AbbVie/Eisai). Remicade’s long- standing success is largely due to its first-to-market status, its strong data in both induction and maintenance of clinical remission, and the availability of efficacy data in multiple patient subgroups. While Humira is perceived to have an overall comparable efficacy profile to Remicade, and benefits from a more convenient formulation, key opinion leaders highlight that Remicade remains the preferred anti-tumor necrosis factor (TNF) biologic for patients with more advanced or complicated Crohn’s disease. This is due to Remicade’s flexible dosing regimen, as well as its perceived faster onset of action compared to subcutaneously administered biologics. Nonetheless, Remicade faces intense competition from the growing presence of cheaper infliximab biosimilars and is forecast to lose its leading position in the market in the near term.

DRUG OVERVIEW

Remicade is a chimeric, humanized monoclonal antibody targeting TNF-alpha. The drug has a long history of use in a number of immune-mediated inflammatory diseases including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriasis, and psoriatic arthritis.

Table 21: Remicade drug profile

Molecule infliximab

Mechanism of action Chimeric TNF-alpha MAb

Originator Janssen Biotech (formerly Centocor Ortho Biotech, a subsidiary of Johnson & Johnson)

Marketing company Johnson & Johnson (US), Merck & Co (EU), Mitsubishi Tanabe (Japan)

Formulation IV

Alternative names n/a

IV = intravenous; MAb = monoclonal antibody; TNF = tumor necrosis factor

Source: Datamonitor Healthcare; Biomedtracker; Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

Remicade was originally developed by Centocor, which became a wholly owned subsidiary of Johnson & Johnson (now under the name Janssen Biotech) in 1999 (Janssen Biotech, 2013). Johnson & Johnson markets Remicade in the US, Canada, Central and South America, the Middle East, Africa, and Asia Pacific. In Europe, Russia, and Turkey, Johnson & Johnson licenses Remicade distribution rights to Merck & Co. In Japan, Indonesia, and Taiwan, Johnson & Johnson licenses Remicade distribution rights to Mitsubishi Tanabe (Johnson & Johnson, 2011).

Remicade was approved in the US in August 1998 for the treatment of moderately to severely active Crohn’s disease. Its initial approval indicated it for the reduction of the disease’s signs and symptoms in patients who have experienced an inadequate response to conventional therapies, and for the treatment of patients with fistulizing Crohn’s disease for the reduction of the number of draining enterocutaneous fistulas (FDA, 1998). The US Food and Drug Administration (FDA) has since approved a number of label updates for Remicade in Crohn’s disease, including an indication for inducing and maintaining clinical remission, and use in pediatric patients aged 6–17 years (FDA, 2013).

Remicade was approved in the EU for Crohn’s disease in August 1999. Its indications for Crohn’s disease in the EU are similar to those in the US, except that the indication for pediatric use (patients aged 6–17 years) in the EU is limited to patients with severely active disease (EMA, 2017).

Remicade was approved in Japan for the treatment of moderately to severely active Crohn’s disease and fistulizing Crohn’s disease in 2002 (Tanabe Seiyaku, 2002). In 2007, Remicade’s Japanese label was expanded to include its indication as a maintenance therapy for Crohn’s disease (Mitsubishi Tanabe, 2007).

PIVOTAL TRIAL DATA

Pivotal trial data that supported approvals of Remicade for the treatment of adult patients with moderately to severely active Crohn’s disease in the US, Japan, and EU are summarized in the table below.

Table 22: Remicade pivotal trial data in adult Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and Results Reference duration

Phase III 108 Adults with moderately to Randomized, double- Single infusion of Clinical response* at Remicade prescribing severely active Crohn’s blind, single-dose, Remicade 5mg/kg versus week 4: 81% Remicade information, 2015 disease, previous multicenter Remicade 10mg/kg 5mg/kg versus 16% inadequate response to versus Remicade placebo; conventional therapies 20mg/kg versus placebo Clinical remission** at week 3: 48% Remicade 5mg/kg versus 4% placebo

ACCENT I 545 Adults with moderately to Randomized, double- Remicade 5mg/kg at week Clinical remission** at Remicade prescribing (NCT00207662) severely active Crohn’s blind, placebo-controlled 0 then randomized to week 30: information, 2015 (Phase III) disease, previous one of three groups: Arm 1: 39% inadequate response to Arm 1: Remicade 5mg/kg Arm 2: 46% conventional therapies at weeks 2 and 6, then Arm 3: 25%; every eight weeks to week A significantly greater 54 proportion of patients in Arm 2: Remicade the Remicade groups 10mg/kg at weeks 2 and were in clinical remission 6, then every eight weeks and able to discontinue to week 54 use of corticosteroids at Arm 3: Placebo week 54 than in the placebo group Disease Coverage | Forecast: Crohn’s Disease 115

Table 22: Remicade pivotal trial data in adult Crohn’s disease

SONIC 508 Adults with moderately to Randomized, double- Arm 1: Remicade 5mg/kg Steroid-free remission*** Remicade prescribing (NCT00094458) severely active Crohn’s blind, active-controlled, at weeks 0, 2, and 6, then at week 26: information, 2015 (Phase III) disease, naïve to multicenter every eight weeks Arm 1: 44.4% immunomodulatory or Arm 2: Azathioprine Arm 2: 30.0% biologic therapy 2.5mg/day Arm 3: 56.8% Arm 3: Remicade 5mg/kg at weeks 0, 2, and 6, then every eight weeks plus azathioprine 2.5mg/day

Phase III 94 Adults with fistulizing Randomized, double- Arm 1: Remicade 5mg/kg Fistula response†: Remicade prescribing Crohn’s disease with blind, placebo-controlled at weeks 0, 2, and 6 Arm 1: 68% information, 2015 fistulas of at least three Arm 2: Remicade Arm 2: 58% months’ duration 10mg/kg at weeks 0, 2, Arm 3: 26%; and 6 Closure of all fistulas Arm 3: Placebo achieved in 52% of Remicade patients versus 13% of placebo patients Disease Coverage | Forecast: Crohn’s Disease 116

Table 22: Remicade pivotal trial data in adult Crohn’s disease

ACCENT II 273 Adults with fistulizing Randomized, double- Remicade 5mg/kg at Before randomization, Remicade prescribing (NCT00207766) Crohn’s disease with one blind, placebo-controlled weeks 0, 2, and 6, then fistula response† at week information, 2015 (Phase III) or more draining randomized to: 14: 65%; enterocutaneous fistulas Arm 1: Remicade 5mg/kg No draining fistulas at every eight weeks week 54: Arm 2: Placebo Arm 1: 38% Arm 2: 22%; Patients randomized to Remicade maintenance group had a significantly longer time to loss of fistula response compared with placebo group

*Clinical response = ≥70-point decrease in CDAI score from baseline.

**Clinical remission = CDAI score <150 points.

***Steroid-free remission = patients in clinical remission who had not received systemic corticosteroids or budesonide for at least three weeks before endpoint.

†Fistula response = ≥50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least two consecutive visits without an increase in medication or surgery.

CDAI = Crohn's Disease Activity Index

Source: see above Disease Coverage | Forecast: Crohn’s Disease 117

Pivotal trial data that supported Remicade’s approval for the treatment of pediatric Crohn’s disease in the US and EU are summarized in the table below.

Table 23: Remicade pivotal trial data in pediatric Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

REACH 112 Pediatric patients aged Randomized, open-label, multicenter Remicade 5mg/kg at weeks 0, 2, and Arm 1: Clinical response* at Remicade (Phase III) 6–17 years with 6, then randomized to (week 10): week 30 = 73%; at week 54 prescribing moderately to severely Arm 1: Remicade 5mg/kg every eight = 64%; Clinical remission** information, 2015 active Crohn’s disease weeks at week 30 = 60%; at week and inadequate response Arm 2: Remicade 5mg/kg every 12 54 = 56%; to conventional therapies weeks Arm 2: Clinical response* at week 30 = 47%; at week 54 = 33%; Clinical remission** at week 30 = 35%; at week 54 = 24%; Proportion of patients able to discontinue corticosteroid use at weeks 30 and 54 significantly higher in Remicade eight- week maintenance group than in 12-week group

*Clinical response = decrease from baseline in the PCDAI score of ≥15 points and total PCDAI score of ≤30 points.

**Clinical remission = PCDAI score of <10 points.

PCDAI = Pediatric Crohn's Disease Activity Index

Source: see above Disease Coverage | Forecast: Crohn’s Disease 119

SWOT ANALYSIS Figure 27: Remicade for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of Remicade’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to all of the other key marketed and pipeline drugs profiled.

Figure 28: Datamonitor Healthcare’s drug assessment summary of Remicade in Crohn’s disease

Source: Datamonitor Healthcare

Figure 29: Datamonitor Healthcare’s drug assessment summary of Remicade in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Remicade compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Remicade for Crohn’s disease:

REGULATORY

• Remicade was approved in the US in August 1998 for the treatment of moderately to severely active Crohn’s disease (FDA, 1998).

• Remicade was approved in the EU for Crohn’s disease in August 1999. In the EU, Remicade’s approval for use in pediatric patients (aged 6–17 years) is limited to patients with severely active disease (EMA, 2017).

• Remicade was approved in Japan for the treatment of moderately to severely active Crohn’s disease and fistulizing Crohn’s disease in 2002 (Tanabe Seiyaku, 2002). In 2007, Remicade’s Japanese label was expanded to include maintenance therapy for Crohn’s disease (Mitsubishi Tanabe, 2007).

COMPETITION

• Celltrion’s infliximab biosimilar (marketed as Remsima by Celltrion and Inflectra by Pfizer) was the first anti-TNF biosimilar to enter the US Crohn’s disease market in Q4 2016. In April 2016, the FDA approved Inflectra for use in all indications for which Remicade is licensed (FDA, 2016). Johnson & Johnson, the originator and marketing company of Remicade in the US, and Pfizer are still in ongoing patent dispute proceedings over a patent covering Remicade’s cell culture media (US6284471); however, Pfizer launched Inflectra at-risk in November 2016 (Johnson & Johnson, 2016a; Pfizer, 2016). Datamonitor Healthcare forecasts further biosimilar competition in the US from Samsung Bioepis's biosimilar infliximab (marketed as Renflexis by Merck & Co and Flixabi by Biogen), which won regulatory approval in April 2017 (FDA, 2017b).

• Celltrion’s infliximab biosimilar was also the first anti-TNF biosimilar to launch in Japan and Europe in Q4 2014 and Q1 2015, respectively (GaBi, 2014; Hospira, 2015). Datamonitor Healthcare forecasts further biosimilar competition in Europe from Samsung Bioepis's biosimilar infliximab, which won EU regulatory approval in May 2016 (Biogen, 2016).

• Datamonitor Healthcare expects the price of biosimilar infliximab in all markets to decrease by approximately 30% over the forecast period, as additional biosimilar infliximab entrants launch.

• Over the 10-year forecast period, Datamonitor Healthcare assumes the price of Remicade will decrease by approximately 30% across all markets, in order to maintain a constant price differential from the average price of biosimilar infliximab.

• Datamonitor Healthcare forecasts Remicade to lose up to 55% of its patient share to biosimilar infliximab over the forecast period, across all markets. Datamonitor Healthcare expects gastroenterologists’ initial caution with biosimilars to translate into relatively slow uptake of biosimilar infliximab, with use limited primarily to new patients. In the long term, growing confidence in biosimilars driven by increasing familiarity and post-marketing data, alongside further reductions in the cost of biosimilar infliximab, will lead to greater erosion of Remicade’s patient share to biosimilar infliximab.

• In the US and five major EU markets (France, Germany, Italy, Spain, and the UK), Remicade is forecast to continue to lose patient share to the anti-integrin therapy Entyvio (vedolizumab; Takeda). Entyvio launched in the US and Europe in June and July 2014, respectively (Takeda, 2014; Biomedtracker, 2017). Remicade is set to lose up to a further 5% of its patient share at first and second line, and up to a further 12% of its patient share at third line and later to Entyvio. Loss of patient share will be lower at first and second lines as anti-TNFs – either the reference brands or their biosimilar versions – are anticipated to remain the preferred first-line biologic agents based on their proven efficacy and preferential formulary placement. Leading gastroenterologists highlight that Entyvio is primarily used in patients who are refractory to TNF inhibition.

“Entyvio is mostly used in later lines in patients who are refractory to anti-TNFs, and only in a few biologic-naïve patients.”

EU key opinion leader

• In Japan, Datamonitor Healthcare forecasts Remicade to lose up to 8% of its patient share at first and second line, and up to 12% of its patient share at third line and later to Entyvio. Datamonitor Healthcare anticipates Entyvio to launch in Japan in Q4 2020 (Takeda, 2017).

• Datamonitor Healthcare forecasts Remicade to lose patient share to the interleukin (IL)-12/23 inhibitor Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe), which was approved for use in Crohn’s disease in the US in September 2016, in Europe in November 2016, and in Japan in February 2017 (Janssen, 2016; Johnson & Johnson, 2016b; Mitsubishi Tanabe Pharma, 2017).

Remicade is set to lose up to 15% of its first- and second-line patient share, and up to 20% of its third-line or later patient share to Stelara. Datamonitor Healthcare anticipates that Stelara will struggle to displace the anti-TNFs from their preferred status as first-line biologics based on established treatment pathways and formulary placement, therefore erosion will be greatest at third line or later. Among the forecast markets, erosion will be greatest in Japan, where Stelara is the first non-TNF biologic approved for use in Crohn’s disease.

• Datamonitor Healthcare forecasts Remicade to lose patient share to the two pipeline oral Janus kinase (JAK)-1 inhibitors, filgotinib (Galapagos/Gilead) and upadacitinib (AbbVie), which are anticipated to launch from 2021. Remicade is forecast to lose up to 4% of its first-line patient share, and up to 6% of its second-line or later patient share to filgotinib. Similarly, Remicade is expected to lose up to 5% of its first-line patient share, and up to 9% of its second-line or later patient share to upadacitinib. Loss of patient share will be lower at first line as concerns remain around the safety profile of JAK inhibitors.

• Remicade is expected to face minimal competition from the late-phase anti-integrin antibody etrolizumab (Roche), which is forecast to launch from 2021. Remicade is set to lose 6–8% of its patient share to etrolizumab at third line and later in all markets.

• Remicade is forecast to lose patient share to the IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim), which is anticipated to launch from 2021. Remicade is set to lose up to 3% of its first- and second-line patient share, and up to 8% of its third-line or later patient share to risankizumab.

• Remicade is forecast to lose up to 3% of its first-line patient share, and up to 6% of its second-line and later patient share to the oral sphingosine-1-phosphate (S1P) modulator ozanimod (Celgene), which is forecast to launch from Q1 2023.

DOSING

• Datamonitor Healthcare has assumed dosing of 5mg/kg every eight weeks as described in the drug’s prescribing information (EMA, 2017; FDA, 2017a). Datamonitor Healthcare assumes that the average weight of a Crohn’s disease patient is 75kg.

PRICING

• Based on discussions with US payers, Datamonitor Healthcare assumes that Remicade’s net price in the US is 30% lower than the list price due to discounts and rebates.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

REMICADE FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Remicade in Crohn’s disease, by country, over 2016–25.

Figure 30: Remicade sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 24: Remicade sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 1,490.6 1,401.7 1,249.3 1,099.6 959.9 825.8 695.6 589.7 510.0 451.9

Japan 78.8 73.8 62.7 53.9 45.8 38.2 31.8 27.0 23.4 20.8

France 52.0 36.6 31.0 29.3 27.8 26.7 25.5 24.1 22.8 21.3

Germany 74.4 51.9 43.4 40.8 38.8 37.2 35.5 33.6 31.6 29.4

Italy 28.6 20.1 17.0 16.1 15.4 14.8 14.2 13.6 12.9 12.1

Spain 46.1 32.5 27.5 26.2 25.1 24.3 23.4 22.4 21.3 20.1

UK 34.0 24.0 20.3 19.3 18.5 17.9 17.3 16.6 15.9 15.0

Total 1,804.4 1,640.6 1,451.2 1,285.0 1,131.3 985.0 843.4 726.9 637.8 570.8

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 126

BIBLIOGRAPHY

Biogen (2016) FLIXABI, Biogen’s Infliximab Biosimilar Referencing Remicade, Approved in the European Union. Available from: http://media.biogen.com/press-release/biosimilars/flixabi-biogens-infliximab-biosimilar-referencing-remicade-approved-europe [Accessed 12 June 2017].

EMA (2017) Prescribing information for Remicade. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000240/WC500050888.pdf [Accessed 26 March 2018].

FDA (1998) Approval letter for Remicade: Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/inflcen082498L.htm [Accessed 12 June 2017].

FDA (2013) Remicade Label and Approval History. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist [Accessed 12 June 2017].

FDA (2017a) Prescribing information for Remicade. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103772s5377lbl.pdf [Accessed 26 March 2018].

FDA (2017b) Renflexis prescribing information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761054Orig1s000lbledt.pdf [Accessed 2 December 2017].

GaBi (2014) Biosimilar infliximab launched in Japan. Available from: http://www.gabionline.net/Biosimilars/News/Biosimilar-infliximab- launched-in-Japan [Accessed 8 December 2016].

Janssen Biotech (2013) Our History. Available from: http://www.janssenbiotech.com/company/history [Accessed 12 June 2017].

Janssen (2016) Phase 3 study results supporting US FDA and European Commission approvals of Stelara in the treatment of moderately to severely active Crohn’s disease published in the New England Journal of Medicine. Available from: http://www.janssen.com/phase-3-study-results-supporting-us-fda-and-european-commission-approvals-stelara-treatment [Accessed 12 June 2017].

Johnson & Johnson (2011) REMICADE® Receives FDA Approval as First Biologic Treatment for Pediatric Ulcerative Colitis. Available from: http://www.jnj.com/NewsArchive/all-news-archive/REMICADE-Receives-FDA-Approval-as-First-Biologic-Treatment-for-Pediatric- Ulcerative-Colitis [Accessed 12 June 2017].

Johnson & Johnson (2016a) Johnson & Johnson Announces Ruling Related to REMICADE® in the District of Massachusetts Federal Court Hearing. Available from: http://www.investor.jnj.com/releaseDetail.cfm?ReleaseID=984719 [Accessed 12 June 2017].

Johnson & Johnson (2016b) FDA Approves STELARA® (Ustekinumab) for Treatment of Adults With Moderately to Severely Active Crohn’s Disease. Available from: https://www.jnj.com/media-center/press-releases/fda-approves-stelara-ustekinumab-for-treatment- of-adults-with-moderately-to-severely-active-crohns-disease [Accessed 23 May 2017].

Mitsubishi Tanabe (2007) Summary of 3rd Quarter Consolidated Financial Results for Fiscal 2007. Available from: http://www.mt- pharma.co.jp/e/ir/data/mtpc/m2003/pdf/e2007_3rdQ.pdf [Accessed 12 June 2017].

Pfizer (2016) Pfizer Announces The U.S. Availability Of Biosimilar INFLECTRA® (infliximab-dyyb). Available from: http://www.pfizer.com/news/press-release/press-releasedetail/pfizer_announces_the_u_s_availability_of_biosimilar_inflectra_infliximab_dyyb [Accessed 8 December 2016].

Remicade prescribing information (2015) Available from: https://www.remicade.com/shared/product/remicade/prescribing- information.pdf [Accessed 26 March 2018].

Takeda (2017) Key Products and Pipeline. Available from: https://www.takeda.com/what-we-do/research-and-development/our- pipeline/ [Accessed 12 June 2017]

Tanabe Seiyaku (2002) Annual Report. Available from: http://www.mt-pharma.co.jp/ir/annual/tanabe/pdf/2002/annual_2002_en.pdf [Accessed 12 June 2017].

PRODUCT PROFILE: STELARA

PRODUCT PROFILE

ANALYST OUTLOOK

Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) is forecast to become the market-leading brand within Crohn’s disease. Stelara’s strongest competitors, Humira (adalimumab; AbbVie/Eisai) and Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe), will lose considerable patient share to biosimilars, while Stelara will remain patent-protected until at least 2025. Stelara’s position in the marketplace is further boosted by its promising clinical performance to date, favorable safety profile with no black box warnings, and convenient subcutaneous (SC) maintenance dosing every eight weeks. Datamonitor Healthcare forecasts Stelara to be used primarily in patients who are refractory to tumor necrosis factor (TNF) inhibition, and as a first-line biologic in unique cases (eg patients with co-morbidities or at high risk of infections).

DRUG OVERVIEW

Stelara is a fully human monoclonal antibody (MAb) that binds with specificity to the p40 protein subunit used by both the interleukin (IL)-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and cluster of differentiation (CD)4+ T-cell differentiation and activation (Stelara prescribing information, 2018).

Table 25: Stelara drug profile

Molecule ustekinumab

Mechanism of action IL-12/23 inhibitor

Originator Medarex (now part of Bristol-Myers Squibb)/Centocor (now part of Johnson & Johnson)

Marketing company Johnson & Johnson/Mitsubishi Tanabe

Formulation IV and SC

Alternative names CNTO 1275

IL = interleukin; IV = intravenous; SC = subcutaneous

Source: Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

The US Food and Drug Administration approved Stelara for the treatment of moderately to severely active Crohn’s disease in adult patients in September 2016 (Johnson & Johnson, 2016a). Stelara received EU and Japanese approvals for use in Crohn’s disease in November 2016 and March 2017, respectively (Janssen, 2016a; Mitsubishi Tanabe, 2017).

Stelara’s efficacy and safety are also being assessed in pediatric patients with moderately to severely active Crohn’s disease, and in adult patients with moderately to severely active ulcerative colitis.

PIVOTAL TRIAL DATA

Pivotal Phase III trial data that supported approvals of Stelara in the US, Japan, and EU are summarized in the table below.

Table 26: Stelara pivotal trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

UNITI-1 769 Adult patients with Randomized, double-blind, placebo- Arm 1: IV Stelara 130mg Clinical response* at week Feagan et al., 2016; (NCT01369329) moderately to severely controlled, parallel-group, Arm 2: IV Stelara 6mg/kg 6: Janssen, 2016b (Phase III) active Crohn’s disease multicenter Arm 3: IV placebo Arm 1: 34.3% (p=0.002) who have failed or are Arm 2: 33.7% (p=0.003) intolerant to anti-TNF Arm 3: 21.5%; therapy Clinical response* at week 8: Arm 1: 33.5% (p<0.001) Arm 2: 37.8% (p<0.001) Arm 3: 20.2%; Clinical remission** at week 8: Arm 1: 15.9% (p=0.003) Arm 2: 20.9% (p<0.001) Arm 3: 7.3%; Rates of AEs: Arm 1: 64.6% Arm 2: 65.9% Arm 3: 64.9%; Patients with serious AEs: Arm 1: 4.9% Arm 2: 7.2% Arm 3: 6.1% Disease Coverage | Forecast: Crohn’s Disease 131

Table 26: Stelara pivotal trial data in Crohn’s disease

UNITI-2 640 Adult patients with Randomized, double-blind, placebo- Arm 1: IV Stelara 130mg Clinical response* at week Feagan et al., 2016; (NCT01369342) moderately to severely controlled, multicenter Arm 2: IV Stelara 6mg/kg 6: Janssen, 2016b (Phase III) active Crohn’s disease Arm 3: IV placebo Arm 1: 51.7% (p<0.001) who have had an Arm 2: 55.5% (p<0.001) inadequate response to Arm 3: 28.7%; conventional therapy Clinical response* at week 8: Arm 1: 47.4% (p<0.001) Arm 2: 57.9% (p<0.001) Arm 3: 32.1%; Clinical remission** at week 8: Arm 1: 30.6% (p=0.009) Arm 2: 40.2% (p<0.001) Arm 3: 19.6%; Rates of AEs: Arm 1: 50.0% Arm 2: 55.6% Arm 3: 54.3%; Patients with serious AEs: Arm 1: 4.7% Arm 2: 2.9% Arm 3: 5.8% Disease Coverage | Forecast: Crohn’s Disease 132

Table 26: Stelara pivotal trial data in Crohn’s disease

IM-UNITI*** 1,282 Adult patients with Randomized, double-blind, placebo- Responders to IV Stelara induction Clinical remission** at week Feagan et al., 2016; (NCT01369355) moderately to severely controlled, parallel-group, therapy randomized (1:1:1): 44: Janssen, 2016c; (Phase III) active Crohn’s disease multicenter Arm 1: SC Stelara 90mg every 12 Arm 1: 48.8% (p=0.04) Johnson & Johnson, who completed UNITI-1 weeks Arm 2: 53.1% (p=0.005) 2016b or UNITI-2 Arm 2: SC Stelara 90mg every eight Arm 3: 35.9%; weeks Clinical response* at week Arm 3: SC placebo every four weeks 44: Non-responders to IV placebo Arm 1: 58.1% (p=0.03) induction therapy: Arm 2: 59.4% (p=0.02) Arm 4: IV Stelara 130mg and SC Arm 3: 44.3%; placebo at week 0, and then, if Clinical remission** at week responded, SC Stelara 90mg at week 44 among patients in 8 and then every 12 weeks clinical remission at week 0 Non-responders to IV Stelara of IM-UNITI: induction therapy: Arm 1: 56.4% (p=0.19) Arm 5: SC Stelara 90mg and IV Arm 2: 66.7% (p=0.007) placebo at week 0, and then, if Arm 3: 45.6%; responded, SC Stelara 90mg every Glucocorticoid-free eight weeks remission at week 44: Responders to IV placebo induction Arm 1: 42.6% received one dose of SC placebo (p=0.04) every four weeks Arm 2: 46.9% (p=0.004) Arm 3: 29.8%; Rates of AEs: Arm 1: 80.3% Arm 2: 81.7% Arm 3: 83.5%; Patients with serious AEs: Disease Coverage | Forecast: Crohn’s Disease 133

Table 26: Stelara pivotal trial data in Crohn’s disease

Arm 1: 12.1% Arm 2: 9.9% Arm 3: 15.0%

*Clinical response = decrease from baseline CDAI score of ≥100 points or CDAI score <150, or being in clinical remission.

**Clinical remission = CDAI score <150 points.

***The IM-UNITI study is ongoing.

AE = adverse event; CDAI = Crohn’s Disease Activity Index; IV = intravenous; SC = subcutaneous; TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Forecast: Crohn’s Disease 134

SWOT ANALYSIS Figure 31: Stelara for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of Stelara’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the biologic comparator drug Remicade and all of the other key marketed and pipeline drugs profiled.

Figure 32: Datamonitor Healthcare’s drug assessment summary of Stelara in Crohn’s disease

Source: Datamonitor Healthcare

Figure 33: Datamonitor Healthcare’s drug assessment summary of Stelara in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Stelara compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Stelara for Crohn’s disease:

REGULATORY

• Stelara received US and EU approvals for the treatment of adult patients with moderately to severely active Crohn’s disease in September and November 2016, respectively (Johnson & Johnson, 2016a; Janssen, 2016a).

• In Japan, Stelara was approved for use in Crohn’s disease in February 2017 (Mitsubishi Tanabe, 2017). Stelara’s approval was based on positive Phase III efficacy and safety data from the pivotal UNITI-1 and UNITI-2 induction studies, and the IM-UNITI maintenance study. The clinical development program for Stelara included approximately 1,400 patients who were new to, experienced with, or had failed anti-TNF therapy.

COMPETITION

• Datamonitor Healthcare forecasts Stelara to become the market-leading brand within Crohn’s disease, as its strongest competitors Humira and Remicade face biosimilar competition.

• Aside from a later patent expiry than Remicade and Humira, Stelara also benefits from a more favorable safety profile and convenient dosing schedule.

US key opinion leader

EU key opinion leader

US key opinion leader

• In the US and EU, Stelara is forecast to erode up to 10% of first- and second-line patient share, and up to 15% of third-line and later patient share, from the anti-TNF biologics Remicade, Humira, and Cimzia (certolizumab pegol; UCB/Astellas). Datamonitor Healthcare anticipates anti-TNF therapies to retain their preferred status as first-line biologics based on physician preference and formulary placement, therefore erosion will be greatest at third line or later.

• In Japan, Stelara is forecast to erode up to 15% of first- and second-line patient share, and up to 20% of third-line or later patient share from the well-established anti-TNF therapies Remicade and Humira. Stelara is forecast to have a greater impact on anti- TNFs in Japan than in the US and Europe as Stelara is the first non-TNF biologic therapy approved in Japan for the treatment of Crohn’s disease.

• Stelara is forecast to erode up to 10% of patient share from Entyvio (vedolizumab; Takeda) across all lines of therapy in the US and Europe. Leading gastroenterologists note that they intend to prescribe Stelara over Entyvio, as Stelara has a faster onset of action and a comparable safety profile.

“I think Entyvio is going to take a hit now that Stelara is approved. Stelara has a faster onset of action than Entyvio in Crohn’s disease, and it has a good safety profile, with no black box warnings, similar to Entyvio. Personally, I will be prescribing Stelara in cases where I would have typically prescribed Entyvio in the past. In my opinion, Stelara will become the alternative to Humira and Remicade. Entyvio is definitely feeling a little pressure now.”

US key opinion leader

• In the US, Stelara is forecast to erode up to 10% of patient share from Tysabri (natalizumab; Biogen) across all lines of therapy.

“To begin with, there were very few patients on Tysabri because of the PML [progressive multifocal leukoencephalopathy] risk. When Entyvio came out, we started prescribing Tysabri even less. Now that Stelara is also available, Tysabri will be very, very rarely used.”

US key opinion leader

• Datamonitor Healthcare forecasts Stelara to erode up to 8% of patient share from commonly prescribed immunomodulators such as azathioprine, mercaptopurine, cyclosporine, and methotrexate at first and second line. Interviewed gastroenterologists note that Stelara is a suitable first-line biologic for older patients who are starting a biologic therapy, who are at high risk for infections, who have a history of malignancy, or who are concerned about the side effects associated with anti-TNF therapy.

“In some special cases, I will be prescribing Stelara as a first-line biologic instead of an anti-TNF. One example is patients at high risk for getting infections; Stelara does not have a black box warning for infections. Another example is older patients who are 65 [years of age] and are starting a biologic. You may also see patients with a personal history of malignancy that maybe had breast cancer several years ago and are now starting biologic therapy; in these cases, I feel more comfortable prescribing a biologic like Stelara that does not have a black box warning of malignancy risk. Of course, there is also a big group of patients who have read up on biologics or have seen too many Humira ads on TV – in the US we have direct-to-consumer ads – and are worried about the risk of malignancy or any side effects they have read or heard about.”

US key opinion leader

• Stelara is expected to face minimal competition from the late-phase anti-integrin antibody etrolizumab (Roche), which is forecast to launch from 2021. Stelara is set to lose 6–8% of its patient share to etrolizumab at third line and later in all markets. No impact is expected at first and second lines, as Stelara is used in specific cases in these early lines, where gastroenterologists will be reluctant to prescribe a new, undifferentiated agent such as etrolizumab.

• Datamonitor Healthcare forecasts Stelara to lose patient share to the two Phase III oral Janus kinase (JAK)-1 inhibitors, filgotinib (Galapagos/Gilead) and upadacitinib (AbbVie), which are anticipated to launch from 2021. Stelara is forecast to lose up to 4% of its first-line patient share, and up to 6% of its second-line or later patient share to filgotinib. Similarly, Stelara is expected to lose up to 5% of its first-line patient share, and up to 9% of its second-line or later patient share to upadacitinib. Loss of patient share will be lower at first line as concerns remain around the safety profile of JAK inhibitors.

• Stelara is forecast to lose patient share to the IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim), which is anticipated to launch from 2021. Stelara is set to lose up to 6% of its patient share to risankizumab across all lines of therapy.

• Stelara is forecast to lose up to 3% of its first-line patient share, and up to 6% of its second-line and later patient share to the oral sphingosine-1-phosphate (S1P) modulator ozanimod (Celgene), which is forecast to launch from Q1 2023.

DOSING

• Datamonitor Healthcare has assumed dosing of 90mg every eight weeks, as described in the drug’s prescribing information (EMA, 2017; FDA, 2016).

PRICING

• Please view the accompanying datapack for a full table of drug costs per patient per year.

STELARA FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Stelara in Crohn’s disease, by country, over 2016–25.

Figure 34: Stelara sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 27: Stelara sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 9.6 307.9 792.3 1,182.3 1,489.4 1,712.5 1,834.9 1,871.8 1,860.8 1,833.4

Japan - 12.6 46.0 59.3 66.1 69.5 68.9 66.0 62.5 59.3

France <0.1 5.4 20.5 38.8 59.4 76.3 84.9 86.1 82.8 78.5

Germany <0.1 11.3 37.6 62.1 84.6 101.1 108.4 108.2 103.7 98.2

Italy <0.1 4.1 14.0 23.7 33.2 40.7 44.7 45.7 44.8 43.4

Spain <0.1 4.4 15.0 24.9 34.2 41.2 44.5 44.8 43.3 41.3

UK <0.1 5.0 17.1 29.1 40.7 49.9 55.0 56.5 55.7 54.4

Total 9.8 350.6 942.5 1,420.1 1,807.5 2,091.2 2,241.3 2,279.1 2,253.6 2,208.4

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 141

BIBLIOGRAPHY

EMA (2017) Prescribing information for Stelara. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000958/WC500058513.pdf [Accessed 26 March 2018].

FDA (2016) Prescribing information for Stelara in the US. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761044lbl.pdf [Accessed 26 March 2018].

Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, et al. (2016) Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. The New England Journal of Medicine, 375(20), 1946–60.

Janssen (2016a) EUROPEAN COMMISSION APPROVES STELARA® (USTEKINUMAB) FOR TREATMENT OF ADULTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE. Available from: http://www.janssen.com/european-commission-approves-stelara- ustekinumab-treatment-adults-moderately-severely-active-crohn-s-disease [Accessed 12 June 2017].

Janssen (2016b) STELARA® Induced Clinical Response And Remission In Phase 3 Study For The Treatment Of Patients With Moderate To Severe Crohn's Disease Who Had Previously Failed Or Were Intolerant To Anti-TNF-Alpha Therapy. Available from: http://www.janssen.com/stelara-induced-clinical-response-and-remission-phase-3-study-treatment-patients-moderate-severe [Accessed 12 June 2017].

Janssen (2016c) Phase 3 study results supporting US FDA and European Commission approvals of Stelara in the treatment of moderately to severely active Crohn’s disease published in the New England Journal of Medicine. Available from: http://www.janssen.com/phase-3-study-results-supporting-us-fda-and-european-commission-approvals-stelara-treatment [Accessed 12 June 2017].

Johnson & Johnson (2016a) FDA Approves STELARA® (Ustekinumab) for Treatment of Adults With Moderately to Severely Active Crohn’s Disease. Available from: https://www.jnj.com/media-center/press-releases/fda-approves-stelara-ustekinumab-for-treatment- of-adults-with-moderately-to-severely-active-crohns-disease [Accessed 12 June 2017].

Johnson & Johnson (2016b) New Phase 3 Study Findings Show STELARA® Maintained Clinical Remission After One Year Of Treatment In Patients With Moderate To Severe Crohn's Disease. Available from: https://www.jnj.com/media-center/press-releases/new-phase-3- study-findings-show-stelara-maintained-clinical-remission-after-one-year-of-treatment-in-patients-with-moderate-to-severe-crohns- disease [Accessed 12 June 2017].

Mitsubishi Tanabe (2017) Notice regarding approval of indication of ulcerative colitis and additional formulation for Simponi subcutaneous injection 50mg syringe (generic name: golimumab), a human monoclonal antibody specific for human TNF a. Available from: http://www.mt-pharma.co.jp/e/release/nr/2017/pdf/e_MTPC170330.pdf [Accessed 12 June 2017].

Stelara prescribing information (2018) Available from: http://www.janssenlabels.com/package-insert/product-monograph/prescribing- information/STELARA-pi.pdf [Accessed 26 March 2018].

PRODUCT PROFILE: TYSABRI

PRODUCT PROFILE

ANALYST OUTLOOK

Tysabri’s (natalizumab; Biogen) status as the first-in-class anti-integrin biologic has not translated to great success in the Crohn’s disease market. Primary research conducted by Datamonitor Healthcare reveals that Tysabri is the least frequently prescribed biologic in the US, the only major market where it is approved for the treatment of Crohn’s disease. Safety issues tarnish Tysabri’s clinical and commercial attractiveness, and Datamonitor Healthcare believes that these issues have rendered it unable to compete in an increasingly competitive environment. Second-to-market integrin inhibitor Entyvio (vedolizumab; Takeda) has captured most of Tysabri’s market share, and the arrival of the interleukin (IL)-12/23 inhibitor Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) will further impact Tysabri’s use.

DRUG OVERVIEW

Tysabri is an intravenous humanized monoclonal antibody indicated for the treatment of moderately to severely active Crohn’s disease. It inhibits alpha-integrin cell adhesion proteins, preventing the migration of lymphocytes into the gut and subsequent inflammation (Denmark and Mayer, 2013).

Table 28: Tysabri drug profile

Molecule natalizumab

Mechanism of action MAb against alpha-4-beta-7 and alpha-4-beta-1 integrin receptors

Originator Elan (now Perrigo) and Biogen Idec

Marketing company Biogen

Formulation IV

Alternative names Antegren, BG00002

IV = intravenous; MAb = monoclonal antibody

Source: Biomedtracker; Pharmaprojects

DEVELOPMENT OVERVIEW

Tysabri was approved for the treatment of Crohn’s disease in the US in January 2008 (FDA, 2008). Datamonitor Healthcare does not forecast Tysabri to gain approval for use in Crohn’s disease in the EU.

The development and approval of Tysabri for Crohn’s disease was delayed by safety concerns that emerged from clinical studies. In February 2005, Biogen Idec and Elan (now part of Perrigo) announced they were voluntarily suspending marketing of Tysabri for multiple sclerosis (MS) and dosing in all clinical trials because of two previously reported cases of progressive multifocal leukoencephalopathy (PML), a rare and frequently fatal disease of the central nervous system (Biogen Idec, 2005). In total, three patients who received Tysabri developed PML, and two died. In light of this, Biogen Idec and Elan initiated a comprehensive safety evaluation concerning a possible link between Tysabri and PML. After this analysis, and with no further deaths, a US Food and Drug Administration (FDA) advisory committee recommended Tysabri’s return to the market as an MS therapy, and Phase III development for Crohn’s disease was resumed. The return of the drug to market and continuation of clinical development was subject to a risk management plan called the Tysabri Outreach: Unified Commitment to Health (TOUCH) (FDA, 2006). Under the TOUCH prescribing program, only prescribers, infusion centers, and their associated pharmacies enrolled with the program are able to prescribe, distribute, or infuse Tysabri (TOUCH, 2017).

In July 2007, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use adopted a negative opinion of Tysabri for the treatment of Crohn’s disease. Biogen Idec and Elan appealed this opinion, but received a second negative opinion in December 2007, which led the EMA to reject the marketing application. The EMA stated that insufficient evidence of the maintenance of Tysabri’s effects, as well as safety concerns regarding increased risk of PML, were behind its decision (EMA, 2007).

In January 2012, the FDA approved a label update for Tysabri to include anti-John Cunningham (JC) virus antibody status as a PML risk factor. The anti-JC virus antibody test allows physicians to stratify the risk of PML in Tysabri-treated patients. Infection with JC virus is required for the development of PML. The new label states that an anti-JC virus negative status indicates that exposure to the JC virus has not been detected. Patients who are JC virus-positive are at increased risk for developing PML, and those who are JC virus-positive and have received prior therapy with immunosuppressants are at even higher risk (Elan, 2012).

Tysabri was first developed by Biogen Idec and Elan (now Perrigo) under a development and marketing collaboration in which both companies were responsible for the development, manufacture, and commercialization of the drug. In April 2013, Biogen Idec purchased Elan’s interest in Tysabri, acquiring full strategic, commercial, and decision-making rights (Elan, 2013). In December 2013, Perrigo acquired Elan, gaining rights to royalties from Tysabri sales (Perrigo, 2013).

PIVOTAL TRIAL DATA

Data supporting the efficacy of Tysabri as an induction and maintenance of remission treatment for Crohn’s disease in the US are summarized in the table below.

Table 29: Tysabri pivotal trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

CD1 896 Adults with moderately Randomized, double-blind, Tysabri 300mg once monthly, Clinical response* at week 10: Tysabri prescribing (Phase III) to severely active placebo-controlled versus placebo once monthly 56% Tysabri versus 49% placebo information, 2016 Crohn’s disease

CD2 (Phase III) 509 Adults with moderately Randomized, double-blind, Tysabri 300mg once monthly, Clinical response* at weeks 8 and Tysabri prescribing to severely active placebo-controlled versus placebo once monthly 12: 48% Tysabri versus 32% information, 2016 Crohn’s disease and placebo; elevated serum CRP Clinical remission** at weeks 8 and 12: 26% Tysabri versus 16% placebo

CD3 331 Adults with moderately Randomized, double-blind, Tysabri 300mg once monthly, Clinical response* at month 9: Tysabri prescribing (Phase III) to severely active placebo-controlled versus placebo once monthly 61% Tysabri versus 29% placebo; information, 2016 Crohn’s disease who Clinical response* at month 15: had clinical response to 54% Tysabri versus 20% placebo; Tysabri at both weeks Clinical remission** at month 9: 10 and 12 of 896- 45% Tysabri versus 26% placebo; patient Phase III trial Clinical remission** at month 15: (CD1) 40% Tysabri versus 15% placebo

*Clinical response = ≥70-point decrease in CDAI score from baseline.

**Clinical remission = CDAI score ≤150 points.

CDAI = Crohn’s Disease Activity Index; CRP = c-reactive protein Disease Coverage | Forecast: Crohn’s Disease 145

Table 29: Tysabri pivotal trial data in Crohn’s disease

Source: see above Disease Coverage | Forecast: Crohn’s Disease 146

SWOT ANALYSIS Figure 35: Tysabri for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of Tysabri’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the biologic comparator drug Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and all of the other key marketed and pipeline drugs profiled.

Figure 36: Datamonitor Healthcare’s drug assessment summary of Tysabri in Crohn’s disease

Source: Datamonitor Healthcare

Figure 37: Datamonitor Healthcare’s drug assessment summary of Tysabri in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Tysabri compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Tysabri for Crohn’s disease:

REGULATORY

• Tysabri was approved for the treatment of Crohn’s disease in the US in January 2008 (FDA, 2008).

• Datamonitor Healthcare does not forecast Tysabri to launch in Japan or the five major EU markets (France, Germany, Italy, Spain, and the UK). There is no evidence of clinical development of Tysabri in Crohn’s disease in Japan. In 2007, the EMA rejected Biogen’s Marketing Authorization Application for Tysabri in Crohn’s disease, stating that there was insufficient evidence of the maintenance of Tysabri’s effects, and that there were safety concerns regarding increased risk of PML (EMA, 2007).

COMPETITION

• In the US, Tysabri is forecast to continue to lose patient share to the anti-integrin therapy Entyvio, which launched in June 2014. Gastroenterologists have historically been wary of prescribing Tysabri due to safety concerns raised in its clinical development for Crohn’s disease and MS, while Entyvio has a very attractive safety profile, with no black box warnings (Takeda, 2014). Tysabri is set to lose up to a further 8% of its patient share to Entyvio across all lines of therapy.

• In the US, Tysabri is forecast to lose up to 10% of its patient share to the newest non-tumor necrosis factor biologic approved for Crohn’s disease, Stelara. Leading gastroenterologists interviewed by Datamonitor Healthcare stress that the availability of Stelara, which is considered to have a superior efficacy profile and comparable safety profile to Entyvio, will further impact Tysabri’s use.

US key opinion leader

“…Stelara has a faster onset of action than Entyvio in Crohn’s disease, and it has a good safety profile, with no black box warnings…”

US key opinion leader

• In the US, Tysabri is forecast to lose up to 7% of its patient share to the novel interleukin (IL)-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim), which is forecast to launch from 2021.

DOSING

• Datamonitor Healthcare has assumed dosing of 300mg every four weeks, as described in the US prescribing information (FDA, 2017).

PRICING

• Please view the accompanying datapack for a full table of drug costs per patient per year.

TYSABRI FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Tysabri in Crohn’s disease, by country, over 2016–25.

Figure 38: Tysabri sales for Crohn’s disease in the US, 2016–25

Source: Datamonitor Healthcare

Table 30: Tysabri sales for Crohn’s disease in the US ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 68.6 73.4 76.3 79.4 83.0 87.2 91.6 95.8 100.3 104.8

Total 68.6 73.4 76.3 79.4 83.0 87.2 91.6 95.8 100.3 104.8

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 152

BIBLIOGRAPHY

Biogen Idec (2005) BIOGEN IDEC AND ELAN ANNOUNCE VOLUNTARY SUSPENSION OF TYSABRI®. Available from: http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1324695 [Accessed 12 June 2017].

Denmark VK, Mayer L (2013) Current status of monoclonal antibody therapy for the treatment of inflammatory bowel disease: an update. Expert Review of Clinical Immunology, 9(1), 77–92.

Elan (2012) FDA Updates TYSABRI® (natalizumab) Label to Include Anti-JC Virus Antibody Status as a PML Risk Factor. Available from: http://newsroom.elan.com/phoenix.zhtml?c=88326&p=irol-newsArticle&ID=1651154&highlight= [Accessed 12 June 2017].

Elan (2013) Elan Announces Closing of TYSABRI® Collaboration Transaction with Biogen Idec. Available from: http://newsroom.elan.com/phoenix.zhtml?c=88326&p=irol-newsArticle&ID=1802637&highlight= [Accessed 12 June 2017].

EMA (2007) QUESTIONS AND ANSWERS ON RECOMMENDATION FOR THE REFUSAL OF THE MARKETING AUTHORISATION for NATALIZUMAB ELAN PHARMA. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/11/WC500015574.pdf [Accessed 12 June 2017].

FDA (2006) FDA Approves Resumed Marketing of Tysabri Under a Special Distribution Program. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108662.htm [Accessed 12 June 2017].

FDA (2008) FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116835.htm [Accessed 12 June 2017].

FDA (2017) Prescribing information for Tysabri. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/1215104s959lbl.pdf [Accessed 26 March 2018].

Perrigo (2013) Perrigo Company plc Completes Acquisition of Elan Corporation, plc. Available from: http://perrigo.investorroom.com/2013-12-18-Perrigo-Company-plc-Completes-Acquisition-of-Elan-Corporation-plc [Accessed 12 June 2017].

TOUCH (2017) TYSABRI® (natalizumab) is available only through the TOUCH Prescribing Program, which stands for TYSABRI Outreach: Unified Commitment to Health. Available from: https://www.touchprogram.com/TTP/ [Accessed 12 June 2017].

Tysabri prescribing information (2016) Available from: https://www.tysabri.com/content/dam/commercial/multiple- sclerosis/tysabri/pat/en_us/pdfs/tysabri_prescribing_information.pdf [Accessed 12 June 2017].

PRODUCT PROFILE (LATE STAGE): ETROLIZUMAB

PRODUCT PROFILE

ANALYST OUTLOOK

Datamonitor Healthcare believes that etrolizumab’s (Roche) commercial success will be limited in the Crohn’s disease market due to its moderate efficacy and lack of differentiation from direct competitor Entyvio (vedolizumab; Takeda). Although there are only limited efficacy data available to date, Phase III results from the exploratory cohort of the Phase III BERGAMOT study suggest moderate efficacy. Additionally, etrolizumab shares a similar mechanism of action with Entyvio, and gastroenterologists anticipate similar results (ie that etrolizumab will have an overall slower onset of action than other approved Crohn’s disease biologics, and modest efficacy in patients who are refractory to TNF inhibition). Furthermore, the lack of head-to-head trials against established biologic therapies is a disadvantage to etrolizumab, and will harm its commercial outlook. With the growing availability of safe and efficacious agents targeting TNF-refractory patients, notably the interleukin (IL) inhibitor Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) and the pipeline IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim), etrolizumab is at risk of being relegated to late lines of therapy.

DRUG OVERVIEW

Etrolizumab is a humanized anti-beta-7 integrin subunit monoclonal antibody. It binds to the beta-7 subunit of the alpha-4-beta-7 and alpha-E-beta-7 integrin heterodimers. This prevents the interaction of alpha-4-beta-7 integrin with mucosal addressin cell adhesion molecule-1 and the interaction of alpha-E-beta-7 integrin with E-cadherin. In turn, this results in interference with immune cell trafficking into the intestine in a selective manner that avoids broad immunosuppression (Vermeire et al., 2014).

Table 31: Etrolizumab drug profile

Molecule etrolizumab

Phase of development Phase III

Mechanism of action Anti-beta-7 integrin subunit MAb

Originator Genentech (now Roche)

Marketing company Roche

Formulation SC

Alternative names RG7413

MAb = monoclonal antibody; SC = subcutaneous

Source: Biomedtracker; Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

Etrolizumab was initially developed by Genentech, which became a wholly owned subsidiary of Roche in 2009 (Genentech, 2009).

Roche initiated a Phase III program for etrolizumab in Crohn’s disease in early 2015. The Phase III studies aim to assess the drug’s efficacy in patients with moderate to severe Crohn’s disease who have had an inadequate response to, have failed, or are intolerant to corticosteroids, immunosuppressants, or anti-TNFs. In October 2017, Roche presented data from an exploratory cohort of the Phase III BERGAMOT study (ClinicalTrials.gov identifier: NCT02394028) at the 25th United European Gastroenterology Week (UEGW) congress (Roche, 2017; Sandborn et al., 2017).

No Phase I or Phase II trials have been conducted for etrolizumab in Crohn’s disease.

PIVOTAL TRIAL DATA

The ongoing Phase III trials for etrolizumab in Crohn’s disease are summarized in the tables below.

Table 32: Ongoing pivotal trials for etrolizumab in Crohn’s disease

Trial Sample Target patients Study design Dosing Results/primary endpoints Start date/primary size completion date Disease Coverage | Forecast: Crohn’s Disease 156

Table 32: Ongoing pivotal trials for etrolizumab in Crohn’s disease

BERGAMOT 1,250 Moderately to Randomized, double-blind, Arm 1: Induction phase = SC Cohort 1 results (exploratory March 2015/July 2019 (NCT02394028) severely active placebo-controlled, multicenter etrolizumab 105mg at weeks 0, 4, analysis): (Phase III) Crohn’s disease study 8, and 12 Week 14: patients Maintenance phase = SC CDAI remission*: etrolizumab 105mg every four Arm 1: 23.3% weeks Arm 2: 28.9% Arm 2: Induction phase only = SC Arm 3: 16.9%; etrolizumab 210mg at weeks 0, 2, PRO2 remission**: 4, 8, and 12 Arm 1: 28.3% Arm 3: Placebo Arm 2: 28.9% Arm 3: 20.3%; Endoscopic improvement***: Arm 1: 21.0% Arm 2: 17.4% Arm 3: 3.4%; Maintenance of clinical remission as determined by PRO2 score at week 66 (US); Clinical remission as determined by CDAI score at week 14 (ex-US) (induction phase); Maintenance of clinical remission as determined by CDAI score and corticosteroid-free after at least 52 weeks (ex-US); Clinical remission as Disease Coverage | Forecast: Crohn’s Disease 157

Table 32: Ongoing pivotal trials for etrolizumab in Crohn’s disease

determined by PRO2 score at week 14 (US) (induction phase)

*Remission defined as CDAI <150.

**PRO2 remission defined as SF ≤3 and AP ≤1.

***Endoscopic improvement defined as ≥50% reduction from baseline SES-CD.

AP = abdominal pain; CDAI = Crohn's Disease Activity Index; PRO2 = two-item patient-reported outcome; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency

Source: Biomedtracker; Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 158

Table 33: Other late-phase trials for etrolizumab in Crohn’s disease

Trial Sample Target patients Study design Dosing Primary endpoints Start date/primary size completion date

JUNIPER 900 Patients with Randomized, two-part, open-label SC etrolizumab 105mg every four Incidence of AEs up to 6.5 June 2015/May 2024 (NCT02403323) moderately to extension and safety monitoring weeks years after first patient is (Phase III) severely active study enrolled Crohn’s disease who were previously enrolled in the BERGAMOT study

AE = adverse event; SC = subcutaneous

Source: Biomedtracker; Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 159

SWOT ANALYSIS Figure 39: Etrolizumab for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of etrolizumab’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the comparator drug Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and all of the other key marketed and pipeline drugs profiled.

Figure 40: Datamonitor Healthcare’s drug assessment summary of etrolizumab in Crohn’s disease

Source: Datamonitor Healthcare

Figure 41: Datamonitor Healthcare’s drug assessment summary of etrolizumab in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how etrolizumab compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of etrolizumab for Crohn’s disease:

REGULATORY

• Datamonitor Healthcare forecasts the dual-action, anti-integrin antibody etrolizumab to launch in Q2 2021 in the US and first EU markets. ClinicalTrials.gov lists one Phase III study for etrolizumab in Crohn’s disease, which aims to evaluate the drug’s efficacy and safety as an induction and maintenance treatment in patients with moderately to severely active Crohn’s disease (ClinicalTrials.gov identifier: NCT02394028). Based on the estimated primary completion date of July 2019 for this trial, Datamonitor Healthcare assumes Roche will file for approval with US and EU regulatory agencies by Q1 2020, provided the trial generates positive data. Assuming a positive decision from regulators, Datamonitor Healthcare anticipates launch in the US, Germany, and the UK in Q2 2021. This is expected to be followed by launch in France, Italy, and Spain a year later (in Q2 2022), following the conclusion of reimbursement negotiations. The relative launch timings are based on historical development and launch timelines in autoimmune indications.

• Datamonitor Healthcare does not forecast etrolizumab to launch in Japan as no evidence of the drug’s clinical development in

Japanese Crohn’s disease patients has been found.

COMPETITION

• Etrolizumab targets the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, while its direct competitor Entyvio only targets the gut-specific α4β7 integrin. Gastroenterologists note it is unclear whether etrolizumab offers any efficacy or safety advantages over Entyvio, as limited data are available for etrolizumab in Crohn’s disease.

“Etrolizumab is blocking α4β7 and αEβ7, whereas Entyvio is only blocking α4β7. The sponsor has been emphasizing that etrolizumab has two mechanisms of action, not just one, which could mean it has better efficacy or safety. However, we just do not have any data in Crohn’s disease to know what etrolizumab’s efficacy is. It is still an unknown for Crohn’s disease.”

US key opinion leader

• Etrolizumab is set to erode up to 12% of first-line patient share, and up to 15% of second-line and later patient share from Entyvio. Erosion will be greatest at second-line and later as gastroenterologists are less likely to prescribe a new, undifferentiated agent such as etrolizumab in early lines.

• Datamonitor Healthcare forecasts etrolizumab to have minimal impact on the anti-TNF biologics (Remicade, Humira [adalimumab; AbbVie/Eisai], Cimzia [certolizumab pegol; UCB/Astellas], and their biosimilar versions). Etrolizumab is forecast to take up to 8% of anti-TNFs’ patient share at third and later lines, in all markets. No impact is expected at earlier lines. Datamonitor Healthcare assumes that in the rare cases where a non-TNF biologic is required at earlier lines, gastroenterologists will prescribe Entyvio or Stelara.

DOSING

• Datamonitor Healthcare assumes dosing of 105mg once every four weeks. This is based on the dosing schedules assessed in the Phase III BERGAMOT and JUNIPER studies.

PRICING

• Datamonitor Healthcare assumes that etrolizumab will be priced at the average annual cost per patient of available biologic therapies in Crohn’s disease.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

ETROLIZUMAB FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of etrolizumab in Crohn’s disease, by country, over 2016–25.

Figure 42: Etrolizumab sales for Crohn’s disease across the US and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 34: Etrolizumab sales for Crohn’s disease across the US and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US - - - - - 3.9 21.9 49.0 80.6 117.3

France ------0.2 1.2 2.5 3.8

Germany - - - - - 0.3 1.6 3.4 5.1 7.0

Italy ------0.1 0.6 1.1 1.7

Spain ------0.1 0.6 1.3 2.0

UK - - - - - 0.1 0.5 1.1 1.7 2.3

Total - - - - - 4.3 24.5 55.9 92.5 134.2

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 165

BIBLIOGRAPHY

Genentech (2009) Roche Completes Acquisition of Genentech. Available from: https://www.gene.com/media/press- releases/12007/2009-03-26/roche-completes-acquisition-of-genentech [Accessed 12 June 2017].

Roche (2017) New data suggest Roche’s etrolizumab can provide clinically meaningful improvements in the treatment of two of the most common forms of inflammatory bowel disease. Available from: https://www.roche.com/dam/jcr:488cf8aa-d9d1-40cf-b983- b9ac51459e1e/en/171031_IR_Etrolizumab_en.pdf [Accessed 6 February 2018].

Sandborn W, Panes J, Jones J, Hassanali A, Jacob R et al. (2017) Etrolizumab as induction therapy in moderate to severe Crohn’s disease: results from BERGAMOT cohort 1. Presented at the 25th United European Gastroenterology Week (UEGW) congress, 28 October to 1 November 2017, Barcelona; Abstract #LB03.

Vermeire S, O'Byrne S, Keir M, Williams M, Lu TT, et al. (2014) Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet, 384(9940), 309–18.

PRODUCT PROFILE (LATE STAGE): FILGOTINIB

PRODUCT PROFILE

ANALYST OUTLOOK

Filgotinib’s (Galapagos/Gilead) novel mechanism of action, oral formulation, once-daily dosing, and positive efficacy data to date boost its clinical attractiveness. However, gastroenterologists stress that comprehensive Phase III data are required to accurately assess filgotinib’s clinical potential, notably in light of the discontinuation of Xeljanz’s (tofacitinib; Pfizer) development program in Crohn’s disease due to inconsistent efficacy and a mixed safety profile. Aside from the uncertainty around the long-term risk-to-benefit profile of filgotinib, the increasing availability of efficacious biologics with favorable safety profiles, such as Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) and risankizumab (AbbVie/Boehringer Ingelheim), will also limit filgotinib’s commercial potential. In addition, once approved and launched, filgotinib’s uptake will largely depend on its price, particularly in light of the growing presence of anti-tumor necrosis factor (TNF) biosimilars, which will act as a barrier to penetrating the early treatment setting.

DRUG OVERVIEW

Filgotinib is an orally available Janus kinase (JAK)-1 inhibitor. The drug inhibits the JAK-1 receptor required for signal transduction upon binding of cytokines at the cell surface. This, in turn, blocks the JAK/STAT signaling pathway required to activate gene expression of various immune cells (Van Rompaey, 2013). Filgotinib is in late-phase development in Crohn’s disease, ulcerative colitis, and rheumatoid arthritis (RA).

Table 35: Filgotinib drug profile

Molecule filgotinib

Phase of development Phase III

Mechanism of action JAK-1 inhibitor

Originator Galapagos

Marketing company Gilead, Galapagos

Formulation Oral

Alternative names GLPG0634

JAK = Janus kinase

Source: Biomedtracker; Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

In June 2006, GlaxoSmithKline and Galapagos entered into a co-development partnership to develop disease-modifying drugs (Galapagos, 2013). Galapagos then re-acquired full rights to develop filgotinib after positive results in preclinical models in RA (Galapagos, 2010). In February 2012, Galapagos entered into a collaboration agreement with Abbott (now part of AbbVie) to fully develop the drug in Phase II trials and complete the clinical development of filgotinib (Galapagos, 2012). AbbVie then decided to withdraw from its partnership with Galapagos in September 2015, leaving full rights to filgotinib to Galapagos (AbbVie, 2015). In December 2015, Galapagos entered into a partnership with Gilead to develop and commercialize filgotinib for inflammatory diseases (Gilead, 2015).

PIVOTAL TRIAL DATA

The table below summarizes the Phase III studies for filgotinib in Crohn’s disease.

Table 36: Ongoing pivotal Phase III trials of filgotinib in Crohn’s disease

Trial Sample Target patients Study design Dosing Primary endpoints Start date/primary size completion date

DIVERSITY 1,320 Adults with Combined, double-blind, Arm 1: Filgotinib dose A + placebo Induction study: Proportion October 2016/November (NCT02914561) moderately to randomized, placebo-controlled to match filgotinib dose B for 10 of patients achieving clinical 2019 (Phase III) severely active studies weeks remission based on PRO2 at Crohn’s disease Arm 2: Filgotinib dose B + placebo week 10; proportion of to match filgotinib dose A for 10 patients achieving weeks endoscopic response at Arm 3: Placebo to match filgotinib week 10 dose A + placebo to match Maintenance study: filgotinib dose B for 10 weeks Proportion of patients Arm 4: Participants who meet achieving clinical remission response or remission criteria at based on PRO2 at week 58; week 10 will continue into the proportion of patients maintenance study and receive achieving endoscopic filgotinib and/or placebo for 48 response at week 58 weeks Disease Coverage | Forecast: Crohn’s Disease 169

Table 36: Ongoing pivotal Phase III trials of filgotinib in Crohn’s disease

NCT02914600 1,000 Adult patients with Non-randomized, parallel- Arm 1: Filgotinib dose A + placebo Percentage of patients March 2017/September (Phase III) Crohn’s disease assignment, long-term extension to match filgotinib dose B for up experiencing AEs and 2022 study to 144 weeks abnormal clinical laboratory Arm 2: Filgotinib dose B + placebo tests (up to 144 weeks plus to match filgotinib dose A for up 30 days) to 144 weeks Arm 3: Placebo for up to 144 weeks Arm 4: Filgotinib dose A for up to 144 weeks Arm 5: Filgotinib dose B for up to 144 weeks

AE = adverse event; PRO2 = two-item patient-reported outcome

Source: Biomedtracker; Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 170

OTHER TRIALS

Phase II efficacy data for filgotinib in Crohn’s disease are summarized in the table below.

Table 37: Phase II trial data of filgotinib in Crohn’s disease

Trial Sample size Target patients Dosing tested and duration Results Reference

FITZROY 175 Adult patients with active Crohn’s Arm 1: One tablet of filgotinib 100mg and one Clinical remission* at week 10: Trialtrove; ClinicalTrials.gov; (NCT02048618) disease with evidence of mucosal placebo tablet, once daily for 20 weeks filgotinib 200mg = 48% (p=0.0067), Galapagos, 2015a/b; (Phase II) ulceration Arm 2: Two tablets of filgotinib 100mg, once placebo = 23%; 2016a/b; Vermeire et al., daily for 20 weeks Clinical response** at week 10: 2016 Arm 3: Two placebo tablets, once daily for 20 filgotinib 200mg = 60% (p=0.0386), weeks placebo = 41%; Mean change in IBDQ score at week 10: filgotinib 200mg = 34% (p=0.0045), placebo = 18%

*Clinical remission = CDAI score <150 points.

**Clinical response = CDAI decrease of ≥100 points.

CDAI = Crohn's Disease Activity Index; IBDQ = Inflammatory Bowel Disease Questionnaire

Source: various (see above) Disease Coverage | Forecast: Crohn’s Disease 172

SWOT ANALYSIS Figure 43: Filgotinib for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of filgotinib’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the comparator drug Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and all of the other key marketed and pipeline drugs profiled.

Figure 44: Datamonitor Healthcare’s drug assessment summary of filgotinib in Crohn’s disease

Source: Datamonitor Healthcare

Figure 45: Datamonitor Healthcare’s drug assessment summary of filgotinib in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how filgotinib compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of filgotinib for Crohn’s disease:

REGULATORY

• Datamonitor Healthcare forecasts the oral, once-daily JAK-1 inhibitor filgotinib to launch in Q2 2021 in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). ClinicalTrials.gov lists two Phase III studies for filgotinib in Crohn’s disease, which aim to evaluate the efficacy and safety of the JAK-1 inhibitor in the induction and maintenance of remission in patients with moderately to severely active Crohn’s disease (ClinicalTrials.gov identifiers: NCT02914561, NCT02914600). Based on the estimated primary completion date of November 2019 for NCT02914561, Datamonitor Healthcare assumes Galapagos and Gilead will file for approval with US, Japanese, and EU regulatory agencies by Q2 2020, provided filgotinib generates positive data in its development program. Assuming a positive decision from regulators, Datamonitor Healthcare anticipates launch in Q2 2021, immediately after approval as it is at a more advanced development stage in RA and is likely to marketed for RA by 2021.

COMPETITION

• While filgotinib has demonstrated positive efficacy to date, Datamonitor Healthcare believes its uptake in Crohn’s disease will be restricted due to concerns around its long-term risk-to-benefit profile. Filgotinib’s Phase II FITZROY study met the primary endpoint of clinical remission at 10 weeks, with a significantly higher percentage of patients in the filgotinib group achieving a Crohn’s Disease Activity Index score lower than 150 compared to patients in the placebo group (Galapagos, 2016a; Vermeire et al., 2016). However, interviewed gastroenterologists hold a reserved outlook for filgotinib and stress that Phase III data are needed to draw firm conclusions on the long-term safety of JAK inhibition in Crohn’s disease.

“Filgotinib’s efficacy looks good, though it is a bit early to say something more definite because we only have Phase II data so far. There is still a question mark about safety because we are still not sure how safe JAK inhibition is in the long term. We have experience in other diseases or with other JAK inhibitors showing that JAK inhibition may increase the risk of infections, viral infections, and so on. It is also worth noting that the study for tofacitinib [Xeljanz], another JAK, in Crohn’s disease was not positive. I think it’s a bit early to conclude on filgotinib.”

US key opinion leader

“Filgotinib is a very effective drug, but safety could be a concern, and we need to see data on a large scale in order to be confident to use it.”

EU key opinion leader

• Datamonitor Healthcare forecasts filgotinib to take up to 8% of patient share from commonly prescribed immunomodulators, including azathioprine, mercaptopurine, cyclosporine, and methotrexate, at first and second lines. Filgotinib is not forecast to impact immunomodulators at third and later lines as immunomodulators are primarily used in combination regimens at these lines.

• Datamonitor Healthcare forecasts filgotinib to take up to 4% of first-line patient share, and up to 6% of second-line and later patient share from the anti-TNF biologics (Remicade, Humira [adalimumab; AbbVie/Eisai], Cimzia [certolizumab pegol; UCB/Astellas], and their biosimilar versions), as well as from Stelara and Entyvio (vedolizumab; Takeda). Erosion will be lower at first line as concerns associated with filgotinib’s safety profile will restrict use early in the treatment paradigm.

• Datamonitor forecasts filgotinib to lose up to 5% of its patient share across all lines of therapy to the oral sphingosine-1- phosphate (S1P) inhibitor ozanimod (Celgene) following its anticipated launch in Q1 2023.

DOSING

• Datamonitor Healthcare has assumed dosing of 150mg once daily. This is based on the dosing regimens (100mg and 200mg once daily) assessed in filgotinib’s Phase II studies.

PRICING

• Datamonitor Healthcare assumes that filgotinib will be priced in line with Pfizer’s Xeljanz in RA, which is equal to or higher than the leading anti-TNF biologics, once discounts are factored in. In the five major EU markets, filgotinib is forecast to be priced in

line with Xeljanz and Olumiant (baricitinib; Eli Lilly/Incyte).

• Please view the accompanying datapack for a full table of drug costs per patient per year.

FILGOTINIB FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of filgotinib in Crohn’s disease, by country, over 2016–25.

Figure 46: Filgotinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 38: Filgotinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US - - - - - 5.0 35.9 85.0 143.0 210.3

Japan - - - - - 0.1 0.6 1.4 2.2 3.1

France - - - - - 0.2 1.7 4.0 6.7 9.8

Germany - - - - - 0.4 2.6 6.1 10.1 14.6

Italy - - - - - 0.1 0.7 1.7 2.8 4.0

Spain - - - - - 0.1 0.9 2.1 3.6 5.2

UK - - - - - 0.2 1.3 3.0 5.1 7.4

Total - - - - - 6.1 43.8 103.3 173.4 254.6

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 178

BIBLIOGRAPHY

AbbVie (2015) AbbVie to Advance Once-Daily ABT-494 to Phase 3 in Rheumatoid Arthritis by Year-End. Available from: https://news.abbvie.com/news/abbvie-to-advance-once-daily-abt-494-to-phase-3-in-rheumatoid-arthritis-by-year-end.htm [Accessed 12 June 2017].

Galapagos (2010) Galapagos initiates Phase I study for JAK inhibitor GLPG0634, acquires full rights to compound from GSK. Available from: http://www.glpg.com/docs/view/882ae7e7-en [Accessed 12 June 2017].

Galapagos (2012) Abbott and Galapagos Announce Global Collaboration for Novel Oral Therapy, GLPG0634, in Phase II to Treat Autoimmune Diseases. Available from: http://www.glpg.com/docs/view/882a8de6-en [Accessed 12 June 2017].

Galapagos (2013) Galapagos delivers candidate drug in GSK alliance and receives milestone payment. Available from: http://files.glpg.com/docs/10440374_2/1_1_0297c83d.pdf [Accessed 12 June 2017].

Galapagos (2015a) Filgotinib meets primary endpoint in phase 2 study in patients with moderate to severe Crohn's disease. Available from: http://www.glpg.com/docs/view/5665ff4ee8e93-en [Accessed 12 June 2017].

Galapagos (2015b) Filgotinib in Crohn’s disease Week 10 results from FITZROY study. Available from: http://www.biomedtracker.com/EventFiles/Galapagos%202015-12-08%20Filgotinib%20FITZROY%2010-Week%20Results.pdf [Accessed 12 June 2017].

Galapagos (2016a) FITZROY Phase 2 study with filgotinib in Crohn’s Disease presented as late breaker at DDW 2016. Available from: http://www.glpg.com/docs/view/5745c42db0469-en [Accessed 12 June 2017].

Galapagos (2016b) Endoscopic improvements with filgotinib are consistent with clinical remission rates in patients with Crohn’s disease. Available from: http://www.glpg.com/docs/view/57e8b1aa37694-en [Accessed 12 June 2017].

Galapagos (2016c) Our filgotinib program in RA. Available from: http://reports.glpg.com/annual-report-2016/en/r-d/rheumatoid- arthritis/filgotinib-program-in-ra.html [Accessed 21 March 2017].

Gilead (2015) Galapagos and Gilead Announce Global Partnership to Develop Filgotinib for the Treatment of Rheumatoid Arthritis and Other Inflammatory Diseases. Available from: http://www.gilead.com/news/press-releases/2015/12/galapagos-and-gilead-announce- global-partnership-to-develop-filgotinib-for-the-treatment-of-rheumatoid-arthritis-and-other-inflammatory-diseases [Accessed 12 June 2017].

Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, et al. (2013) Preclinical Characterization of GLPG0634, a Selective Inhibitor of JAK-1, for the Treatment of Inflammatory Diseases. Journal of Immunology, 191(7), 3568–77.

Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, et al. (2016) Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet, 389 (10066), 226–75.

PRODUCT PROFILE (LATE STAGE): OZANIMOD

PRODUCT PROFILE

ANALYST OUTLOOK

Although ozanimod’s (Celgene) oral formulation and convenient once-daily administration boost its clinical attractiveness, Datamonitor Healthcare believes that its prospects in Crohn’s disease are unfavorable, as leading gastroenterologists note that ozanimod’s modest efficacy profile alongside concerns around its side-effect profile will limit its uptake, should it be approved and launched. Due to cardiac adverse events observed with sphingosine 1-phosphate (S1P) modulators, gastroenterologists note that cardiac monitoring will be required before initiating therapy with ozanimod, which would be highly inconvenient for both physicians and patients.

DRUG OVERVIEW

Ozanimod is an S1P receptor agonist, with selectivity for the sphingosine 1-phosphate type 1 receptor (S1P1) and sphingosine 1- phosphate receptor 5 (S1P5). The drug modulates the expression of S1P receptors, which is thought to reduce the overall number of circulating lymphocytes by preventing their migration from secondary lymphoid organs (Sandborn et al., 2016). The drug is being developed in multiple sclerosis, ulcerative colitis, and Crohn’s disease.

Table 39: Ozanimod drug profile

Molecule ozanimod

Mechanism of action S1P1 and S1P5 receptor agonist

Originator Receptos

Marketing company Celgene

Formulation Oral

Alternative names RPC-1063

S1P = sphingosine 1-phosphate

Source: Datamonitor Healthcare

DEVELOPMENT OVERVIEW

Ozanimod was originally discovered and developed by Receptos (Receptos, 2009), which was then acquired by Celgene in July 2015 for $7.2bn (Celgene, 2015).

PIVOTAL TRIAL DATA

The table below summarizes the design of the Phase III studies.

Table 40: Ozanimod Phase III trials in Crohn’s disease

Trial Sample size Target patients Study design Dosing Primary endpoints Start date/primary completion date

NCT03440372 600 Patients with Randomized, Arm 1: Ozanimod 1mg Proportion of subjects with a CDAI March 2018/March 2020 (Phase III) moderate to severe double-blind, capsules with dose score <150 at week 12 Crohn’s disease with placebo-controlled escalation for seven days an inadequate Arm 2: Placebo response to corticosteroids, immunomodulators, and/or biologics

NCT03440385 600 Patients with Randomized, Arm 1: Ozanimod 1mg Proportion of subjects with a CDAI March 2018/March 2020 (Phase III) moderate to severe double-blind, with dose escalation for score <150 at week 12 Crohn’s disease with placebo-controlled seven days an inadequate Arm 2: Placebo response to corticosteroids, immunomodulators, and/or biologics

NCT03464097 485 Patients who Randomized, Arm 1: Ozanimod 1mg Proportion of subjects with a CDAI July 2018/July 2021 (Phase III) responded to the double-blind, once daily for 40 weeks score <150; SES-CD score induction studies placebo-controlled Arm 2: Placebo decrease from baseline of ≥50%

CDAI = Crohn's Disease Activity Index; SES-CD = Simple Endoscopic Score for Crohn’s Disease

Source: Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 182

The table below summarizes the Phase II data for ozanimod which led to the initiation of the Phase III studies.

Table 41: Ozanimod Phase II data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and Results Reference duration

STEPSTONE 69 Patients with moderate Open-label, single- Arm 1: Ozanimod 1mg 12 weeks: Celgene, 2017 (NCT02531113) to severe Crohn’s disease group assignment once daily for 12 weeks SES-CD reductions from with an inadequate baseline of <50%: 27% response to SES-CD reductions from aminosalicylates, baseline of <25%: 43% corticosteroids, CDAI remission*: 46% immunomodulators, or biologic therapy

*Clinical remission is defined based on average stool frequency and average daily abdominal pain score.

CDAI = Crohn's Disease Activity Index; SES-CD = Simple Endoscopic Score for Crohn's Disease

Source: see above; Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 184

SWOT ANALYSIS Figure 47: Ozanimod for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of ozanimod’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the comparator drug Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and all of the other key marketed and pipeline drugs profiled.

Figure 48: Datamonitor Healthcare’s drug assessment summary of ozanimod in Crohn’s disease

Source: Datamonitor Healthcare

Figure 49: Datamonitor Healthcare’s drug assessment summary of ozanimod in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how ozanimod compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

FORECAST ASSUMPTIONS

Datamonitor Healthcare makes the following assumptions in its forecast of ozanimod for Crohn’s disease:

REGULATORY

• Datamonitor Healthcare forecasts ozanimod to launch in the US, Japan, and EU in Q1 2023. ClinicalTrials.gov lists three pivotal Phase III trials for ozanimod in Crohn’s disease (ClinicalTrials.gov identifiers: NCT03440372, NCT03440385, NCT03464097). Based on the latest estimated primary completion date of July 2021, Datamonitor Healthcare anticipates Celgene to file for approval with US, Japanese, and EU regulatory agencies in Q1 2022, provided the trials generate positive data. Assuming a positive decision from regulators, Datamonitor Healthcare anticipates launch in all major markets in Q1 2023. Ozanimod is forecast to launch immediately upon approval as it is at a more advanced development stage in multiple sclerosis and ulcerative colitis.

COMPETITION

• Ozanimod’s modest efficacy data to date, as well as safety concerns associated with S1P modulators, are anticipated to limit its uptake.

US key opinion leader

“If that [cardiac monitoring] is on the label for ozanimod for Crohn’s or colitis, that would be a challenge for gastroenterologists to be doing EKGs in the office on these patients before they start therapy.”

US key opinion leader

• Ozanimod is forecast to take up to 6% of patient share from the commonly prescribed immunomodulators (azathioprine, methotrexate, mercaptopurine, sulfasalazine, and cyclosporine) at first and second lines.

• Datamonitor Healthcare forecasts ozanimod to take up to 4% of first-line patient share, and up to 6% of second-line and later patient share from the anti-tumor necrosis factor (TNF) biologics (Remicade, Humira [adalimumab; AbbVie/Eisai], Cimzia [certolizumab pegol; UCB/Astellas], and their biosimilar versions), as well as from the non-TNF biologics Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) and Entyvio (vedolizumab; Takeda).

DOSING

• Datamonitor Healthcare has assumed dosing of 1mg once daily. This is based on the dosing schedule assessed in ozanimod’s Phase III program.

PRICING

• Datamonitor Healthcare anticipates that Celgene will price ozanimod competitively against biologics in order to successfully penetrate the biologic-naïve treatment setting. This is based on the example of Otezla (apremilast; Celgene) in psoriasis. Ozanimod is expected to be priced at approximately a 20% discount to Humira, once discounts are factored in.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

OZANIMOD FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of ozanimod in Crohn’s disease, by country, over 2016–25.

Figure 50: Ozanimod sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 42: Ozanimod sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US ------15.3 48.7 96.6

Japan ------0.3 1.4 2.8

France ------1.1 3.6 7.2

Germany ------1.7 5.3 10.4

Italy ------0.5 1.5 3.0

Spain ------0.7 2.1 4.1

UK ------0.7 2.1 4.2

Total ------20.2 64.9 128.2

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 190

BIBLIOGRAPHY

Celgene (2015) Celgene to Acquire Receptos, Advancing Leadership in Immune-Inflammatory Diseases. Available from: http://ir.celgene.com/releasedetail.cfm?ReleaseID=922090 [Accessed 15 March 2017].

Celgene (2017) Results from Phase 2 Studies of Oral Ozanimod in Crohn's Disease and Ulcerative Colitis to Be Presented at World Congress of Gastroenterology at ACG2017. Available from: http://ir.celgene.com/releasedetail.cfm?ReleaseID=1044007 [Accessed 2 March 2018].

Receptos (2009) Receptos Completes $25M Series A Financing. Available from: http://www.receptos.com/pdfs/Receptos-Series-A- Financing.pdf [Accessed 15 March 2017].

Sandborn WJ, Feagan BG, Wolf DC, D’Haens G, Vermeire S, et al. (2016) Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. The New England Journal of Medicine, 374(18), 1754–62.

PRODUCT PROFILE (LATE STAGE): RISANKIZUMAB

PRODUCT PROFILE

ANALYST OUTLOOK

Risankizumab’s (AbbVie/Boehringer Ingelheim) clinical performance to date has been comparable to that of the interleukin (IL)-12/23 inhibitor Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe), hence gastroenterologists expect to use risankizumab in the same treatment setting where Stelara is currently used – primarily in non-responders to tumor necrosis factor (TNF) inhibition. Leading gastroenterologists suggest that risankizumab may have a cleaner side-effect profile than Stelara since it only targets IL-23; however, they stress this will need to be demonstrated in the clinical development program and in a real-world setting. Datamonitor Healthcare anticipates that risankizumab will face several challenges once it enters the Crohn’s disease market; its relatively late market entry in 2021, alongside increasing physician familiarity and experience with Stelara, will restrict risankizumab’s overall market share.

DRUG OVERVIEW

Risankizumab is a humanized anti-IL-23 subunit p19 monoclonal antibody that binds and neutralizes the p19 subunit of IL-23. It is being developed in psoriasis and Crohn’s disease.

Table 43: Risankizumab drug profile

Molecule risankizumab

Phase of development Phase III

Mechanism of action IL-23 inhibitor

Originator Boehringer Ingelheim

Marketing company AbbVie/Boehringer Ingelheim

Formulation SC

Alternative names BI655066; ABBV-066

IL = interleukin; SC = subcutaneous

Source: Biomedtracker; Pharmaprojects

DEVELOPMENT OVERVIEW

AbbVie is conducting three Phase III studies to evaluate the safety and efficacy of risankizumab in the US, Japan, and EU. The M15-991 study (ClinicalTrials.gov identifier: NCT03104413) is evaluating the induction of clinical and endoscopic remission with risankizumab in patients with moderate to severe Crohn’s disease who have failed previous biologic therapy. Meanwhile, the M16-006 study (ClinicalTrials.gov identifier: NCT03105128) is evaluating the induction of clinical and endoscopic remission with risankizumab in patients with moderate to severe Crohn’s disease who have failed conventional therapy and/or biologic therapy.

Risankizumab is also being evaluated in the maintenance of clinical and endoscopic remission in the M16-006/M15-991 extension (ClinicalTrials.gov identifier: NCT03105102) for patients who have completed the M15-991 and M16-006 induction studies.

PIVOTAL TRIAL DATA

The table below summarizes the design of the Phase III studies.

Table 44: Risankizumab Phase III trials in Crohn’s disease

Trial Sample size Target patients Study design Dosing Primary endpoints Start date/primary completion date

M15-991 579 Patients with Randomized, Induction period 1: Proportion of participants with December 2017/March (NCT03104413) moderate to severe double-blind, Arm 1: Risankizumab IV dose clinical remission* after 12 2019 (Phase III) Crohn’s disease who placebo-controlled 1 weeks; failed previous Arm 2: Risankizumab IV dose Proportion of subjects with biologic therapy 2 endoscopic response** after Arm 3: Placebo; 12 weeks Induction period 2: Arm 4: Patients who received placebo in period 1 and had an inadequate response after 12 weeks receive risankizumab IV Arm 5: Patients with inadequate response at week 12 receive risankizumab SC dose 2 Arm 6: Patients with inadequate response at week 12 receive risankizumab SC dose 3 Disease Coverage | Forecast: Crohn’s Disease 194

Table 44: Risankizumab Phase III trials in Crohn’s disease

M16-006 940 Patients with Randomized, Induction period 1: Proportion of participants with November 2017/October (NCT03105128) moderate to severe double-blind, Arm 1: Risankizumab IV dose clinical remission* after 12 2019 (Phase III) Crohn’s disease who placebo-controlled 1 weeks; were intolerant or had Arm 2: Risankizumab IV dose Proportion of subjects with an inadequate 2 endoscopic response** after response to Arm 3: Placebo; 12 weeks conventional and/or Induction period 2: biologic therapy*** Arm 4: Patients who received for Crohn’s disease placebo in period 1 and had an inadequate response after 12 weeks receive risankizumab IV Arm 5: Patients with inadequate response at week 12 receive risankizumab SC dose 2 Arm 6: Patients with inadequate response at week 12 receive risankizumab SC dose 3 Disease Coverage | Forecast: Crohn’s Disease 195

Table 44: Risankizumab Phase III trials in Crohn’s disease

M16-006/M15-991 extension 912 Patients who Randomized, Sub-study 1: Proportion of participants with March 2018/April 2020 (NCT03105102) responded to the double-blind, Arm 1: Risankizumab SC dose clinical remission* after 52 induction studies placebo-controlled 1 weeks; M16-006 or M15-991 Arm 2: Risankizumab SC dose Proportion of subjects with 2 endoscopic response** after Arm 3: Placebo; 52 weeks Sub-study 2: Arm 1: Risankizumab SC dose 1 followed by risankizumab open-label Arm 2: Risankizumab SC dose 2 followed by risankizumab open-label Sub-study 3: Arm 1: Open-label risankizumab beginning at week 56 for participants who completed sub-study 1 or 2

*Clinical remission is defined based on average stool frequency and average daily abdominal pain score.

**Endoscopic response is defined as a decrease in SES-CD from baseline.

***Except p40 inhibitors (Stelara) or p19 inhibitors (risankizumab).

IV = intravenous; SC = subcutaneus; SES-CD = Simple Endoscopic Score for Crohn’s Disease

Source: Biomedtracker; Pharmaprojects Disease Coverage | Forecast: Crohn’s Disease 196

The table below summarizes the Phase II trial for risankizumab which led to the initiation of the Phase III trials.

Table 45: Risankizumab Phase II data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

NCT02031276 121 Patients with moderate to Randomized, Arm 1: Risankizumab IV 200mg at 12 weeks: Feagan et al., 2017 (Phase II) severe Crohn’s disease who double-blind, weeks 0, 4, and 8 Clinical remission: are naïve to/or were placebo-controlled Arm 2: Risankizumab IV 600mg at Arm 1: 24% (p=0.308) previously treated with anti- weeks 0, 4, and 8 Arm 2: 37% (p=0.025) TNF therapy Arm 3: Placebo Arm 3: 15%

IV = intravenous; TNF = tumor necrosis factor

Source: see above; Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 198

SWOT ANALYSIS Figure 51: Risankizumab for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of risankizumab’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the comparator drug Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and all of the other key marketed and pipeline drugs profiled.

Figure 52: Datamonitor Healthcare’s drug assessment summary of risankizumab in Crohn’s disease

Source: Datamonitor Healthcare

Figure 53: Datamonitor Healthcare’s drug assessment summary of risankizumab in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how risankizumab compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

FORECAST ASSUMPTIONS

Datamonitor Healthcare makes the following assumptions in its forecast of risankizumab for Crohn’s disease:

REGULATORY

• Datamonitor Healthcare forecasts risankizumab to launch in the US and EU in Q4 2021. ClinicalTrials.gov lists three pivotal Phase III trials for risankizumab in Crohn’s disease – M15-991, M16-006, and the M16-006/M15-991 extension study – aiming to evaluate the drug’s safety and efficacy in the induction and maintenance of remission in patients with moderate to severe Crohn’s disease. Based on the estimated primary completion date of April 2020, Datamonitor Healthcare anticipates AbbVie to file for approval with US, Japanese, and EU regulatory agencies in Q4 2020, provided the trials generate positive data. Assuming a positive decision from regulators, Datamonitor Healthcare anticipates launch in all major markets in Q4 2021. Risankizumab is forecast to launch immediately upon approval as it is at a more advanced development stage in psoriasis, and is likely to be marketed for psoriasis by 2021.

COMPETITION

• Leading gastroenterologists note that risankizumab’s clinical performance to date has been positive.

“The reported efficacy data in Crohn’s disease report remission rates of about 40%, there were no unexpected safety signals reported, so I think that looks like a useful agent...”

US key opinion leader

• Risankizumab is forecast to erode up to 3% of first- and second-line patient share and up to 8% of third-line and later patient share from the TNF biologics (Remicade, Humira [adalimumab; AbbVie/Eisai], Cimzia [certolizumab pegol; UCB/Astellas], and their biosimilar versions). Datamonitor Healthcare anticipates anti-TNF therapies to retain their preferred status as first-line biologics based on physician preference and formulary placement, therefore erosion will be greatest at the third line and later.

• Risankizumab is forecast to erode up to 6% of patient share from Stelara. Based on risankizumab’s clinical performance to date, leading gastroenterologists note that they would consider using it in the same treatment setting where Stelara is currently used – primarily in non-responders to TNF inhibition. In addition, some gastroenterologists suggest that risankizumab may have a cleaner side-effect profile than Stelara since it only targets IL-23; however, they stress this will need to be demonstrated in risankizumab’s clinical development program and in a real-world setting.

“…It will be placed in the same position where Stelara is right now.”

US key opinion leader

• Risankizumab is forecast to erode up to 7% of patient share from Entyvio (vedolizumab; Takeda) across all lines of therapy in the US, Japan, and Europe.

• In the US, risankizumab is also forecast to erode up to 7% of patient share from Tysabri (natalizumab; Biogen) across all lines of therapy.

• Datamonitor Healthcare forecasts risankizumab to erode up to 5% of patient share from the commonly prescribed immunomodulators, including azathioprine, mercaptopurine, cyclosporine, and methotrexate, at first and second lines. Risankizumab is not forecast to impact immunomodulators at third and later lines as immunomodulators are primarily used in combination regimens at these lines.

• Risankizumab is forecast to lose up to 3% of its first-line patient share, and up to 6% of its second-line and later patient share to the sphingosine-1-phosphate (S1P) inhibitor ozanimod (Celgene).

DOSING

• Datamonitor Healthcare assumes an average monthly dose of 160mg, based on the various doses being assessed in

risankizumab’s clinical development program.

PRICING

• Datamonitor Healthcare assumes that risankizumab will be priced at the average annual cost per patient of the IL-12/23 inhibitor Stelara in all forecast markets. Datamonitor Healthcare uses national formularies to gather pricing information per product and applies backing-out formulas to adjust formulary prices in order to obtain estimates of ex-factory wholesale prices for each country.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

RISANKIZUMAB FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of risankizumab in Crohn’s disease, by country, over 2016–25.

Figure 54: Risankizumab sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 46: Risankizumab sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US - - - - - 2.6 99.6 278.3 452.3 622.2

Japan - - - - - 0.1 4.4 10.8 15.4 18.7

France - - - - - 0.4 10.9 26.3 36.2 42.0

Germany - - - - - 0.5 13.3 31.5 42.5 48.0

Italy - - - - - 0.1 3.6 8.9 12.8 15.6

Spain - - - - - 0.2 4.5 11.1 15.6 18.7

UK - - - - - 0.2 7.2 17.5 24.1 28.0

Total - - - - - 4.1 143.4 384.3 599.0 793.2

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 204

BIBLIOGRAPHY

Feagan BG, Sandborn WJ, D’Haens G, Panés J, Kaser A, et al. (2017) Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study. The Lancet, 389 (10080), 1699–1709.

PRODUCT PROFILE (LATE STAGE): UPADACITINIB

PRODUCT PROFILE

ANALYST OUTLOOK

Upadacitinib’s (AbbVie) convenient oral formulation and positive efficacy data to date boost its clinical attractiveness. However, gastroenterologists stress that comprehensive Phase III data are required to fully assess the clinical potential of the Janus kinase (JAK)- 1 inhibitors, notably in light of the discontinuation of Xeljanz’s (tofacitinib; Pfizer) development program in Crohn’s disease due to inconsistent efficacy and a mixed safety profile. Aside from the uncertainty around the long-term risk-to-benefit profile of upadacitinib, the increasing availability of efficacious non-tumor necrosis factor (TNF) biologics with favorable safety profiles, such as Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe) and risankizumab (AbbVie/Boehringer Ingelheim), will also limit upadacitinib’s commercial potential. Once approved and launched, upadacitinib’s uptake will also depend on its price, particularly in light of the growing presence of anti-TNF biosimilars, which will act as a barrier to penetrating the early treatment setting.

DRUG OVERVIEW

Upadacitinib is an oral small molecule inhibitor of JAK-1 that is being developed in several indications including Crohn’s disease, rheumatoid arthritis (RA), psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, and ulcerative colitis.

Table 47: Upadacitinib drug profile

Molecule upadacitinib

Phase of development Phase III

Mechanism of action JAK-1 inhibitor

Originator AbbVie

Marketing company AbbVie

Formulation Oral

Alternative names ABT-494

JAK = Janus kinase

Source: Datamonitor Healthcare; Biomedtracker; Pharmaprojects

DEVELOPMENT OVERVIEW

Following positive results from the Phase II CELEST trial (ClinicalTrials.gov identifier: NCT02365649), AbbVie initiated three Phase III studies. The M14-433 and M14-431 studies (ClinicalTrials.gov identifiers: NCT03345849, NCT03345836) are evaluating the safety and efficacy of upadacitinib in patients with moderate to severe Crohn’s disease who have an inadequate response to conventional therapies. The M14-433 study includes patients who have discontinued biologic therapy for reasons other than intolerance, such as insurance, whereas the M14-431 study specifically targets patients who have failed biologic therapy with infliximab, adalimumab, certolizumab pegol, vedolizumab, and ustekinumab. The M14-430 study (ClinicalTrials.gov identifier: NCT03345849) is evaluating the safety and efficacy of upadacitinib as a maintenance therapy for patients who achieved clinical response in the M14-433 and M14-431 studies.

PIVOTAL TRIAL DATA

The table below summarizes the Phase III studies for upadacitinib in Crohn’s disease.

Table 48: Upadacitinib Phase III trials in Crohn’s disease

Trial Sample size Target patients Study design Dosing Primary endpoints Start date/primary completion date

M14-433 300 Patients with moderate to Randomized, Arm 1: Upadacitinib dose A Proportion of participants with November 2017/December (NCT03345849) severe active CD with double-blind, for 12 weeks clinical remission** after 12 2019 (Phase III) inadequate response to placebo-controlled Arm 2: Placebo weeks; conventional therapy but Proportion of subjects with not biologic therapy* endoscopic response*** after 12 weeks

M14-431 855 Patients with moderate to Randomized, Arm 1: Upadacitinib dose A Proportion of participants with November 2017/January (NCT03345836) severe active CD with double-blind, for 12 weeks clinical remission** after 12 2020 (Phase III) inadequate response or placebo-controlled Arm 2: Placebo weeks; intolerance to any biologic Arm 3: Open-label Proportion of subjects with therapy† upadacitinib dose A for 12 endoscopic response*** after weeks 12 weeks

M14-430 738 Patients who achieved Randomized, Arm 1: Upadacitinib dose B Proportion of participants with February 2018/January 2019 (NCT03345849) clinical response to dose double-blind, for 52 weeks clinical remission** after 52 (Phase III) A in studies M14-431 and placebo-controlled Arm 2: Upadacitinib dose C weeks; M14-433 for 52 weeks Proportion of subjects with Arm 3: Placebo endoscopic response*** after 52 weeks

*Patients who discontinued biologic therapy for reasons other than inadequate response or intolerance.

**Clinical remission is defined based on average stool frequency and average daily abdominal pain score. Disease Coverage | Forecast: Crohn’s Disease 208

Table 48: Upadacitinib Phase III trials in Crohn’s disease

***Endoscopic response is defined as a decrease in SES-CD from baseline.

†Biologics include infliximab, adalimumab, certolizumab pegol, vedolizumab, and ustekinumab.

SES-CD = Simple Endoscopic Score for Crohn’s Disease

Source: Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 209

Phase II efficacy and safety data were presented at the 2017 Digestive Disease Week. Results were positive and supported the initiation of the Phase III pivotal trials (AbbVie, 2017).

The table below describes the results from the Phase II trial.

Table 49: Upadacitinib Phase II data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

CELEST 219 Patients with moderate to Randomized, Arm 1: Upadacitinib 3mg twice Week 16: Sandborn et al., 2017 (NCT02365649) severe Crohn’s disease who double-blind, daily Endoscopic remission: (Phase II) have inadequately placebo-controlled Arm 2: Upadacitinib 6mg twice Arm 1: 10%* responded to, or are daily Arm 2: 8% intolerant to Arm 3: Upadacitinib 12mg twice Arm 3: 8%* immunomodulators or anti- daily Arm 4: 22%*** TNF therapy Arm 4: Upadacitinib 24mg twice Arm 5: 14%** daily Arm 6: 0%; Arm 5: Upadacitinib 24mg once Clinical remission: daily Arm 1: 13% Arm 6: Placebo Arm 2: 27%* Arm 3: 11% Arm 4: 22% Arm 5: 14% Arm 6: 11%

*p<1 vs placebo

**p<0.05 vs placebo

***p<0.01 vs placebo

TNF = tumor necrosis factor

Source: see above; Trialtrove; ClinicalTrials.gov Disease Coverage | Forecast: Crohn’s Disease 211

SWOT ANALYSIS Figure 55: Upadacitinib for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s assessment of upadacitinib’s clinical and commercial attractiveness as a therapy for Crohn’s disease in relation to the comparator drug Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and all of the other key marketed and pipeline drugs profiled.

Figure 56: Datamonitor Healthcare’s drug assessment summary of upadacitinib in Crohn’s disease

Source: Datamonitor Healthcare

Figure 57: Datamonitor Healthcare’s drug assessment summary of upadacitinib in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how upadacitinib compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

FORECAST ASSUMPTIONS

Datamonitor Healthcare makes the following assumptions in its forecast of upadacitinib for Crohn’s disease:

REGULATORY

• Datamonitor Healthcare forecasts upadacitinib to launch in the US, EU, and Japan in Q3 2021. ClinicalTrials.gov lists three pivotal Phase III trials for upadacitinib in Crohn’s disease, M14-433, M14-431, and M14-430, which are aiming to evaluate the safety and efficacy of upadacitinib in the induction and maintenance of remission of patients with moderate to severe Crohn’s disease. Based on the estimated primary completion date of January 2020, Datamonitor Healthcare anticipates AbbVie to file for approval with US, Japanese, and EU regulatory agencies in Q3 2020, provided the Phase III trials generate positive data. Assuming a positive decision from regulators, Datamonitor Healthcare anticipates launch in all major markets in Q3 2021. Upadacitinib is forecast to launch immediately upon approval as it is at a more advanced development stage in RA and is likely to be marketed for RA by 2021.

COMPETITION

• While upadacitinib has demonstrated positive efficacy to date, Datamonitor Healthcare believes its uptake in Crohn’s disease will be restricted due to concerns around its long-term risk-to-benefit profile (Sandborn et al., 2017).

• While it is difficult to directly compare upadacitinib to the other Phase III JAK inhibitor filgotinib (Galapagos/Gilead), Datamonitor Healthcare believes that AbbVie’s extensive marketing experience in autoimmune indications will give upadacitinib a competitive edge.

“I guess you could argue AbbVie already has a marketing force for GI diseases, so it will be relatively easy for them to switch them to marketing upadacitinib, whereas Galapagos does not, so that might impede initial market penetration.”

US key opinion leader

• Datamonitor Healthcare forecasts upadacitinib to take up to 8% of patient share from commonly prescribed immunomodulators, including azathioprine, mercaptopurine, cyclosporine, and methotrexate, at first and second lines. Upadacitinib is not forecast to impact immunomodulators at third and later lines as immunomodulators are primarily used in combination regimens at these lines.

• Datamonitor Healthcare forecasts upadacitinib to take up to 5% of first-line patient share, and up to 9% of second-line and later patient share from the TNF biologics (Remicade, Humira [adalimumab; AbbVie/Eisai], Cimzia [certolizumab pegol; UCB/Astellas], and their biosimilar versions), as well as from Stelara and Entyvio (vedolizumab; Takeda). Erosion will be lower at first line as concerns associated with the safety profiles of the JAK inhibitors will restrict use early in the treatment paradigm.

• Upadacitinib is forecast to lose up to 5% of its patient share to the oral sphingosine-1-phosphate (S1P) inhibitor ozanimod (Celgene), following its anticipated launch in Q1 2023. Datamonitor Healthcare believes that ozanimod’s anticipated superior safety profile compared to the JAK inhibitors, as well as an anticipated lower price, will give it an advantage over upadacitinib.

DOSING

• The dosing regimens included in the Phase III studies are yet to be announced. Datamonitor Healthcare has assumed dosing of 12mg twice daily; this dose generated positive results in the Phase II study, and is likely to be pursued in the Phase III program (AbbVie, 2018).

PRICING

• In the US, Datamonitor Healthcare assumes that upadacitinib will be priced in line with Xeljanz in RA, which is at parity to or higher than the leading anti-TNF biologics, once discounts are factored in. In the five major EU markets (France, Germany, Italy, Spain, and the UK), upadacitinib is forecast to be priced in line with Xeljanz and Olumiant (baricitinib; Eli Lilly/Incyte).

• Please view the accompanying datapack for a full table of drug costs per patient per year.

UPADACITINIB FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of upadacitinib in Crohn’s disease, by country, over 2016–25.

Figure 58: Upadacitinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 50: Upadacitinib sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US - - - - - 2.9 36.6 97.0 167.6 248.6

Japan - - - - - 0.1 1.4 3.5 5.9 8.4

France - - - - - 0.1 1.6 4.1 7.0 10.2

Germany - - - - - 0.2 2.6 6.7 11.4 16.6

Italy - - - - - 0.1 0.7 1.8 3.1 4.5

Spain - - - - - 0.1 0.9 2.4 4.0 6.0

UK - - - - - 0.1 1.2 3.2 5.5 8.1

Total - - - - - 3.5 45.0 118.8 204.5 302.4

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Forecast: Crohn’s Disease 217

BIBLIOGRAPHY

AbbVie (2017) AbbVie Announces Positive Phase 2 Study Results for Upadacitinib (ABT-494), an Investigational JAK1-Selective Inhibitor, in Crohn’s Disease. Available from: https://news.abbvie.com/alert-topics/immunology/abbvie-announces-positive-phase-2-study- results-for-upadacitinib-abt-494-an-investigational-jak1-selective-inhibitor-in-crohns-disease.htm [Accessed 25 April 2018].

AbbVie (2018) AbbVie Announces New Phase 2 Data for Upadacitinib Showing Clinical and Endoscopic Outcomes in Crohn's Disease at 52 Weeks. Available from: https://news.abbvie.com/article_print.cfm?article_id=11607 [Accessed 25 April 2018].

Sandborn WJ, Feagan BG, Panes J, D’Haens GR, Colombel JF, et al. (2017) Safety and Efficacy of ABT-494 (Upadacitinib), an Oral JAK-1 Inhibitor, as Induction Therapy in Patients with Crohn's Disease: Results from Celest. Gastroenterology, 152(5), S1308–S1309.

TREATMENT: CROHN’S DISEASE

OVERVIEW

Description Datamonitor Healthcare surveyed 240 gastroenterologists in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) to gain insight into Crohn’s disease diagnosis, patient segmentation, and current and future prescribing patterns.

This module is accompanied by a datapack showing treatment trees, which provide an approximation of the potential patient populations at each step in the treatment algorithm and indicate estimated patient numbers; they should not be interpreted as showing exact patient numbers.

Highlights Datamonitor Healthcare’s 2016 survey reveals that biologic usage in the US, Japan, and five major EU markets increases as Crohn’s disease patients progress through lines of therapy. This is in line with available clinical guidelines. Infliximab – the reference brand and its biosimilar versions – remains the most frequently prescribed biologic in the Crohn’s disease market.

The use of integrin receptor inhibitors remains low. US gastroenterologists favor Entyvio over Tysabri due to its superior safety profile.

The development of therapies that achieve long-term remission without the need for immunosuppression remains the most prominent unmet need in Crohn’s disease.

Datamonitor Healthcare expects the use of biosimilars to increase in all patient subpopulations in the near future, driven by lower costs and increasing availability of long-term safety data.

Methodology Datamonitor Healthcare conducted a survey of 240 gastroenterologists in the US, Japan, and five major EU markets on their Crohn’s disease treatment choices and prescribing habits.

EXECUTIVE SUMMARY

Biologic usage increases as Crohn’s Datamonitor Healthcare’s 2016 survey shows that across the US, Japan, and five disease patients progress through major EU markets (France, Germany, Italy, Spain, and the UK), the prescribing of lines of therapy biologics increases as Crohn’s disease patients progress through lines of therapy. The percentage of drug-treated Crohn’s disease patients who receive anti-tumor necrosis factor (TNF) biologics or integrin receptor inhibitors increases from 32.3% and 1.0%, respectively, at first line to 67.1% and 7.6%, respectively, at fourth line or later. These findings are consistent with available treatment guidelines, which cite that biologics should be prescribed after conventional treatments such as corticosteroids and immunomodulators have failed.

Infliximab remains the preferred Infliximab – the reference brand Remicade (infliximab; Johnson & Johnson/Merck & biologic in Crohn’s disease Co/Mitsubishi Tanabe) and its biosimilar versions – remains the most frequently prescribed biologic for the treatment of Crohn’s disease across the US, Japan, and five major EU markets. Datamonitor Healthcare attributes this to the extensive experience physicians have with the agent. Remicade was the first anti-TNF to be approved for use in Crohn’s disease in 1998, and it held a unique position in the market as the only approved biologic until Humira (adalimumab; AbbVie/Eisai) gained approval in 2007. Survey data show that Humira is the second most frequently prescribed biologic in Crohn’s disease. While there are no direct head-to- head trials of Remicade and Humira, retrospective cohort studies suggest that the efficacy of the two biologics is similar overall.

US gastroenterologists favor Entyvio Survey data show that Entyvio (vedolizumab; Takeda) is the integrin receptor over Tysabri due to its superior safety inhibitor of choice in the US, despite its launch behind first-in-class Tysabri profile (natalizumab; Biogen). Datamonitor Healthcare attributes this to Entyvio’s superior safety profile. Tysabri has failed to win European Medicines Agency approval, and its approval in the US was accompanied by a black box warning for increased risk of brain infection and a risk management plan specific to Crohn’s disease. By contrast, Entyvio is approved in both the US and Europe, and its clinical profile is enhanced by the absence of a black box warning in its label.

The development of therapies that Significant unmet need remains for treatments that lead to sustained remission achieve long-term remission without without needing to employ immunosuppressive medications. Clinical guidelines for the need for immunosuppression Crohn’s disease state that immunomodulators are very effective at maintaining remains the most prominent unmet medically induced remission. However, immunomodulators are also associated with need in Crohn’s disease a higher rate of serious adverse events. Datamonitor Healthcare believes that manufacturers able to demonstrate the induction and maintenance of remission without the negative immunosuppressive profile of current agents will be successful in the Crohn’s disease market.

PRIMARY RESEARCH METHODOLOGY

PHYSICIAN RESEARCH

Table 51: Gastroenterologists surveyed for the Crohn’s disease primary research study, 2016

US Japan France Germany Italy Spain UK

Sample size 35 31 31 38 35 37 33

Mean number of 13.4 20.3 15.9 15.9 18.3 17.2 12.0 years in specialty

Mean number of 9.2 9.0 8.7 8.5 8.3 8.1 8.2 hours per day spent in clinical practice

Mean number of 135 34 67 96 115 130 104 Crohn’s disease patients actively treated by respondents

Source: Datamonitor Healthcare’s proprietary Crohn’s disease survey, April 2016

The primary research study was conducted online, with all the respondents self-completing a 30-minute questionnaire in their own language. The questionnaire was divided into three sections:

• screening questions

• main questionnaire

• demographic questions.

Datamonitor Healthcare’s questionnaire was carefully designed and included a number of screening questions to ensure the most appropriate targeting of respondents for this study. Respondents needed to have clinical responsibility for the treatment and management of a minimum number of Crohn’s disease patients to ensure that responses were broadly representative of current treatment practices. The participating physicians also had to be working in clinical practice daily, have a minimum number of years of experience in their specialty, and to not work directly for a pharmaceutical company, other than involvement in clinical trials. All these

criteria aimed to ensure, as far as possible, that respondents were experienced, practicing specialists with unbiased views.

The objectives of the main questionnaire for this study were to gain an understanding and insight into the following:

• key epidemiological datasets (diagnosis and treatment rates)

• patient management pathways

• patient segmentation by severity

• prescribing behavior, including the use of monotherapy and/or combination therapy, by severity

• patient compliance

• assessment of unmet treatment needs

• future trends and uptake of new therapies and their impact on the market.

• was “fit-for-purpose” and able to gather data that answered the research objectives

• was straightforward for the respondents to complete in the allocated time period

• covered all relevant aspects of treatment and management for Crohn’s disease.

After the mainstage fieldwork was completed, the raw data at the respondent level were carefully reviewed and quality-checked by the research team prior to data processing and analysis.

PATIENT SEGMENTATION

NO SINGLE GOLD-STANDARD MEASUREMENT OF DISEASE ACTIVITY HAS BEEN ESTABLISHED

The heterogeneous patterns of Crohn’s disease and the fact that it can affect any part of the gastrointestinal tract, alongside the frequent presence of extra-intestinal complications, have meant that defining Crohn’s disease activity is challenging, and no single gold-standard measurement of disease activity has been established. In clinical practice, physicians examine several clinical parameters, systemic manifestations, and the impact of the disease on the patient’s quality of life in order to evaluate disease severity (Peyrin-Biroulet et al., 2016; Lichtenstein et al., 2009). Japanese guidelines suggest that Crohn’s disease severity should be assessed by a subjective evaluation of symptoms, clinical findings, and laboratory investigations by a gastroenterologist in general clinical practice (Ueno et al., 2013). The European Crohn’s and Colitis Organisation guidelines recommend the use of the Montreal revision of the Vienna classification to assess Crohn’s disease severity. This classification considers age at diagnosis, as well as the location, behavior, and modifiers (eg perianal fistulas and abscesses) of the disease at any time during the disease course as the most relevant parameters (Gomollon et al., 2016). Key opinion leaders confirm that there are no standard definitions of mild, moderate, or severe Crohn’s disease that can be used in clinical practice, and that physicians assess severity by examining a range of parameters. This means that clinical treatment for Crohn’s disease is highly personalized to each individual.

“This classification – mild, moderate, and severe – does not mean that much, because this is just a reflection of disease activity when you see the patient. What is very important is to take into account all parameters and predictors of bad outcome when you see a patient in your clinic. For instance, we know that the risk of progression of the disease, the risk of complication, the risk of a colectomy, and so on, are increased by several parameters such as age, disease extent, endoscopic severity, presence of extra-intestinal manifestations such as primary sclerosing cholangitis, and so on. So, on top of assessing disease severity at one point in time, it is very important to have a global view of the patient.”

US key opinion leader

MILD AND MODERATE PATIENTS CONSTITUTE THE LARGEST SEGMENT

Datamonitor Healthcare’s 2016 survey of 240 gastroenterologists reveals that mild and moderate patients make up the largest segment across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). While the majority of patients have mild and moderate Crohn’s disease, Datamonitor Healthcare believes that the ideal target population for manufacturers of novel therapies is the moderate to severe patient population. Indeed, these patients are the target population of the key market drivers within Crohn’s disease, specifically biologics such as Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and Humira (adalimumab; AbbVie/Eisai).

The definitions of Crohn’s disease severity used in Datamonitor Healthcare’s 2016 survey were based on Crohn's Disease Activity Index (CDAI) score, which is used in the majority of clinical trials to assess therapeutic outcomes. The CDAI score is primarily based on symptomology. The definitions of disease activity based on CDAI parameters are summarized below (Van Assche et al., 2010):

• Mild (mildly active) – Equivalent to a CDAI of 150–220. Ambulatory, eating and drinking, less than 10% weight loss. No features of obstruction, fever, dehydration, abdominal mass, or tenderness. C-reactive protein (CRP) usually increased above the upper limit of normal.

• Moderate (moderately active) – Equivalent to a CDAI of 220–450. Intermittent vomiting or weight loss of more than 10%. Treatment for mild disease is ineffective or tender mass. No overt obstruction. CRP elevated above the upper limit of normal.

• Severe (severely active) – Equivalent to a CDAI of above 450. Cachexia (body mass index less than 18kg/m2) or evidence of obstruction or abscess. Persistent symptoms despite intensive treatment. CRP increased.

Figure 59: Severity of diagnosed Crohn’s disease patients, by country

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

BIBLIOGRAPHY

Gomollon F, Dignass A, Annese V, Tilg H, Van Assche G (2016) EUROPEAN Evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 1: Diagnosis and medical management. Journal of Crohn’s and Colitis, pii: jjw168 [Epub ahead of print].

Lichtenstein GR, Hanauer SB, Sandborn WJ (2009) Management of Crohn’s Disease in Adults. The American Journal of Gastroenterology, 104(2), 465–483.

Peyrin-Biroulet L, Panés J, Sandborn WJ, Vermeire S, Danese S, et al. (2016) Defining Disease Severity in Inflammatory Bowel Diseases: Current and Future Directions. Clinical Gastroenterology and Hepatology, 14(3), 348–354.

Ueno F, Matsui T, Matsumoto T, Matsuoka K, Watanabe M, et al. (2013) Evidence-based clinical practice guidelines for Crohn's disease, integrated with formal consensus of experts in Japan. Journal of Gastroenterology, 48(1), 31–72.

Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, et al. (2010) The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. Journal of Crohn’s and Colitis, 4(1), 7–27.

CURRENT TREATMENT OPTIONS

TREATMENT GUIDELINES

Crohn’s disease guidelines have been published by the American College of Gastroenterology (ACG), the European Crohn’s and Colitis Organisation (ECCO), and the Japanese Society of Gastroenterology (JSG). Each set of guidelines recommends how gastroenterologists should select and sequence treatment options for patients based upon the severity of their Crohn’s disease. The clinical data supporting the treatment recommendations are reviewed and rated or ranked according to the strength of the recommendation. Each of these guidelines has been formulated primarily to achieve two goals: to cause a patient’s active disease to go into remission, and to sustain the medically induced remission when it is attained. The ACG and ECCO guidelines provide a deeper insight into how to effectively treat Crohn’s disease depending on where it manifests in the gastrointestinal tract – recommended treatments for ileocolonic (disease affecting the final section of the small intestine and the large intestine), colonic (disease affecting the large intestine only), and extensive small bowel (ileal; disease affecting large sections of the small intestine only) Crohn’s disease are subtly different. The two tables below summarize the pharmacological therapy approaches recommended by the ACG, ECCO, and JSG guidelines for the treatment of active Crohn’s disease and for the maintenance of medically induced remission, respectively.

Table 52: Treatment guidelines: initial treatment of active Crohn’s disease, by severity

Guidelines Mildly active CD Moderately active CD Severely active CD Reference

ACG guidelines, 2009 - Mesalamine less effective than See mildly active CD and severely active - Prednisolone recommended Lichtenstein et al., 2009 budesonide or conventional CD - Anti-TNF biologics Remicade, Humira, and corticosteroids Cimzia recommended in patients who have - Sulfasalazine an option for ileocolonic or not responded to corticosteroids or colonic CD immunosuppressants - Controlled-release budesonide effective - Integrin inhibitor Tysabri effective for patients when disease localized to ileum and/or who do not respond or become intolerant to right colon anti-TNFs Disease Coverage | Treatment: Crohn’s Disease 227

Table 52: Treatment guidelines: initial treatment of active Crohn’s disease, by severity

ECCO guidelines, 2016 Ileocolonic CD: Ileocolonic CD: Ileocolonic CD: Gomollon et al., 2016 - Oral budesonide recommended - Budesonide or systemic corticosteroids - Initial treatment with systemic corticosteroids Colonic CD: recommended - Immunomodulators in combination with - Systemic corticosteroids recommended - Immunomodulators in combination with corticosteroids an appropriate option for Extensive small bowel disease: corticosteroids an appropriate option for patients with infrequently relapsing disease - Initial therapy with systemic patients with infrequently relapsing - Anti-TNF biologics can be considered for corticosteroids plus immunomodulators disease corticosteroid-refractory, -dependent, or - recommended - Anti-TNF biologics can be considered for intolerant patients - Early therapy with anti-TNF biologic with corticosteroid-refractory, -dependent, or - - Vedolizumab recommended for or without immunomodulator intolerant patients corticosteroid- or anti-TNF-refractory, or - recommended for patients with high - Vedolizumab recommended for intolerant patients disease activity and features indicating corticosteroid- or anti-TNF-refractory, or - Colonic CD: poor prognosis intolerant patients - Systemic corticosteroids recommended Colonic CD: - For relapsed patients, anti-TNF biologics with - Systemic corticosteroids recommended or without an immunomodulator are - For relapsed patients, anti-TNF biologics appropriate with or without an immunomodulator are - Vedolizumab recommended for appropriate corticosteroid- or anti-TNF-refractory, or - - Vedolizumab recommended for intolerant patients corticosteroid- or anti-TNF-refractory, or - Extensive small bowel disease: intolerant patients - For relapsed patients, anti-TNF biologics with Extensive small bowel disease: or without an immunomodulator are - For relapsed patients, anti-TNF biologics appropriate with or without an immunomodulator are appropriate Disease Coverage | Treatment: Crohn’s Disease 228

Table 52: Treatment guidelines: initial treatment of active Crohn’s disease, by severity

Japan MHLW/JSG CD guidelines, - Mesalamine recommended as first-line - Oral prednisolone - IV prednisolone Ueno et al., 2013 2013 treatment - Where corticosteroids ineffective, - Anti-TNF biologic for corticosteroid-resistant - Sulfasalazine recommended for patients consider use of an anti-TNF biologic disease with colonic lesions - Enteral nutrition equivalent or slightly inferior to corticosteroids for induction of remission

Note: Immunomodulators refer to thiopurines (ie 6-mercaptopurine or azathioprine) and methotrexate.

ACG = American College of Gastroenterology; ECCO = European Crohn’s and Colitis Organisation; IV = intravenous; JSG = Japanese Society of Gastroenterology; MHLW = Ministry of Health, Labour and Welfare; TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Treatment: Crohn’s Disease 229

Table 53: Treatment guidelines: maintenance of medically induced remission of Crohn’s disease and other therapy recommendations

Guidelines Maintenance therapy recommendations Other therapy recommendations Reference

ACG guidelines, 2009 - Azathioprine recommended for maintaining corticosteroid-induced - Parenteral methotrexate effective for corticosteroid- Lichtenstein et al., 2009 clinical remission dependent/refractory CD - Maintenance therapy with anti-TNF biologics Remicade, Humira, and - Remicade recommended for fistulating CD, antibiotics and Cimzia is effective immunosuppressants are also options - Remicade or Remicade plus azathioprine more effective than azathioprine monotherapy - Maintenance therapy with Tysabri is effective - Azathioprine can maintain remission in patients who received Remicade as induction therapy and are corticosteroid-naïve

ECCO guidelines, 2016 - If remission achieved with systemic corticosteroids, an Esophageal or gastroduodenal CD: Gomollon et al., 2016 immunomodulator should be considered - Proton pump inhibitor, if necessary combined with systemic - For relapse of localized disease, escalation of maintenance therapy corticosteroids and immunomodulators can be considered - Anti-TNFs for severe or refractory disease - For patients with extensive disease, azathioprine is recommended - For corticosteroid-dependent patients, immunomodulators with or without an anti-TNF should be considered - If induction of remission is achieved with an anti-TNF, maintenance with an anti-TNF with or without azathioprine should be considered

Japan MHLW/JSG CD guidelines, - Azathioprine recommended for maintenance of remission - Immunomodulators or anti-TNF biologics can be used for Ueno et al., 2013 2013 - Anti-TNF biologics recommended for maintenance when previously treatment of fistulas used to induce remission - Treatment of intestinal stenosis with corticosteroids - Mesalamine is effective for post-surgery maintenance of remission - Remicade can be used to stop hemorrhage from CD lesions Disease Coverage | Treatment: Crohn’s Disease 230

Table 53: Treatment guidelines: maintenance of medically induced remission of Crohn’s disease and other therapy recommendations

Note: Immunomodulators refer to thiopurines (ie 6-mercaptopurine or azathioprine) and methotrexate.

ACG = American College of Gastroenterology; ECCO = European Crohn’s and Colitis Organisation; JSG = Japanese Society of Gastroenterology; MHLW = Ministry of Health, Labour and Welfare; TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Treatment: Crohn’s Disease 231

OVERVIEW OF THE AVAILABLE DRUG CLASSES

Datamonitor Healthcare defines the Crohn’s disease market in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) as comprising the drug classes and molecules shown in the table below. This is based on country-specific proprietary market research with prescribing gastroenterologists, secondary research, and key opinion leader discussions. Please view the accompanying Excel deliverable to see country-specific uptake of each drug class and molecule within each surveyed country.

Table 54: Summary of key classes and products included in Datamonitor Healthcare’s Crohn’s disease survey

Brand (molecule) Company

Integrin receptor inhibitors

Entyvio (vedolizumab) Takeda

Tysabri (natalizumab) Biogen

TNF inhibitors

Cimzia (certolizumab pegol) UCB/Astellas

Humira (adalimumab) AbbVie/Eisai

Remicade (infliximab) Johnson & Johnson/Merck & Co/Mitsubishi Tanabe

Simponi (golimumab) Johnson & Johnson/Merck & Co/Mitsubishi Tanabe

Biosimilar infliximab This group estimates uptake for all biosimilar versions of infliximab

Aminosalicylates

balsalazide This group estimates uptake for all branded/generic versions of balsalazide

mesalamine* This group estimates uptake for all branded/generic versions of mesalamine

olsalazine This group estimates uptake for all branded/generic versions of olsalazine

sulfasalazine This group estimates uptake for all branded/generic versions of sulfasalazine

Immunomodulators

azathioprine** This group estimates uptake for all branded/generic versions of azathioprine

cyclosporine This group estimates uptake for all branded/generic versions of cyclosporine

mercaptopurine** This group estimates uptake for all branded/generic versions of mercaptopurine

methotrexate This group estimates uptake for all branded/generic versions of methotrexate

Table 54: Summary of key classes and products included in Datamonitor Healthcare’s Crohn’s disease survey

Systemic corticosteroids

hydrocortisone This group estimates uptake for all branded/generic versions of hydrocortisone

prednisolone This group estimates uptake for all branded/generic versions of prednisolone

Non-systemic corticosteroids

budesonide This group estimates uptake for all branded/generic versions of budesonide

Note: Datamonitor Healthcare’s 2016 primary research survey was conducted in April 2016, before the approval of the IL-12/23 inhibitor Stelara (ustekinumab; Johnson & Johnson) for the treatment of moderate to severe Crohn’s disease.

*Mesalamine is also referred to as 5-ASA.

**Commonly referred to as thiopurines in treatment guidelines.

IL = interleukin; TNF = tumor necrosis factor

Source: Datamonitor Healthcare

BIBLIOGRAPHY

Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of the American College of Gastroenterology (2009) Management of Crohn's disease in adults. American Journal of Gastroenterology, 104(2), 465–483.

PRESCRIBING TRENDS

PHARMACOLOGICAL THERAPY DOMINATES THE TREATMENT OF CROHN’S DISEASE

Datamonitor Healthcare’s 2016 primary research survey of 240 gastroenterologists shows that the majority of Crohn’s disease patients across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) are prescribed pharmacological therapy to manage their disease. There are no major variations in pharmacological prescribing rates between countries. Datamonitor Healthcare believes that the high uptake of pharmacological therapy highlights that surgery is still considered to be a last resort by many gastroenterologists. Clinical treatment guidelines generally recommend the use of surgery in very severe cases of the disease, primarily when pharmacological therapy has already proved ineffective. More precisely, indications for surgical intervention include obstruction, perforation, intractable hemorrhage, persisting or recurrent obstruction, abscess, and fistulas (Lichtenstein et al., 2009; Ueno et al., 2013; Gomollon et al., 2016). The figure below summarizes the use of pharmacological and non-pharmacological therapy in Crohn’s disease in the US, Japan, and five major EU markets.

Figure 60: Mean percentage of Crohn’s disease patients receiving pharmacological therapy or non-pharmacological therapy only, by country

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Table 55: Crohn’s disease patients receiving pharmacological therapy or non-pharmacological therapy only, by country

Therapy US Japan France Germany Italy Spain UK

Pharmacological therapy 91.2% 83.3% 86.5% 84.1% 86.1% 88.1% 83.2%

Non-pharmacological therapy only 8.8% 16.7% 13.5% 15.9% 13.9% 11.9% 16.8%

Note: Pharmacological therapy refers to pharmacological therapy alone or in combination with non-pharmacological therapy. Non-pharmacological therapy is defined as lifestyle advice (eg diet) or no therapy at all.

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016 Disease Coverage | Treatment: Crohn’s Disease 236

There is moderate uptake of aminosalicylates despite limited recommendations for their use in the US and EU

Datamonitor Healthcare’s survey data show there is moderate uptake of aminosalicylates for the treatment of Crohn’s disease, despite the fact that use of this drug class is not widely recommended by US and EU clinical guidelines due to its marginal benefit and high incidence of side effects (Lichtenstein et al., 2009; Gomollon et al., 2016). At first line, an average of 42.2% of drug-treated Crohn’s disease patients are prescribed aminosalicylates in the US, Japan, and five major EU markets. The proportion of aminosalicylate-treated patients declines in subsequent lines of therapy, but this class is still used in nearly one third of drug-treated patients at fourth line or later. Prescribing of aminosalicylates is highest in Japan (75.2% at first line), where treatment guidelines recommend mesalamine as a first-line induction therapy (Ueno et al., 2013). For a breakdown of aminosalicylate use by country, line of therapy, and molecule, please see Datamonitor Healthcare’s accompanying Excel datapack.

Table 56: Mean percentage of drug-treated Crohn’s disease patients receiving each drug class, by line of therapy and country (%)

Drug class US Japan France Germany Italy Spain UK

First line

Integrin receptor 2.8% 0.0% 0.5% 1.6% 0.6% 1.1% 0.2% inhibitors

TNF inhibitors 47.4% 33.2% 34.6% 20.2% 35.5% 36.0% 18.9%

Aminosalicylates 35.1% 75.2% 31.3% 42.1% 41.4% 34.4% 36.0%

Immunomodulators 30.8% 11.3% 35.2% 34.1% 25.2% 38.5% 44.4%

Systemic 6.8% 24.4% 19.7% 18.8% 14.6% 14.8% 21.9% corticosteroids

Non-systemic 12.2% 1.8% 13.3% 33.7% 19.7% 18.2% 9.8% corticosteroids

Other 0.0% 0.6% 0.3% 0.3% 1.1% 0.3% 0.0%

Second line Disease Coverage | Treatment: Crohn’s Disease 238

Table 56: Mean percentage of drug-treated Crohn’s disease patients receiving each drug class, by line of therapy and country (%)

Integrin receptor 7.7% 0.0% 1.9% 3.0% 0.6% 2.1% 0.3% inhibitors

TNF inhibitors 68.5% 45.6% 51.1% 35.6% 48.0% 50.1% 32.6%

Aminosalicylates 27.7% 73.6% 19.8% 37.3% 36.2% 32.2% 37.3%

Immunomodulators 36.0% 28.7% 48.1% 44.3% 34.2% 50.5% 50.0%

Systemic 4.6% 27.0% 19.1% 15.5% 13.7% 18.9% 18.2% corticosteroids

Non-systemic 9.9% 1.8% 7.4% 25.0% 16.9% 13.4% 13.2% corticosteroids

Other 0.0% 1.6% 0.5% 0.3% 0.3% 1.1% 0.0%

Third line

Integrin receptor 12.9% 0.0% 6.3% 5.8% 0.6% 2.7% 1.8% inhibitors

TNF inhibitors 71.6% 60.3% 65.0% 51.3% 60.0% 68.2% 45.0% Disease Coverage | Treatment: Crohn’s Disease 239

Table 56: Mean percentage of drug-treated Crohn’s disease patients receiving each drug class, by line of therapy and country (%)

Aminosalicylates 21.5% 71.3% 14.7% 35.5% 31.9% 29.4% 27.3%

Immunomodulators 45.0% 25.5% 45.6% 40.5% 41.6% 51.5% 62.2%

Systemic 7.9% 32.3% 13.2% 17.0% 14.5% 12.6% 18.2% corticosteroids

Non-systemic 8.5% 1.7% 4.6% 23.1% 12.2% 10.4% 11.4% corticosteroids

Other 0.2% 0.0% 0.7% 0.3% 0.2% 1.3% 0.0%

Fourth line or later

Integrin receptor 21.5% 0.0% 6.9% 12.2% 0.3% 10.2% 1.9% inhibitors

TNF inhibitors 63.8% 61.3% 72.1% 55.7% 77.6% 73.9% 65.4%

Aminosalicylates 18.6% 70.4% 19.0% 33.4% 33.8% 32.1% 20.4%

Immunomodulators 50.7% 26.7% 43.5% 37.4% 37.4% 46.4% 56.7% Disease Coverage | Treatment: Crohn’s Disease 240

Table 56: Mean percentage of drug-treated Crohn’s disease patients receiving each drug class, by line of therapy and country (%)

Systemic 3.3% 30.5% 20.7% 12.7% 10.1% 12.9% 20.1% corticosteroids

Non-systemic 7.3% 2.3% 4.3% 20.1% 10.7% 11.0% 8.5% corticosteroids

Other 2.7% 0.4% 1.0% 0.4% 0.2% 0.0% 0.0%

Note: totals at each line of therapy sum to more than 100% due to use of combination therapy.

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016 Disease Coverage | Treatment: Crohn’s Disease 241

Systemic corticosteroids are preferred over non-systemic corticosteroids at all lines of therapy

Datamonitor Healthcare’s 2016 survey reveals that gastroenterologists favor systemic corticosteroids over non-systemic corticosteroids at all lines of therapy. This is surprising given the fact that budesonide, a non-systemic corticosteroid, is recommended as a first-line therapy by Crohn’s disease clinical treatment guidelines developed in the US and EU (Lichtenstein et al., 2009; Gomollon et al., 2016). In the US, Japan, and five major EU markets, 17.3% of drug-treated Crohn’s disease patients receive systemic corticosteroids at first line, falling to 15.8% at fourth line or later. Although the proportion of drug-treated patients receiving non- systemic corticosteroids at first line is similar to those receiving systemic corticosteroids (15.5%), this proportion falls in subsequent therapy lines to 9.2% at fourth line or later. Datamonitor Healthcare believes that gastroenterologists’ preference for systemic corticosteroids, especially at later lines of therapy, highlights that they are generally perceived to be more efficacious than their non- systemic counterparts. This trend also suggests that the superior efficacy of systemic corticosteroids is considered more important than the improved tolerability profile of non-systemic corticosteroids (Lichtenstein et al., 2009; Gomollon et al., 2016).

The figure below shows the mean percentage use of systemic and non-systemic corticosteroids for the treatment of Crohn’s disease across the US, Japan, and five major EU markets, by line of therapy.

Figure 61: Mean percentage use of systemic and non-systemic corticosteroids in the US, Japan, and five major EU markets, by line of therapy

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Combination therapy usage increases as patients progress through lines of therapy

Datamonitor Healthcare’s 2016 survey data show that across the US, Japan, and five major EU markets, the use of combination therapy increases as patients progress through lines of therapy. Correspondingly, the prescribing of monotherapies declines as patients progress through the treatment algorithm. This trend is in line with available treatment guidelines for Crohn’s disease. Guidelines recommend the use of anti-TNFs with or without immunomodulators (eg azathioprine or methotrexate) for moderate to severe patients (Lichtenstein et al., 2009; Ueno et al., 2013; Gomollon et al., 2016). While the long-term benefits of combination therapy over monotherapy remain unclear, several studies suggest that combination regimens consisting of an anti-TNF and an immunomodulator are associated with higher and sustained remission as well as lower immunogenicity. Since the risk of immunogenicity is higher during the first few months of anti-TNF therapy, gastroenterologists often discontinue immunomodulators after six to 12 months of combination therapy (Colombel, 2010; Nguyen et al., 2015). The figure below shows the mean percentage of drug-treated Crohn’s disease patients in the US, Japan, and five major EU markets receiving monotherapy versus combination therapy, by line of therapy.

Figure 62: Mean percentage of drug-treated Crohn’s disease patients receiving monotherapy versus combination therapy, by line of therapy

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Table 57: Mean percentage of drug-treated Crohn’s disease patients receiving monotherapy or combination therapy, by line of therapy and country (%)

Therapy US Japan France Germany Italy Spain UK type

First line

Monotherapy 70.5% 63.7% 70.8% 60.9% 72.1% 66.3% 73.9%

Combination 29.5% 36.3% 29.2% 39.1% 27.9% 33.7% 26.1% therapy

Second line

Monotherapy 54.6% 34.8% 60.8% 52.4% 61.9% 49.0% 57.9%

Combination 45.4% 65.2% 39.2% 47.6% 38.1% 51.0% 42.1% therapy

Third line

Monotherapy 40.8% 33.8% 58.3% 42.4% 54.0% 41.8% 45.4%

Combination 59.2% 66.2% 41.7% 57.6% 46.0% 58.2% 54.6% therapy

Fourth line or later

Monotherapy 39.1% 35.6% 49.1% 44.3% 45.0% 38.6% 37.7%

Combination 60.9% 64.4% 50.9% 55.7% 55.0% 61.4% 62.3% therapy

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Anti-TNF usage is higher in the US compared to Japan and Europe Datamonitor Healthcare’s 2016 survey shows that, across most lines of therapy, prescribing of anti-TNFs is higher in the US compared

to Japan and the five major EU markets. This finding is consistent with US clinical guidelines, which highlight that the efficacy and cost of anti-TNFs outweigh their risks and the high economic impact of uncontrolled disease (Terdiman et al., 2013). Datamonitor Healthcare’s 2016 survey data show that, on average, Crohn’s disease patients in the UK are significantly less likely to receive anti- TNFs compared to their counterparts in the US, Japan, and the remaining major EU markets at first, second, and third lines of therapy. Datamonitor Healthcare attributes this to the National Institute for Health and Care Excellence’s (NICE’s) restrictive recommendation for the use of anti-TNFs. NICE recommends the use of Remicade (infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) and Humira (adalimumab; AbbVie/Eisai) only in adult patients with severely active disease who have not responded to conventional therapy or who are intolerant of or contraindicated to conventional therapy, thereby restricting the eligible patient population (NICE, 2016). Furthermore, Datamonitor Healthcare’s survey data show that, overall, anti-TNF use is lower in Germany compared to the US, Japan, France, Italy, and Spain. Gastroenterologists in Germany follow practice guidelines issued by the regulatory body, the Gemeinsamer Bundesausschuss, which are based on an evaluation of the added therapeutic benefit of a drug compared to an appropriate comparative treatment. These guidelines are legally binding for physicians in the statutory health insurance system. In addition, the prescription of therapies with high annual treatment costs or a high risk potential in Germany is subject to a second opinion by a suitably qualified physician (Organisation for Economic Co-operation and Development, 2008; Ruof et al., 2014).

The figure below shows the mean percentage use of anti-TNF biologics for the treatment of Crohn’s disease, by country and line of therapy.

Figure 63: Mean percentage of drug-treated Crohn’s disease patients receiving anti-TNF therapy, by country and line of therapy

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Infliximab remains the most frequently prescribed biologic in the Crohn’s disease market

Datamonitor Healthcare’s 2016 primary research survey data show that, overall, infliximab – the reference brand Remicade and its biosimilar versions – remains the most frequently prescribed biologic for the treatment of Crohn’s disease across the US, Japan, and five major EU markets. This is largely due to its proven efficacy in both the induction and maintenance of clinical remission, its fast onset of action, and physician and patient familiarity with the drug. Remicade was the first anti-TNF to be approved for use in Crohn’s disease in 1998, and it held a unique position in the market as the only approved biologic until Humira gained approval in 2007 (Biomedtracker, 2016; FDA, 2007).

“Remicade was the first biologic in Crohn’s disease, and it still has the best efficacy data we have seen so far, which explains its position as the preferred biologic...”

US key opinion leader

The figure below shows the percentage use of biologic brands for the treatment of drug-treated Crohn’s disease patients in the US, Japan, and five major EU markets, by line of therapy.

Figure 64: Mean percentage use of biologic therapies for the treatment of drug-treated Crohn’s disease patients, by biologic and line of therapy

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Humira is the second most frequently prescribed biologic in the Crohn’s disease market

Datamonitor Healthcare’s 2016 survey data show that Humira is the second most frequently prescribed biologic in the treatment of Crohn’s disease. While there are no direct head-to-head trials of infliximab and adalimumab, secondary sources suggest that the efficacy of the two biologics is similar overall. A retrospective cohort study conducted using Medicare data between 2006 and 2010 suggests that the efficacy of the two biologics is similar across a number of clinical endpoints, including persistence on therapy, surgery, and hospitalization (Osterman et al., 2014). A retrospective study presented at the Congress of the European Crohn’s and Colitis Organisation (ECCO) in 2016 compared the long-term outcomes in patients treated with adalimumab and infliximab using registry records of Crohn’s disease patients. Results showed that discontinuation rates and treatment failure rates were similar in the infliximab and adalimumab groups at five years (57.7% vs 68.4%, and 24.6% vs 20.9%, respectively) (ECCO, 2016). Leading gastroenterologists stress a similar view: while Remicade remains the preferred biologic, Humira’s efficacy profile is broadly comparable.

“Remicade was the first biologic in Crohn’s disease, and it still has the best efficacy data we have seen so far, which explains its position as the preferred biologic. But I think that Humira is similarly effective in Crohn’s [disease].”

US key opinion leader

Table 58: Mean percentage of drug-treated Crohn’s disease patients receiving each biologic therapy, by line of therapy and country (%)

Biologic US Japan France Germany Italy Spain UK

First line

Remicade 22.3% 16.1% 15.5% 7.7% 17.5% 15.5% 10.0%

biosimilar - 0.8% 4.5% 2.7% 5.7% 4.2% 2.0% infliximab

Humira 21.3% 12.3% 13.8% 9.1% 12.1% 12.9% 6.0%

Cimzia 3.3% 2.9% 0.0% 0.1% 0.0% 2.1% 0.5%

Simponi 0.6% 1.1% 0.8% 0.6% 0.1% 1.4% 0.3%

Tysabri 0.6% ------

Entyvio 2.2% - 0.5% 1.6% 0.6% 1.1% 0.2%

Second line

Remicade 29.6% 25.5% 22.6% 13.5% 22.9% 21.9% 17.5%

biosimilar - 0.8% 6.9% 3.8% 7.5% 5.2% 4.5% infliximab

Humira 31.1% 15.6% 20.6% 15.9% 17.3% 19.0% 9.5%

Cimzia 7.9% 2.7% 0.2% 1.2% 0.0% 2.3% 0.7%

Simponi 0.0% 1.1% 0.8% 1.2% 0.3% 1.7% 0.5%

Tysabri 0.7% ------

Entyvio 7.0% - 1.9% 3.0% 0.6% 2.1% 0.3%

Third line

Remicade 35.3% 34.0% 27.2% 19.0% 28.0% 31.5% 23.7%

Table 58: Mean percentage of drug-treated Crohn’s disease patients receiving each biologic therapy, by line of therapy and country (%)

biosimilar 0.0% 0.8% 7.8% 5.1% 7.6% 4.6% 7.3% infliximab

Humira 27.3% 22.2% 27.6% 24.2% 23.8% 25.1% 12.0%

Cimzia 9.1% 2.3% 1.3% 1.2% 0.0% 4.4% 0.6%

Simponi 0.0% 0.9% 1.0% 1.8% 0.6% 2.5% 1.4%

Tysabri 0.0% ------

Entyvio 12.9% - 6.3% 5.8% 0.6% 2.7% 1.8%

Fourth line or later

Remicade 32.5% 31.1% 37.3% 23.0% 32.7% 31.6% 21.0%

biosimilar 0.0% 1.0% 4.7% 7.0% 14.1% 6.0% 16.6% infliximab

Humira 23.1% 25.4% 28.4% 23.4% 29.1% 28.6% 25.3%

Cimzia 8.3% 2.6% 0.0% 0.2% 0.0% 4.2% 0.0%

Simponi 0.0% 1.2% 1.7% 2.2% 1.7% 3.5% 2.5%

Tysabri 0.0% ------

Entyvio 21.5% - 6.9% 12.2% 0.3% 10.2% 1.9%

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

There is some off-label prescribing of Cimzia and Simponi due to their use in ulcerative colitis and other inflammatory disorders

Datamonitor Healthcare’s 2016 survey indicates that there is a small amount of off-label prescribing of anti-TNF biologics Cimzia (certolizumab pegol; UCB/Astellas) and Simponi (golimumab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe) for the treatment of Crohn’s disease. In Japan and the five major EU markets there is some off-label prescribing of Cimzia. Cimzia is approved for the

treatment of Crohn’s disease in the US, but not in Japan and the EU. However, Cimzia is available to Japanese gastroenterologists through its indication for the treatment of rheumatoid arthritis. Cimzia is also available to EU physicians as it has European Medicines Agency approval for the treatment of other autoimmune indications, namely rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

In the US, Japan, and five major EU markets, there is also some off-label use of Simponi. Simponi is available to gastroenterologists in these markets through its approval for other indications, namely ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in the US and EU, and rheumatoid arthritis in Japan (Biomedtracker, 2016).

Tysabri is the least prescribed biologic in the US

Datamonitor Healthcare’s 2016 survey data show that Tysabri (natalizumab; Biogen) is the least frequently prescribed biologic in the US, the only major market where it is approved for the treatment of Crohn’s disease (FDA, 2008). Gastroenterologists have been wary of prescribing Tysabri due to its black box warning for an increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that can lead to death or severe disability (FDA, 2016). Leading gastroenterologists note that second-to-market integrin inhibitor Entyvio (vedolizumab; Takeda) has captured most of Tysabri’s market share. While Entyvio has an overall modest efficacy profile in Crohn’s disease, it has not been associated with increased risk of PML and has a more attractive safety profile in general (Entyvio prescribing information, 2014). The arrival of the interleukin (IL)-12/23 inhibitor Stelara (ustekinumab; Johnson & Johnson/Mitsubishi Tanabe), which has a faster onset of action than Entyvio and a comparable safety profile, is expected to further impact Tysabri’s use.

US key opinion leader

BIBLIOGRAPHY

Colombel JF (2010) Current Developments in the Treatment of Inflammatory Bowel Diseases. Gastroenterology and Hepatology, 6(8), 486–490.

ECCO (2016) Congress: Abstract OP034. Presented 17 March 2016.

Entyvio prescribing information (2014) Available from: http://general.takedapharm.com/content/file.aspx?FileTypeCode=ENTYVIOPI&cacheRandomizer=ff188ec8-ce00-4840-835a- 36457cec5519 [Accessed 6 December 2016].

FDA (2007) Approval letter. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/125057s089Ltr.pdf [Accessed 6 December 2016].

FDA (2008) Approval letter. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/125104s0033ltr.pdf [Accessed 6 December 2016].

FDA (2016) Tysabri (Natalizumab) injection. Available from: http://www.fda.gov/safety/medwatch/safetyinformation/ucm355780.htm [Accessed 6 December 2016].

Nguyen DL, Flores S, Sassi K, Bechtold ML, Nguyen ET, et al. (2015) Optimizing the use of anti-tumor necrosis factor in the management of patients with Crohn’s disease. Therapeutic Advances in Chronic Disease, 6(3), 147–154.

NICE (2016) Crohn's disease: management. Clinical guideline. Available from: https://www.nice.org.uk/guidance/cg152/chapter/Recommendations [Accessed 5 December 2016].

Organisation for Economic Co-operation and Development (2008) Pharmaceutical pricing and reimbursement policies in Germany. Available from: https://www.oecd.org/germany/41586814.pdf [Accessed 5 December 2016].

Ruof J, Dintsios CM, Schwartz FW (2014) Questioning Patient Subgroups for Benefit Assessment: Challenging the German Gemeinsamer Bundesausschuss Approach. Value in Health, 17, 307–309.

Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-Ytter YT (2013) American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology, 145(6), 1459–63.

COMPLIANCE

Compliance is an issue that affects all stakeholders in the healthcare industry. Studies have found that approximately a third of inflammatory bowel disease patients are low adherers to medication, with younger age, medication cost, and low education levels considered some of the key risk factors for non-adherence (Cerveny et al., 2007; Ediger et al., 2007; D’Inca et al., 2008; Horne et al., 2009). A cross-sectional study of 1,871 members of the National Association for Colitis and Crohn's Disease conducted in 2008 found that reported adherence to medication differed significantly according to therapeutic modality. Participants in the study were taking aminosalicylates, corticosteroids, or immunosuppressants, and both intentional and unintentional non-adherence were reported by many participants (32% and 28% of physicians, respectively). Furthermore, increased doubts about personal need for maintenance therapy and increased concerns about the maintenance therapy regimen were found to be associated with non-adherence. Those taking steroid medication had the greatest concerns about their treatment and also reported the lowest adherence. Patients taking immunosuppressive medication reported the highest adherence rates (Horne et al., 2009).

As part of Datamonitor Healthcare’s 2016 primary research, gastroenterologists in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) were asked how compliant their Crohn’s disease patients, irrespective of severity, are with six different types of formulation: oral tablets, oral solutions, liquid therapies, rectal therapies, subcutaneous therapies, and intravenous therapies. For example, if, on average, patients take half of their prescribed weekly dose, this was defined as 50% compliance.

COMPLIANCE IS HIGHEST AMONG PATIENTS TAKING SYSTEMIC INTRAVENOUS MEDICATIONS

According to Datamonitor Healthcare’s 2016 survey data, the highest compliance is seen in patients who receive systemic intravenous medications (see figure below). Key opinion leaders note that drugs which are administered intravenously are more likely to ensure higher compliance rates since a healthcare professional in a clinic or hospital setting administers them. While self-injected products and oral therapies allow patients greater flexibility, their use is more reliant on patients’ discretion.

“When you have a patient you do not trust then you prefer Remicade [infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe] because then you see the patient every eight weeks, and you are assured that the patient gets the infusion. That is the big problem between Cimzia and Humira, you essentially do not know if the patient applied it on time or cheated, and if they fail, whether it is a failure of the drug or a failure of compliance.”

EU key opinion leader

Datamonitor Healthcare attributes the lower compliance rates for suppositories and enemas to the discomfort or inconvenience associated with these treatments.

Figure 65: Mean compliance rates for drug-treated Crohn’s disease patients, by formulation type

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Table 59: Compliance rates for Crohn’s disease patients, by formulation type and country (%)

Formulation US Japan France Germany Italy Spain UK

Oral (tablets) 77.4% 66.5% 68.4% 73.5% 73.1% 77.6% 68.2%

Oral 66.9% 61.2% 64.3% 73.2% 68.8% 75.8% 63.4% (solutions)

Liquid 40.7% 52.6% 51.9% 53.1% 47.0% 59.4% 44.5% (enemas, foam)

Rectal 47.6% 52.3% 49.0% 54.2% 54.4% 61.2% 43.5% (suppository)

Subcutaneou 77.2% 68.5% 76.7% 74.5% 76.3% 80.2% 73.8% s

Intravenous 80.7% 70.4% 83.2% 80.9% 75.4% 83.0% 75.4%

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

BIBLIOGRAPHY

Cerveny P, Bortlik M, Kubena A, Vlcek J, Lakatos PL, et al. (2007) Nonadherence in Inflammatory Bowel Disease: Results of Factor Analysis. Inflammatory Bowel Diseases, 13(10), 1244–1249.

Ediger JP, Walker JR, Graff L, Lix L, Clara I, et al. (2007) Predictors of Medication Adherence in Inflammatory Bowel Disease. The American Journal of Gastroenterology, 102(7), 1417–1426.

Horne R, Parham R, Driscoll R, Robinson A (2009) Patients' attitudes to medicines and adherence to maintenance treatment in inflammatory bowel disease. Inflammatory Bowel Diseases, 15(6), 837–44.

UNMET NEEDS IN CROHN’S DISEASE

Datamonitor Healthcare asked gastroenterologists across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) to indicate the relative importance of treatment challenges in Crohn’s disease by ranking six challenges on a scale of one to six, with one being the highest priority challenge and six being the lowest priority challenge. The results are summarized in the table below.

Table 60: Relative importance of treatment challenges in Crohn’s disease, by country

Challenge Mean US Japan France Germany Italy Spain UK

Effective agents for 1.98 1.63 1.97 1.97 1.82 2.14 2.19 2.18 maintaining remission without immunosuppression

An effective treatment for 2.83 2.83 3.06 2.94 2.95 2.57 2.65 2.82 fistulizing disease

Predicting response to 3.18 3.29 3.23 3.45 2.89 3.11 3.24 3.09 biologic therapy

An effective cost-saving non- 3.91 3.69 4.58 3.94 4.21 3.74 3.70 3.55 biologic

Better activity measures in 4.33 4.57 3.74 4.45 4.58 4.46 4.24 4.15 clinical trials

Drugs targeted for the mild 4.78 5.00 4.42 4.26 4.55 4.97 4.97 5.21 patient population

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Datamonitor Healthcare has analyzed the three most important challenges according to the surveyed gastroenterologists. These are summarized in the figure below.

Figure 66: Top treatment challenges in Crohn’s disease

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

THE DEVELOPMENT OF THERAPIES THAT ACHIEVE LONG-TERM REMISSION WITHOUT THE NEED FOR IMMUNOSUPPRESSION REMAINS THE MOST PROMINENT UNMET NEED IN CROHN’S DISEASE

Datamonitor Healthcare’s 2016 survey across the US, Japan, and five major EU markets indicates that significant unmet need remains for treatments that lead to sustained remission without needing to employ immunosuppressive medications. Clinical guidelines for Crohn’s disease state that immunomodulators are very effective at maintaining medically induced remission (Lichtenstein et al., 2009; Ueno et al., 2013; Gomollon et al., 2016). Studies have shown that azathioprine and mercaptopurine are superior to placebo at inducing and maintaining remission as well as reducing or eliminating steroid dependence while maintaining a steroid-free remission. However, immunomodulators are also associated with a higher rate of adverse events, including bone marrow suppression, and a series of allergic reactions such as fever, rash, and pancreatitis. Immunomodulators are also associated with an increased risk of infections, including viral infections such as cytomegalovirus (Pearson et al., 1995; Feldman et al., 2007). Datamonitor Healthcare believes that manufacturers able to demonstrate the induction and maintenance of remission without the negative immunosuppressive profile of current agents will be successful in the Crohn’s disease market.

EFFECTIVE THERAPIES ARE NEEDED FOR THE TREATMENT OF FISTULIZING CROHN’S DISEASE

Datamonitor Healthcare’s 2016 survey across the US, Japan, and five major EU markets indicates that there is a need for effective therapies to treat fistulizing Crohn’s disease. Population-based studies have found that up to 50% of Crohn’s disease patients are affected by fistulas, with perianal fistulas being the most common. Perianal fistulas cause significant impairment in patients’ quality of

life and are a potential source of sepsis (Gecse et al., 2013; Hellers et al., 1980). Current treatment involves a combined surgical and pharmacological approach. First-line pharmacological treatment is usually antibiotics, with a step up to immunosuppressants such as azathioprine or 6-mercaptopurine, and then tumor necrosis factor (TNF) inhibitors (either Remicade [infliximab; Johnson & Johnson/Merck & Co/Mitsubishi Tanabe] or its biosimilar versions) in patients who do not respond adequately to their previous treatments (Marzo et al., 2015). Leading gastroenterologists stress there remains significant need for effective therapies suitable for patients with perianal fistulas that are refractory to existing treatments.

“…Fistulas are very distressing, they cause a lot of pain and can often turn into abscesses. Bad fistulizing perianal Crohn’s disease is one of the reasons why patients have to have proctectomy or have their rectum removed. Patients can often deal with the stool frequency and the urgency, but it is the fistula pain and the abscesses that are very bothersome and that might drive them to have their rectum removed. Having your rectum removed means you will have a permanent ostomy. So a therapy that can heal the fistulas could theoretically prevent these patients from having a really big, life-changing surgery...”

US key opinion leader

The late-phase stem cell therapy Cx601 (TiGenix/Takeda) has the potential to address a high burden in the treatment of perianal fistulizing Crohn’s disease. Key opinion leaders note that while Cx601’s efficacy to date has been modest, patients with complex perianal fistulas who are refractory to existing therapies will appreciate having another treatment option that could potentially help them avoid surgery.

“Looking at the one-year trial data that were presented at ECCO [European Crohn’s and Colitis Organisation], combined remission at week 52 was 56% for Cx601 versus 39% for placebo, so it is not as big of a delta as I would like, but it is still a delta. Cx601 is going to be modestly effective. It is not a SONIC-type result. Like I said, the patients who are in that niche are going to appreciate having the possibility of trying this [Cx601], but this is definitely not going to take over the market.”

US key opinion leader

SIGNIFICANT UNMET NEED EXISTS FOR TESTS TO PREDICT PATIENTS' RESPONSE TO BIOLOGIC THERAPIES

Datamonitor Healthcare’s 2016 survey reveals that significant unmet need remains for tests to predict patients’ response to biologic therapies. Although the biologics available for Crohn’s disease have demonstrated strong efficacy, a significant proportion of patients either do not respond adequately to the available agents (13–40%), or they respond initially and then lose response over time (5–46%) (Ding et al., 2016). Studies have found that the expression profiles of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) predict response to infliximab treatment (Medrano et al., 2015; Arijs et al., 2010). In addition, it has been reported that carriers of the single-nucleotide polymorphism ABCB1 G2677T/A have a lower chance of responding to biologics, although this has to be replicated in future pharmacogenomics studies (Cravo et al., 2014). Ding et al. suggest that therapeutic drug monitoring – using anti-TNF and anti-drug antibody levels – can be used to determine the underlying mechanism of treatment failure or loss of response, and can therefore guide physicians in terms of choosing the most appropriate therapeutic approach. Eder et al. (2015) suggest that imaging techniques such as magnetic resonance enterography could also be used to predict patient response to anti-TNF treatment. Datamonitor Healthcare believes that the standardization of these tests and their successful incorporation into the Crohn’s disease treatment algorithm will significantly improve patient outcomes.

BIBLIOGRAPHY

Arijs I, Quintens R, Van Lommel L, Van Steen K, De Hertogh G, et al. (2010) Predictive value of epithelial gene expression profiles for

response to infliximab in Crohn's disease. Inflammatory Bowel Diseases, 16(12), 2090–2098.

Cravo M, Ferreira P, Sousa P, Moura-Santos P, Velho S, et al. (2014) Clinical and genetic factors predicting response to therapy in patients with Crohn’s disease. United European Gastroenterology Journal, 2(1), 47–56.

Ding NS, Hart A, De Cruz P (2016) Systematic review: predicting and optimising response to anti-TNF therapy in Crohn’s disease – algorithm for practical management. Alimentary Pharmacology & Therapeutics, 43(1), 30–51.

Eder P, Michalak M, Katulska K, Lykowska-Szuber L, Krela-Kazmierczak I, et al. (2015) Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn's disease treated with anti-tumor necrosis factor antibodies. Scientifics Reports, 5, 10223, 1–13.

Feldman PA, Wolfson D, Barkin JS (2007) Medical Management of Crohn's Disease. Clinics in Colon and Rectal Surgery, 20(4), 269–281.

Gecse K, Khanna R, Stoker J, Jenkins JT, Gabe S (2013) Fistulizing Crohn’s disease: Diagnosis and management. United European Gastroenterology Journal, 1(3), 206–213.

Hellers G, Bergstrand O, Ewerth S, Holmström B (1980) Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease. Gut, 21(6), 525–527.

Marzo M, Felice C, Pugliese D, Andrisani G, Mocci G, et al. (2015) Management of perianal fistulas in Crohn's disease: An up-to-date review. World Journal of Gastroenterology, 21(5), 1394–403.

Medrano LM, Taxonera C, Gonzalez-Artacho C, Pascual V, Gomez-Garcia M, et al. (2015) Response to Infliximab in Crohn’s Disease: Genetic Analysis Supporting Expression Profile. Mediators of Inflammation, 318207, 1–8.

Pearson DC, May GR, Fick GH, Sutherland LR (1995) Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Annals of Internal Medicine, 123(2), 132–42.

PRESCRIBING INFLUENCES

Datamonitor Healthcare asked gastroenterologists across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) to indicate the relative importance of 10 factors that influence their prescribing decisions for Crohn’s disease patients. Gastroenterologists were asked to consider prescribing influences for biologics and aminosalicylates. The points had to sum to a total of 100, with more points signifying greater importance. The results are summarized in the table below.

Table 61: Relative importance of factors that influence gastroenterologists’ prescription of biologics and aminosalicylates in Crohn’s disease, by country

Weighted mean US Japan France Germany Italy Spain UK

Biologics

Symptomatic 20.07 21.11 24.61 26.55 19.58 15.60 14.97 20.03 improvement

Promoting mucosal 18.74 16.40 16.75 20.16 18.08 23.37 18.84 17.22 healing

Speed of onset of 14.53 14.17 13.75 13.26 12.69 18.37 16.05 12.91 remission

Side-effect profile 10.87 10.34 8.21 11.10 10.78 12.49 10.73 12.06

Patient tolerability 10.03 12.09 8.64 9.16 11.69 7.94 9.38 11.03

Drug delivery 6.57 7.74 7.36 6.39 6.11 5.77 6.95 5.75 method (eg oral, enema, injection type)

Dosing frequency 5.99 7.17 6.07 6.23 3.64 5.54 7.92 5.31

Cost (formulary or 5.67 7.29 6.61 2.29 9.00 3.77 4.35 6.19 reimbursement status)

Time on the 4.76 2.63 4.29 3.81 4.56 4.11 6.27 7.59 market/familiarity with product

Marketing company 2.77 1.06 3.71 1.06 3.86 3.03 4.54 1.91

Aminosalicylates

Symptomatic 17.82 21.28 20.10 21.09 18.33 14.10 15.26 16.10 improvement

Promoting mucosal 13.10 15.16 12.35 11.50 12.27 13.45 15.77 11.10 healing

Table 61: Relative importance of factors that influence gastroenterologists’ prescription of biologics and aminosalicylates in Crohn’s disease, by country

Side-effect profile 12.40 10.44 11.65 14.68 12.76 12.55 11.29 13.73

Patient tolerability 12.13 13.80 12.77 10.82 10.67 14.87 9.68 12.37

Speed of onset of 11.84 11.72 13.52 9.59 10.91 12.81 13.26 10.43 remission

Drug delivery 9.91 8.08 8.84 14.18 11.30 10.16 7.90 9.70 method (eg oral, enema, injection type)

Cost (formulary or 7.40 8.68 5.81 3.73 6.76 7.61 9.03 9.50 reimbursement status)

Dosing frequency 6.91 6.00 7.42 6.18 6.00 5.55 9.06 7.83

Time on the 6.08 3.44 4.35 6.14 7.82 7.06 5.77 7.43 market/familiarity with product

Marketing company 2.40 1.40 3.19 2.09 3.18 1.84 2.97 1.80

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

On average, the factor with the highest influence on the prescribing of biologics and aminosalicylates across the US, Japan, and five major EU markets is symptomatic improvement. This is not surprising as the main goal of treatment is to induce and maintain remission of symptoms (Lichtenstein et al., 2009; Ueno et al., 2013; Gomollon et al., 2016). The second most important factor in the surveyed markets is mucosal healing. Indeed, US guidelines indicate that the induction and maintenance of mucosal healing is considered a relatively newer goal of therapy in Crohn’s disease (Lichtenstein et al., 2009). Factors such as administration route, dosing frequency, and cost are clearly identified by gastroenterologists as being far less important than symptomatic improvement and promoting mucosal healing. This was also highlighted during discussions with key opinion leaders.

“I think [the mode of administration] does not really matter, let us say we have a super-effective drug which works in 70% of the patients and it is infused every four weeks, everybody will go for that, so it does not matter. However, if you have similar efficacy then the mode of administration becomes important, and the cost and co-pays become important.”

US key opinion leader

“[Price] is not important, it does not limit us, no. Of course, again if two treatments can be compared with all the other points, and just differ on price, we can consider the price, and when I say ‘we’ of course first of all social security is considering the price, authorizing or not this new

drug to be introduced in the country. So, that is the goal of the agencies, but for my daily practice the price is not a dramatic problem at all.”

EU key opinion leader

In order to promote strong uptake of future products that are launched onto the market for the treatment of Crohn’s disease, the focus of developers should be on efficacy, with other factors being accounted for only after efficacy has been firmly demonstrated.

BIBLIOGRAPHY

IMPACT OF BIOSIMILARS

In order to gauge potential changes in the treatment algorithm for Crohn’s disease, Datamonitor Healthcare asked gastroenterologists to consider the future uptake of biosimilars.

Respondents who had indicated that they were using biosimilar infliximab at the time of the survey were asked to identify the types of patients to whom they first prescribed biosimilar infliximab. Similarly, respondents who were not using biosimilar infliximab when the survey was conducted were asked to indicate the type of patients they were intending to prescribe biosimilar infliximab to, once it became available to them. Gastroenterologists were also asked to consider and provide estimates for the percentage of Crohn’s disease patients who would be expected to receive regimens containing biosimilars in comparison to currently approved biologic regimens, either as a monotherapy or as part of a combination regimen, one and three years after the launch of biosimilars. Respondents were asked to provide these estimates in three separate scenarios, which were treatment-naïve patients, patients who would be switched from a branded biologic to its biosimilar version, and patients who would be switched from a branded biologic to a biosimilar of a different reference brand.

GASTROENTEROLOGISTS PRESCRIBE AND EXPECT TO PRESCRIBE BIOSIMILAR INFLIXIMAB PRIMARILY TO BIOLOGIC TREATMENT-NAÏVE PATIENTS

Datamonitor Healthcare’s 2016 survey reveals that when gastroenterologists in Japan and the five major EU markets (France, Germany, Italy, Spain, and the UK) started to prescribe biosimilar infliximab, they primarily prescribed it to biologic treatment-naïve patients. Similarly, gastroenterologists who were not prescribing biosimilar infliximab at the time of the survey (April 2016) indicated that, once it becomes available to them, they will primarily prescribe it to biologic treatment-naïve patients. This trend is in line with the European Crohn’s and Colitis Organisation’s (ECCO’s) initial cautious approach towards the use of biosimilars in the treatment of inflammatory bowel disease (IBD). In its 2013 position statement, ECCO noted that biosimilars should be specifically tested in IBD patients, and their efficacy and safety should be compared to the associated originator product. Switching from the reference brand to its biosimilar version was generally not recommended, and it was noted that any decision to substitute a product should be made on an individual basis with the prescribing healthcare provider’s specific approval and patient’s knowledge (Danese and Gomollon, 2013).

Datamonitor Healthcare believes that the increasing availability of data supporting the biosimilarity of biosimilar infliximab and Remicade will mean that patients receiving the reference product will be switched more readily to the biosimilar in the coming years. For example, results from the NOR-SWITCH study showed that there were no differences in terms of clinical response, maintenance of remission, or adverse events in patients with autoimmune diseases, including IBD, receiving CT-P13 (biosimilar infliximab) compared with those receiving originator infliximab. Indeed, the NOR-SWITCH data, alongside robust data from other studies and a deeper understanding of the process of biosimilar development and regulatory approval, led to a change in ECCO’s position statement regarding biosimilar use in IBD. In December 2016, ECCO indicated that data for the usage of biosimilars in IBD can be extrapolated from another sensitive indication, and that switching from the originator to a biosimilar in patients with IBD is acceptable (Danese et al., 2017).

Table 62: Initial usage of biosimilar infliximab, according to respondents using biosimilar infliximab at the time of the survey, by country (%)

Initial usage Japan France Germany Italy Spain UK

Respondents 57.1% 15.0% 41.7% 36.0% 40.9% 69.6% who switched patients from branded Remicade to the biosimilar

Respondents 42.9% 5.0% 41.7% 20.0% 9.1% 26.1% who switched patients from other branded biologics to biosimilar infliximab

Respondents 28.6% 90.0% 87.5% 84.0% 68.2% 56.5% who prescribed biosimilar infliximab to biologic treatment-naïve patients

Note: columns sum to over 100% as respondents were allowed to choose multiple responses; since biosimilar infliximab was not available in the US when Datamonitor Healthcare’s survey was conducted in April 2016, US respondents were not asked to provide estimates for the use of biosimilar infliximab.

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

Table 63: Expected usage of biosimilar infliximab, according to respondents who did not prescribe biosimilar infliximab at the time of the survey, by country (%)

Expected US Japan France Germany Italy Spain UK usage

Respondents 60.0% 41.7% 18.2% 21.4% 30.0% 26.7% 40.0% who will switch patients from branded Remicade to the biosimilar

Respondents 25.7% 12.5% 9.1% 7.1% 10.0% 20.0% 20.0% who will switch patients from other branded biologics to biosimilar infliximab

Respondents 60.0% 25.0% 63.6% 64.3% 40.0% 26.7% 40.0% who will prescribe biosimilar infliximab to biologic treatment- naïve patients

Respondents 17.1% 37.5% 18.2% 28.6% 50.0% 46.7% 20.0% who will not use biosimilar infliximab in any patient group

Note: columns sum to over 100% as respondents were allowed to choose multiple responses.

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

USE OF BIOSIMILARS IS EXPECTED TO INCREASE IN ALL PATIENT SUBPOPULATIONS, DRIVEN BY LOWER COSTS AND INCREASING AVAILABILITY OF LONG-TERM SAFETY DATA

On average, respondents from the US, Japan, and five major EU markets expect the use of biosimilars to increase from one year to three years post-launch in subpopulations including biologic treatment-naïve patients, patients who would be switched from a branded biologic to its biosimilar version, and patients who would be switched from a branded biologic to a biosimilar of a different reference brand. Datamonitor Healthcare anticipates that this rise in use will be driven by the increasing availability of low-cost anti- tumor necrosis factor biosimilars and the associated long-term safety data. ECCO’s new positive view on switching from reference infliximab to biosimilar infliximab is also likely to drive biosimilar use.

The figure below shows the average percentage of respondents across the US, Japan, and five major EU markets who expect to switch patients from a branded biologic to its biosimilar version (A), to switch patients from a branded biologic to a biosimilar of a different reference brand (B), and to prescribe any available biosimilar to biologic treatment-naïve patients (C) at both one year and three years after the launch of the biosimilar drug.

Figure 67: Summary of future usage of biosimilar infliximab at one year and three years post-launch

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

RESPONDENTS ARE LESS LIKELY TO PRESCRIBE A BIOSIMILAR APPROVED ONLY ON THE BASIS OF INDICATION EXTRAPOLATION

Datamonitor Healthcare’s 2016 survey reveals that a large number of gastroenterologists in the US, Japan, and five major EU markets are less likely to prescribe a biosimilar that is approved only on the basis of indication extrapolation. This caution among surveyed physicians is unsurprising, particularly in light of ECCO’s 2013 position statement, which highlighted that the clinical efficacy of biosimilars in IBD cannot be predicted by effectiveness in other indications such as rheumatoid arthritis, and that specific trials in IBD patients are needed. In addition, regulators including the US Food and Drug Administration and European Medicines Agency require biosimilars to demonstrate proof of similar efficacy to the branded biologic but not de novo efficacy (Feagan et al., 2014). Biosimilarity

is indicated primarily through preclinical analytical, structural, and functional data and toxicology, and confirmed with a randomized controlled trial only carried out in one indication, with the safety and efficacy data used to support indication extrapolation to other conditions (Dörner et al., 2016).

Datamonitor Healthcare believes the increasing availability of real-world data on biosimilars and ongoing pharmacovigilance will help to alleviate concerns associated with indication extrapolation. In addition, ECCO’s 2016 position statement on the use of biosimilars, indicating that clinical studies of equivalence in the most sensitive indication can provide the basis for extrapolation, will mean that gastroenterologists will more readily prescribe a biosimilar approved on the basis of indication extrapolation in the near future (Danese et al., 2017).

The figure below indicates the percentage of respondents comfortable with prescribing biosimilars that have been approved on the basis of indication extrapolation.

Figure 68: Physician confidence in prescribing biosimilars for Crohn’s disease approved on the basis of indication extrapolation, by country

Source: Datamonitor Healthcare's proprietary Crohn’s disease survey, April 2016

BIBLIOGRAPHY

Danese S, Fiorino G, Raine T, Ferrante M, Kemp K, et al. (2017) ECCO Position Statement on the Use of Biosimilars for Inflammatory Bowel Disease—An Update. Journal of Crohn's and Colitis, 11(1), 26–34.

Danese S, Gomollon F (2013) ECCO position statement: the use of biosimilar medicines in the treatment of inflammatory bowel disease [IBD]. Journal of Crohn’s and Colitis, 7(7), 586–589.

Dörner T, Strand V, Cornes P, Gonçalves J, Gulácsi L, et al. (2016) The changing landscape of biosimilars in rheumatology. Annals of the Rheumatic Diseases, 75(6), 974–82.

Feagan BG, Choquette D, Ghosh S, Gladmann DD, Ho V, et al. (2014) The challenge of indication extrapolation for infliximab biosimilars. Biologicals, 42(4), 177–83.

EPIDEMIOLOGY: CROHN’S DISEASE

OVERVIEW

Description This epidemiologic analysis uses robust, country-specific data sources to estimate and forecast Crohn’s disease (CD) prevalence in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) between 2017 and 2037.

The accompanying epidemiology datapack includes forecasted diagnosed prevalent cases for 2017–37 split by age, gender, and disease severity, and proprietary physician research survey data on treatment trends, including managed and drug-treated prevalent cases.

Disease CD involves inflammation of the gastrointestinal (GI) tract and most commonly affects the terminal ileum or background colon. Because CD can occur in various areas of the GI tract, disease activity and severity can vary widely over time, and the symptoms of CD range from mild to severe and depend on the location in the GI tract at which the disease is active. CD is a chronic, incurable disease with low mortality that is generally diagnosed in adolescence and early adulthood.

CD is currently an idiopathic condition, the pathogenesis of which is yet to be fully elucidated. However, it is known to involve an interaction between genetics, the immune system, and environmental factors. Risk factors include ethnicity, smoking, family history, antibiotic or non-steroidal anti-inflammatory agent use, and diet. Incidence and prevalence have been increasing over the past two decades in most regions of the world.

Forecast Datamonitor Healthcare estimates that in 2017, there were 2.5 million diagnosed prevalent cases of CD in highlights the US, Japan, and five major EU markets. By 2037, Datamonitor Healthcare forecasts that the number of diagnosed prevalent cases of CD in the US, Japan, and five major EU markets will increase to 2.8 million.

Note: Datamonitor Healthcare used a newer data source published by the Centers for Disease Control and Prevention as the basis for forecasting diagnosed prevalent cases of CD in the US. This nationally representative large cross-sectional survey has resulted in a substantially higher number of prevalent CD cases compared with Datamonitor Healthcare’s previous analysis.

Across all analyzed countries, the largest proportion of diagnosed cases were classified as mild severity in 2017 (39.6%), although a substantial percentage were severe (21.2%).

Overall, Datamonitor Healthcare expects CD prevalence to increase over the forecast period, although the magnitude of growth will vary by market. A major driver of this expected increase in diagnosed prevalent cases is an increasing trend in CD prevalence proportions over time, which was incorporated into the forecast. Another important factor is the phenomenon of compounding prevalence; a large rise in prevalence due to cumulative addition of incident cases in a chronic disease such as CD that has a young age of onset and low mortality. Also, a cure for CD remains elusive, and even with pharmacological or surgical treatment, relapse is common.

Methodology Proprietary epidemiologic forecasting methodology using robust, population-based studies from the US, Japan, and five major EU markets, in addition to proprietary physician research survey data.

DISEASE BACKGROUND

INFLAMMATORY BOWEL DISEASE IS A TERM USED TO DESCRIBE DISORDERS THAT INVOLVE INFLAMMATION OF THE GASTROINTESTINAL TRACT

Inflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of all or part of the gastrointestinal (GI) tract, which results from a combination of genetic predisposition, environmental factors, and abnormal immune responses to GI microbiota and luminal antigens. IBD represents a heterogeneous group of diseases with similar phenotypes but different etiologies that affect an estimated 1.5 million Americans, 2.2 million people in Europe, and several hundreds of thousands more worldwide (Duricova et al., 2014; Molodecky et al., 2012). The condition comprises a significant burden to the patient, including that of therapy, hospitalizations, and surgery, as well as impaired quality of life, economic productivity, and social functioning (Ananthakrishnan, 2015; Burisch et al., 2013). As a whole, the incidence and prevalence of IBD are highest in developed countries, including Canada, Northern Europe, and Australia (Molodecky et al., 2012).

INFLAMMATORY BOWEL DISEASE MAINLY ENCOMPASSES ULCERATIVE COLITIS AND CROHN'S DISEASE

The term IBD is mainly used to describe two conditions, ulcerative colitis (UC) and Crohn's disease (CD). Both UC and CD are chronic conditions that involve inflammation of the GI tract, although patients may experience periodic episodes of remission and relapse. The major difference between the two conditions is the area of the GI tract affected; UC affects the colon only, while CD can affect all of the digestive system, from the mouth to the anus.

THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE REMAINS TO BE DETERMINED, ALTHOUGH GENETIC AND ENVIRONMENTAL FACTORS PLAY A ROLE

Patients with IBD often have a genetic predisposition to the development of such diseases; however, this predisposition in isolation does not appear sufficient for the onset of inflammation (Ng et al., 2013). Rather, there appears to be a complex interplay between genetic and environmental risk factors in IBD development; for example, genetic risk factors do not act in isolation but in synergy with the external environment as well as the internal “environment,” namely the gut microbiota and luminal antigens (Ananthakrishnan, 2015). Risk factors for IBD include family history and disruption or changes to intestinal microbiota. The external environment is a strong determinant of the gut microbiota. Indeed, it has been demonstrated that larger family size, early life exposure to pets and farm animals, and a greater number of siblings increase the risk of IBD, whereas breastfeeding has a protective effect. All these early life parameters are known to be important determinants of the gut microbiota in adults, lending plausibility to the role of the gut microbiota in disease pathogenesis. This difference in microbial diversity is greater for CD than UC, the latter of which more closely resembles the microbiota of healthy individuals (Ananthakrishnan, 2015). Also pointing to the important role of the environment in disease development is the emergence of IBD in areas that traditionally experienced very low prevalence, such as Asia, and the increased prevalence in urban rather than rural areas (Molodecky et al., 2012). Other proposed environmental triggers are listed in the table below.

Table 64: Inflammatory bowel disease risk factors

Risk factor Risk profile/further information

Smoking Increases risk of CD Protective effect against UC

Antibiotic exposure Increases IBD risk

Oral contraceptive use Increases IBD risk

Non-steroidal anti-inflammatory agents Increases IBD risk

Decreased vitamin D levels Increases IBD risk

Appendectomy in children Increases risk of CD Protective effect against UC

Diet More research is needed to better understand how diet may impact IBD, but high carbohydrate and fat and low fiber diets and are believed to increase risk

Age Although CD and UC can occur at any age, people are more frequently diagnosed in early adulthood

Geographic distribution IBD is found mainly in developed countries, more commonly in urban areas, and more often in northern climates. However, some of these disease patterns are gradually shifting, and incidence is increasing in developing countries

CD = Crohn’s disease; IBD = inflammatory bowel disease; UC = ulcerative colitis

Source: Cosnes et al., 2011; Crohn’s & Colitis Foundation of America, 2011; El-Tawil, 2013; Frolkis et al., 2013; Ponder and Long, 2013

IBD has also been associated with certain personality types, including neuroticism, obsessive-compulsive behavior, dependency, and perfectionism, as well as psychosocial stressors (Bernstein et al., 2010; Ponder and Long, 2013).

COMPOUNDING PREVALENCE IS A PHENOMENON THAT CONTINUES TO ADD TO THE INFLAMMATORY BOWEL DISEASE CASE POOL

IBD is a chronic, incurable disease with low mortality that is generally diagnosed in adolescence and early adulthood. Therefore, combined with worldwide increasing life expectancy, newly diagnosed patients with IBD further expand the number of prevalent cases year-on-year. This phenomenon may be referred to as compounding prevalence; an exponential rise in prevalence due to cumulative addition of incident cases in a chronic disease that has a young age of onset and low mortality. The prevalence of IBD is, therefore, expected to steadily climb over the next decade in the Western world (Kaplan, 2015; Loftus, 2004). Overall, the incidence and prevalence of IBD has been shown to be increasing worldwide, especially in developing countries, and there have also been

reports of an increasing trend in early-onset IBD (Benchimol et al., 2011; Burisch et al., 2013; Cosnes et al., 2011; Molodecky et al., 2012). In North America and Western Europe, there are reports that the incidence of UC has plateaued over recent years, and may even be decreasing. The same cannot be said, however, for the prevalence (Da Silva et al., 2014).

See Datamonitor Healthcare’s Epidemiology: Ulcerative Colitis for comprehensive coverage of the epidemiology of UC. Collagenous colitis and lymphocytic colitis are other, less common types of IBD. These rarer conditions are not covered in the aforementioned analysis.

CROHN'S DISEASE IS A TYPE OF INFLAMMATORY BOWEL DISEASE THAT MAY AFFECT ANY PART OF THE GASTROINTESTINAL TRACT

CD involves inflammation of any part of the GI tract, although the most common area affected is the terminal ileum or colon. In CD, inflammation may extend through the entire thickness of the bowel wall of the affected area. Because CD can occur in various areas of the GI tract, disease activity and severity can vary widely over time. Symptoms may include abdominal pain and diarrhea, tiredness and fatigue, general malaise or fever, mouth ulcers, loss of appetite and weight loss, and anemia (Cosnes et al., 2011).

THE CLINICAL PRESENTATION AND OBSERVED PHENOTYPE OF CROHN’S DISEASE VARIES BY AGE

Patients with CD are usually diagnosed in their 20s and 30s; however, diagnosis can be made at any age. The average age of diagnosis for patients with CD is generally 5–10 years earlier than in patients with UC. The clinical presentation and observed phenotype of CD differ according to age, with younger-onset patients often experiencing more severe disease course and more frequent extension of disease within the GI tract compared with adult and elderly age groups (Duricova et al., 2014). CD phenotype is defined using the Montreal classification, which classifies CD patients based on age at diagnosis, location in the bowel, and behavior (stricturing and penetrating). This classification is shown in the table below.

Table 65: Montreal classification of Crohn’s disease

Montreal classification Sub-categories

Age at diagnosis A1; 16 years or under A2; 17–40 years A3; over 40 years

Location L1; ileal L2; colonic L3; ileocolonic L4; isolated upper disease*

Behavior B1; non-stricturing, non-penetrating B2; stricturing B3; penetrating

*L4 is a modifier that can be added to L1–3 when concomitant upper gastrointestinal disease is present.

Source: Satsangi et al., 2006; Silverberg et al., 2005

CROHN’S DISEASE IS CURRENTLY AN IDIOPATHIC CONDITION, WITH INCREASED MORTALITY RELATIVE TO THE GENERAL POPULATION

The pathogenesis of Crohn’s disease is yet to be fully elucidated. However, CD is known to involve an interaction between genetics, the immune system, and environmental factors, as indicated above. One genetic variant has been studied in detail; the nucleotide- binding oligomerization domain-containing protein 2 (NOD2) polymorphism, which shows strong associations with CD (Philpott et al., 2013). Among CD patients, evidence shows overall mortality is slightly but significantly higher than in the general population, which is primarily explained by deaths from GI, respiratory, and genitourinary diseases (Duricova et al., 2010). Mortality is up to 40% higher in European patients with CD as compared to the general population (Burisch et al., 2013; Card et al., 2003; Loftus, 2006).

METHODOLOGY

Datamonitor Healthcare undertook market-specific literature reviews in order to provide a robust analysis of the diagnosed prevalent Crohn’s disease (CD) population in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). A variety of secondary data sources were identified, including literature reviews and epidemiological study reports, before quality appraisal, forming a robust foundation on which to model and forecast the patient population. Sources were evaluated for inclusion based on their epidemiological quality, including study settings, demographic sample profiles, sampling procedures and sample size, and potential sources of bias. Prevalence proportions were extracted, by age and gender where available, for diagnosed CD.

This analysis covers individuals of all ages, as CD can be diagnosed and prevalent at any age (Cosnes et al., 2011).

DISEASE DEFINITION

There is no universal standard approach to CD diagnosis. Instead, diagnosis is based on a combination of endoscopic, histological, radiological, and/or biochemical investigations. For the purpose of this forecast, diagnosed CD cases were defined as follows:

• International Classification of Diseases (ICD)-10 code K50.x.

• ICD-9 code 555.x.

• Cases identified using the diagnostic criteria set out by Lennard-Jones (1989) and recommended for use within the second European evidence-based consensus on the diagnosis and management of Crohn's disease (Van Assche et al., 2010). These criteria are also consistent with recommendations of the American College of Gastroenterology (American College of Gastroenterology, 2009). Diagnosis is confirmed by clinical evaluation and a combination of endoscopic, histological, radiological, and/or biochemical investigations (Lennard-Jones, 1989; Van Assche et al., 2010).

• For populations using a health insurance provider as the sampling frame; individuals with at least one claim for CD who also had at least one pharmacy claim for an IBD-specific medication (University of Minnesota IBD Epidemiology Database definition; validated by Bernstein et al. [1999]).

• Excluding CD diagnosed purely on the basis of genetic mutations. Currently, the measurement of genetic mutations in patients with CD remains a research tool that is not yet proven to be of clinical benefit for the general assessment of diagnosis, guidance of patient care, or prediction of response to specific medical therapies (Lichtenstein et al., 2018).

• For studies where the specific diagnosis method was not described, primary or secondary care data describing a specific CD diagnosis were accepted.

Details of sources and methodologies used are provided in the tables below.

DATA SOURCES

The below table details the sources used to estimate CD prevalence in the US, Japan, and five major EU markets.

Table 66: Sources used for Crohn’s disease analysis in the US, Japan, and five major EU markets

Country Time period Method of data Region Sample size Case ascertainment Source(s) collection method

US 2015 The National Health Nationwide 33,672 Respondents were Dahlhamer et al., 2016; Interview Survey, a identified as having a Kappelman et al., 2013 nationally representative diagnosis of CD if they cross-sectional survey of responded affirmatively the civilian, to the question, “Have noninstitutionalized you ever been told by a population doctor or other health professional that you had Crohn’s disease?” Disease Coverage | Epidemiology: Crohn’s Disease 278

Table 66: Sources used for Crohn’s disease analysis in the US, Japan, and five major EU markets

Japan 2010–15 Japanese intractable Nationwide Unknown (total CD cases Patients are diagnosed as Asakura et al., 2009; disease register; a registered in 2015 = being CD cases based on MHLW, 2010; 2011; 2012; nationwide registration 41,279; 2014 = 40,885; the diagnostic criteria 2013; 2014; 2016; Yao et system of patients with 2013 = 38,271; 2012 = suggested by the IBD al., 2000 “intractable” diseases. 36,418; 2011 = 34,721; research committee Patients with such 2010 = 31,652) reported in 1995. diseases, including CD, For a definite CD are required to submit a diagnosis, one of the registration application following three conditions form annually, and each is required: 1) longitudinal patient’s attending doctor ulcer or luminal deformity must also supply detailed induced by longitudinal information about the ulcer or cobblestone patient’s condition on the pattern, 2) intestinal small form. The submitted aphthous ulcerations forms are evaluated by arranged in a longitudinal specialists on each fashion for at least three prefecture’s Committee months plus on Measures for noncaseating Intractable Diseases, and granulomas, or 3) those patients who pass multiple small aphthous this screening become ulcerations in both the eligible for financial aid upper and lower digestive for their treatment tract not necessarily with longitudinal arrangement, for at least three months, plus noncaseating granulomas Disease Coverage | Epidemiology: Crohn’s Disease 279

Table 66: Sources used for Crohn’s disease analysis in the US, Japan, and five major EU markets

Germany/France* 2010 Claims database from a Hesse 265,102 Cases were defined Hein et al., 2014 large German SHI fund based on ICD-10 code (AOK) located in the (k50) through inspection federal state of Hesse of hospital inpatient and and covering discharge notes, or approximately 37% of all diagnosis code at death members of the SHI system in Germany. A random sample of 18.75% of AOK members was analyzed

Italy 2009 Population-based cross- Lazio Approximately 5.6 million Cases were extracted Di Domenicantonio et al., sectional study based on from the disease-specific 2014 hospital discharge or co- payment exemptions payment exemptions register and hospital data, obtained from the information system. A Lazio region health hospital discharge with an administrative databases, ICD-9 diagnosis code of which provide universal 555.xx as the principal or health insurance for secondary diagnosis or residents the activation of co- payment exemption for CD (code 900.555) were used as the case definition criteria Disease Coverage | Epidemiology: Crohn’s Disease 280

Table 66: Sources used for Crohn’s disease analysis in the US, Japan, and five major EU markets

Spain 2000–12 Retrospective, Ciudad Real province 514,368 Cases were defined Lennard-Jones, 1989; multicenter study carried based on standard Lucendo et al., 2014; Van out within the Ciudad clinical, endoscopic, Assche et al., 2010 Real province IBD working histological, and group, which represents radiological criteria and all the adult IBD units in extracted from hospital the region. The data recruitment area for this study included five public hospitals located in the Ciudad Real province, central Spain

UK 2002 Cross-sectional study of Central England 86,801 Practices identified all Stone et al., 2003 data extracted by 15 patients with a diagnosis general practices in of CD confirmed by central England recruited colonoscopy, through the Trent Focus sigmoidoscopy, radiology, Collaborative Research or surgery, including any Network in remission but not any who had had an isolated episode of colitis specifically described as acute or self-limiting

*No high-quality source describing the prevalence of CD in France was available, therefore data from Germany were used.

CD = Crohn’s disease; IBD = inflammatory bowel disease; ICD = International Classification of Diseases; MHLW = Japanese Ministry of Health, Labour and Welfare; SHI = statutory health insurance Disease Coverage | Epidemiology: Crohn’s Disease 281

Table 66: Sources used for Crohn’s disease analysis in the US, Japan, and five major EU markets

Source: various (see above) Disease Coverage | Epidemiology: Crohn’s Disease 282

DATA ASSUMPTIONS AND APPROACH TO TRENDING

The below table details the data and trend assumptions applied for the US, Japan, and five major EU markets.

Table 67: Crohn’s disease data processing methods in the US, Japan, and five major EU markets

Market Data source Demographic segmentations Trend assumptions* Other assumptions Source(s) available from main data source

US National Health Interview Age group (18–24, 25–44, None; insufficient trend data Prevalence in children aged under 15 Dahlhamer et al., 2016; Survey 45–64, 65+ years) and gender available years was estimated using ratios Kappelman et al., 2013 calculated from an older source describing prevalence by age in a commercially insured US population, applied to the National Health Interview Survey age-specific estimates

Japan Japanese intractable disease Gender Gender-specific logarithmic trend Applied age segmentation from an Asakura et al., 2009; MHLW, register generated from six data points older, more detailed analysis of the 2010; 2011; 2012; 2013; 2014; (2010, 2011, 2012, 2013, 2014, same patient register (Asakura et al., 2016; Research Group for 2015) 2009). Intractable Inflammatory Applied ratio describing the proportion Bowel Disease, 2006 of IBD cases not captured by the intractable disease registry (Asakura et al., 2009).

Germany/France Claims database from a large Age group (0–9, 10–19, 20–29, Gender-specific logarithmic trend None Hein et al., 2014 German SHI fund (AOK) 30–39, 40–49, 50–59, 60–69, generated from 10 data points located in the federal state of 70–79, 80+ years) and gender (2001–10) Hesse Disease Coverage | Epidemiology: Crohn’s Disease 284

Table 67: Crohn’s disease data processing methods in the US, Japan, and five major EU markets

Italy Population-based cross- Age group (0–9, 10–19, 20–29, No trend data were available. Age distribution was re-calculated using Di Domenicantonio et al., sectional study from Lazio 30–39, 40–49, 50–59, 60–69, Identical prevalence trend crude total prevalence 2014; Lucendo et al., 2014 region health administrative 70–79, 80+ years) and gender assumed to that derived from databases, central Italy Spain

Spain Retrospective, multicenter, Gender Gender-specific logarithmic trend Age distribution from Italy source was Di Domenicantonio et al., hospital-based study carried generated from 13 data points applied to gender-specific prevalence 2014; Lucendo et al., 2014 out within the Ciudad Real (2000–12) estimates province

UK Cross-sectional study of None No trend data were available. Germany gender split in prevalence Di Domenicantonio et al., primary care data from central Identical prevalence trend applied to UK estimates. 2014; Hein et al., 2014; Stone England assumed to that derived from Age distribution from Italy source was et al., 2003 Germany applied to prevalence estimates

*Any trends were fitted for 10 years from the most recent time point available, then held constant for the remainder of the forecast period. Logarithmic regression models used the natural log.

IBD = inflammatory bowel disease; SHI = statutory health insurance

Source: various (see above) Disease Coverage | Epidemiology: Crohn’s Disease 285

Evidence arising from the late 20th and early 21st centuries shows that incidence of CD is increasing or stable in virtually every region of the world, including the US, Japan, and five major EU markets (Burisch et al., 2013; Molodecky et al., 2012). CD is a chronic, incurable disease with low mortality that is generally diagnosed in adolescence and early adulthood. Therefore, combined with worldwide increasing life expectancy, newly diagnosed patients with CD further expand the number of prevalent cases year-on-year. This phenomenon may be referred to as compounding prevalence; a large rise in prevalence due to cumulative addition of incident cases in a chronic disease that has a young age of onset and low mortality. The prevalence of CD is, therefore, expected to steadily climb over at least the next decade in the Western world (Kaplan, 2015; Loftus, 2004).

An analysis of prevalence trends in Alberta, Canada, which has a high incidence and prevalence of IBD, illustrates compounding prevalence. In 2005, the incidence and prevalence of IBD in Alberta were 25 per 100,000 and 500 per 100,000, respectively. Assuming stable incidence, net zero migration and immigration of individuals with IBD, negligible mortality, and a 2% per year natural growth in the population, the prevalence of IBD is expected to increase from 660 to 790 per 100,000 between 2015 and 2025 (Kaplan, 2015). This epidemiological phenomenon of compounding prevalence, in addition to external evidence indicating recent increases in prevalence across the analyzed countries (Burisch et al., 2013; Goh and Xiao, 2009; Kaplan, 2015; Kappelman et al., 2013; Loftus, 2004), formed the basis of the assumption of introducing an increasing trend in CD prevalence across all analyzed markets apart from the US, where insufficient time series data were available.

In order to fit a realistic increasing trend to the data, where possible for each analyzed country, Datamonitor Healthcare selected data sources that estimated temporal trends in CD prevalence using the same sampling approach or cohort, in the same study location. A minimum of five data points were required to generate a trend in CD prevalence. The most recently available high-quality data from population-representative data sources were utilized to generate trend assumptions through the calculation of logarithmic regression coefficients and their application in deriving an estimated regression forecast.

FORECASTING

To calculate the number of diagnosed prevalent cases of CD in the 2017–37 forecast period, Datamonitor Healthcare multiplied calculated prevalence proportions by the corresponding country-, age-, and gender-specific population estimates from the UN World Population Prospects database (United Nations, 2017). The UN database was chosen as a reliable population denominator; the data include standard sets of demographic indicators and populations by five-year age group and gender. The forecasted numbers of prevalent cases were validated against national benchmarks where possible, in order to check for any inconsistencies or unusual trends in the analysis.

FORECAST

For a further detailed breakdown of case numbers, please consult the accompanying datapack, which includes segmentation of prevalent cases by severity, and proprietary physician research survey data on treatment trends. The datapack provides the following:

• diagnosed prevalent cases of Crohn's disease (CD), by gender, age group, and country, 2017–37

• prevalence proportions of diagnosed prevalent cases of CD, by gender, age group, and country, 2017–37

• diagnosed prevalent cases of CD, by severity and country, 2017–37

• diagnosed prevalent cases of CD being managed by a gastroenterologist, by country, 2017–37

• drug-treated prevalent cases of CD, by line of therapy and country, 2017–37.

DIAGNOSED PREVALENT CASES OF CROHN’S DISEASE

• Datamonitor Healthcare estimates that in 2017, there were 2.5 million diagnosed prevalent cases of CD in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK).

• Note: Datamonitor Healthcare used a newer data source published by the Centers for Disease Control and Prevention as the basis for forecasting diagnosed prevalent cases of CD in the US. This nationally representative large cross-sectional survey has resulted in a substantially higher number of prevalent CD cases compared with Datamonitor Healthcare’s previous analysis.

• By 2037, Datamonitor Healthcare forecasts that the number of diagnosed prevalent cases of CD in the US, Japan, and five major EU markets will increase to 2.8 million. This trend is driven by the trend of increasing prevalence proportions over time in all countries apart from the US (where time series data were unavailable), as determined by historical data, and changes in population demographics, whereby the older population is forecasted to increase across all analyzed markets (United Nations, 2017).

Table 68: Diagnosed prevalent cases of Crohn’s disease in the US, Japan, and five major EU markets, by country, 2017–37

Year US Japan France Germany Italy Spain UK 5EU Total

2017 1,694,500 51,700 207,700 281,000 65,900 56,900 118,100 729,600 2,475,800

2018 1,711,500 51,900 209,700 283,300 67,100 57,900 119,700 737,700 2,501,100

2019 1,728,800 52,000 211,700 285,300 68,100 58,900 121,200 745,300 2,526,100

2020 1,746,600 52,000 213,600 287,000 68,000 59,900 122,800 751,300 2,549,900

2021 1,762,500 51,900 214,100 286,300 67,900 60,700 123,400 752,400 2,566,800

2022 1,779,100 51,700 214,500 285,300 67,800 61,500 124,100 753,200 2,584,100

2023 1,796,200 51,500 215,000 284,200 67,700 61,500 124,700 753,200 2,600,800

2024 1,813,200 51,200 215,500 283,000 67,600 61,500 125,300 753,000 2,617,400

2025 1,830,100 51,000 216,000 281,800 67,500 61,500 126,000 752,800 2,633,900

2026 1,846,000 50,400 216,500 280,600 67,300 61,500 126,600 752,500 2,648,800

2027 1,861,600 49,900 217,000 279,300 67,200 61,500 127,200 752,200 2,663,700 Disease Coverage | Epidemiology: Crohn’s Disease 288

Table 68: Diagnosed prevalent cases of Crohn’s disease in the US, Japan, and five major EU markets, by country, 2017–37

2028 1,877,200 49,400 217,500 278,200 67,100 61,500 127,800 752,000 2,678,600

2029 1,892,900 48,900 217,900 277,200 66,900 61,500 128,400 751,800 2,693,600

2030 1,908,800 48,400 218,300 276,300 66,700 61,400 129,000 751,600 2,708,900

2031 1,923,500 48,000 218,600 275,400 66,600 61,400 129,500 751,400 2,722,800

2032 1,938,100 47,500 218,800 274,700 66,400 61,300 130,000 751,200 2,736,800

2033 1,952,700 47,100 219,100 274,100 66,200 61,200 130,600 751,100 2,750,900

2034 1,967,300 46,700 219,300 273,600 66,000 61,100 131,100 751,100 2,765,000

2035 1,981,800 46,200 219,600 273,100 65,800 61,000 131,600 751,100 2,779,100

2036 1,994,700 45,800 219,900 272,600 65,500 60,800 132,100 751,000 2,791,500

2037 2,007,300 45,500 220,300 272,100 65,300 60,700 132,600 751,000 2,803,800

Absolute change 18.5% -12.0% 6.1% -3.2% -0.9% 6.7% 12.3% 2.9% 13.2%

Note: totals may not sum due to rounding. Disease Coverage | Epidemiology: Crohn’s Disease 289

Table 68: Diagnosed prevalent cases of Crohn’s disease in the US, Japan, and five major EU markets, by country, 2017–37

5EU = five major EU markets (France, Germany, Italy, Spain, and the UK)

Source: Datamonitor Healthcare; Asakura et al., 2009; Dahlhamer et al., 2016; Di Domenicantonio et al., 2014; Hein et al., 2014; Kappelman et al., 2013; Lucendo et al., 2014; MHLW, 2010; 2011; 2012; 2013; 2014; 2016; Stone et al., 2003; United Nations, 2017 Disease Coverage | Epidemiology: Crohn’s Disease 290

Figure 69: Trends in diagnosed prevalent cases of Crohn’s disease in the US, Japan, and five major EU markets, by country, 2017–37

BIBLIOGRAPHY

American College of Gastroenterology (2009) Management of Crohn’s Disease in Adults. Available from: http://gi.org/guideline/management-of-crohn%25E2%2580%2599s-disease-in-adults/ [Accessed 6 March 2018].

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Asakura K, Nishiwaki Y, Inoue N, Hibi T, Watanabe M, et al. (2009) Prevalence of ulcerative colitis and Crohn’s disease in Japan. Journal of Gastroenterology, 44(7), 659–65.

Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, et al. (2011) Epidemiology of pediatric inflammatory bowel disease: A systematic review of international trends. Inflammatory Bowel Diseases, 17(1), 423–39.

Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A (1999) Epidemiology of Crohn’s Disease and Ulcerative Colitis in a Central Canadian Province: A Population-based Study. American Journal of Epidemiology, 149(10), 916–24.

Bernstein CN, Singh S, Graff LA, Walker JR, Miller N, et al. (2010) A prospective population-based study of triggers of symptomatic flares in IBD. The American Journal of Gastroenterology, 105(9), 1994–2002.

Burisch J, Jess T, Martinato M, Lakatos PL (2013) The burden of inflammatory bowel disease in Europe. Journal of Crohn’s and Colitis, 7(4), 322–37.

Card T, Hubbard R, Logan RFA (2003) Mortality in inflammatory bowel disease: a population-based cohort study. Gastroenterology, 125(6), 1583–90.

Cosnes J, Gowerrousseau C, Seksik P, Cortot A (2011) Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology, 140(6), 1785–94.

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Dahlhamer JM, Zammitti EP, Ward BW, Wheaton AG, Croft JB (2016) Prevalence of Inflammatory Bowel Disease Among Adults Aged ≥18 Years — United States, 2015. Morbidity and Mortality Weekly Report, 65(42), 1166–69.

Di Domenicantonio R, Cappai G, Arcà M, Agabiti N, Kohn A, et al. (2014) Occurrence of inflammatory bowel disease in central Italy: a study based on health information systems. Digestive and Liver Disease, 46(9), 777–82.

Duricova D, Pedersen N, Elkjaer M, Gamborg M, Munkholm P, et al. (2010) Overall and cause-specific mortality in Crohn’s disease: a meta-analysis of population-based studies. Inflammatory Bowel Diseases, 16(2), 347–53.

Duricova D, Burisch J, Jess T, Gower-Rousseau C, Lakatos PL (2014) Age-related differences in presentation and course of inflammatory bowel disease: An update on the population-based literature. Journal of Crohn’s and Colitis, 8(11), 1351–61.

El-Tawil AM (2013) Epidemiology and inflammatory bowel diseases. World Journal of Gastroenterology, 19(10), 1505–07.

Frolkis A, Dieleman LA, Barkema HW, Panaccione R, Ghosh S, et al. (2013) Environment and the inflammatory bowel diseases. Canadian Journal of Gastroenterology, 27(3), e18–24.

Goh K, Xiao S-D (2009) Inflammatory bowel disease: a survey of the epidemiology in Asia. Journal of Digestive Diseases, 10(1), 1–6.

Hein R, Köster I, Bollschweiler E, Schubert I (2014) Prevalence of inflammatory bowel disease: estimates for 2010 and trends in Germany from a large insurance-based regional cohort. Scandinavian Journal of Gastroenterology, 49(11), 1325–35.

Kaplan GG (2015) The global burden of IBD: from 2015 to 2025. Nature Reviews: Gastroenterology & Hepatology, 12(12), 720–27.

Kappelman MD, Moore KR, Allen JK, Cook SF (2013) Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive Diseases and Sciences, 58(2), 519–25.

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Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, et al. (2018) ACG Clinical Guideline: Management of Crohn’s Disease in Adults. The American Journal of Gastroenterology, 113(4), 481–517.

Loftus EV (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology, 126(6), 1504–17.

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Lucendo AJ, Hervías D, Roncero Ó, Lorente R, Bouhmidi A, et al. (2014) Epidemiology and temporal trends (2000-2012) of inflammatory bowel disease in adult patients in a central region of Spain. European Journal of Gastroenterology & Hepatology, 26(12), 1399–1407.

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Stone MA, Mayberry JF, Baker R (2003) Prevalence and management of inflammatory bowel disease: a cross-sectional study from central England. European Journal of Gastroenterology & Hepatology, 15(12), 1275–80.

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Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, et al. (2010) The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. Journal of Crohn’s and Colitis, 4(1), 7–27.

Yao T, Matsui T, Hiwatashi N (2000) Crohn’s disease in Japan: diagnostic criteria and epidemiology. Diseases of the Colon & Rectum, 43(10 Suppl), S85–93.

APPENDIX: ADDITIONAL SOURCES

For further information regarding the general etiology, pathology, treatment, and epidemiology of Crohn’s disease, Datamonitor Healthcare recommends consulting the following sources:

• The Crohn’s & Colitis Foundation of America and Crohn’s & Colitis UK are excellent resources describing disease etiology, risk factors, and diagnostic approaches, and also highlight the latest research evidence in the US and UK: http://www.crohnscolitisfoundation.org/what-are-crohns-and-colitis/ https://www.crohnsandcolitis.org.uk/

• A high-quality review on the epidemiology and natural history of inflammatory bowel disease (IBD) was published in Gastroenterology in 2011: http://www.gastrojournal.org/article/S0016-5085(11)00164-8/fulltext

• A review on the genetics, epigenetics, and pathogenesis of IBD was published in 2015: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629465/

• A high-quality systematic review of the incidence and prevalence of IBD with time was published in Gastroenterology in 2012: http://www.gastrojournal.org/article/S0016-5085(11)01378-3/fulltext

• An analysis of the burden of IBD in Europe was published in 2013 in the Journal of Crohn’s and Colitis: https://www.sciencedirect.com/science/article/pii/S1873994613000305

MARKETED DRUGS: CROHN'S DISEASE

OVERVIEW

Description In-depth analysis of key marketed drugs for Crohn’s disease across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK).

Includes clinical data and provides a comparative evaluation of clinical and commercial drug attributes to determine competitiveness in the marketplace.

Remicade shares preferred Remicade has managed to maintain its status as the preferred biologic for patients who fail first-line biologic status conventional therapy, but is now sharing the position with Humira. Remicade’s long-standing with Humira success is largely due to is first-to-market status, its strong data in both induction and maintenance of clinical remission, as well as the availability of efficacy data in multiple patient subgroups. While Humira is perceived to have an overall comparable efficacy profile to Remicade, and benefits from a more convenient formulation, key opinion leaders highlight that Remicade remains the preferred anti-TNF biologic for patients with more advanced or complicated Crohn’s disease.

Entyvio has seen high use Entyvio has seen high use in Crohn’s disease since its launch in 2014, despite its modest efficacy despite its modest efficacy in patients who are refractory to TNF inhibition, and its slower onset of action compared with in TNF-failure patients, and other marketed biologics. Its high use is largely due to its favorable safety profile, with no black overall slow onset of action box warnings, and the overall lack of novel biologic therapies suitable for TNF-refractory patients, or patients with contraindications to TNF inhibition. Up until Stelara’s approval in late 2016, Entyvio and Tysabri were the only non-TNF biologics in Crohn’s disease. Tysabri is approved for use in Crohn’s disease only in the US, and its use has been limited due to the associated increased risk of progressive multifocal leukoencephalopathy. Datamonitor Healthcare expects Entyvio to face significant competition from Stelara, which has a faster onset of action than Entyvio and a comparable safety profile.

Stelara will be the market Datamonitor Healthcare forecasts Stelara to become the market-leading brand within Crohn’s leader in Crohn’s disease disease. Aside from its strong clinical performance to date, favorable safety profile with no black box warnings, and convenient subcutaneous maintenance dosing every eight weeks, Stelara also benefits from a later patent expiry than Remicade and Humira, resulting in delayed biosimilar competition. Leading gastroenterologists note that Stelara will be used primarily in patients who are refractory to TNF inhibition, and in unique cases as a first-line biologic (eg patients with co-morbidities or at high risk of infections).

Leading anti-TNFs face With drug costs being a major influencer of prescribing trends, the increasing availability of significant pressure from cheaper biosimilars threatens to undercut established TNF inhibitors. The first infliximab the increasing availability biosimilar was launched in Japan in Q4 2014, in the five major EU markets in Q1 2015, and in of lower-cost biosimilars the US in Q4 2016. The first adalimumab biosimilar was approved by the US Food and Drug Administration in September 2016, and is anticipated to launch in the US in Q1 2023, as well as in the EU and Japan in 2018 and 2021, respectively. Datamonitor Healthcare anticipates initial biosimilar uptake to be slow, with prescribing expected to be weighted toward new patients and driven by differences in pricing. However, in the longer term, the lower cost of biosimilars and the increasing availability of post-marketing safety data are expected to lead to higher uptake.

PRODUCT OVERVIEW

KEY MARKETED DRUGS FOR CROHN’S DISEASE

The table below summarizes the key marketed drugs profiled in this report.

Table 69: Profiled key marketed drugs for Crohn’s disease

Drug Lead company Target Drug type Geographic availability

Alofisel TiGenix n/a Stem cell therapy EU

Cimzia UCB TNF MAb US

Entyvio Takeda Alpha-4-beta-7 integrin MAb US, EU receptor

Humira AbbVie TNF MAb US, EU, Japan

Remicade Johnson & Johnson TNF MAb US, EU, Japan

Stelara Johnson & Johnson IL-12/23 MAb US, EU, Japan

Tysabri Biogen Alpha-4-beta-7 and alpha-4- MAb US beta-1 integrin receptors

IL = interleukin; MAb = monoclonal antibody; TNF = tumor necrosis factor

Source: Biomedtracker; Pharmaprojects

PRODUCT PROFILE: ALOFISEL

PRODUCT PROFILE

ANALYST OUTLOOK

DRUG OVERVIEW

Table 70: Alofisel drug profile

Molecule darvadstrocel

Mechanism of action Stem cell therapy; anti-inflammatory and tissue regenerative properties

Originator Cellerix (now TiGenix)

Marketing company TiGenix/Takeda

Formulation Intralesional injection

Alternative names Cx601

Source: Biomedtracker; Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

In 2009, the European Commission granted Alofisel orphan designation for the treatment of anal fistulas (EMA, 2009).

PIVOTAL TRIAL DATA

The European Phase III ADMIRE-CD study is summarized in the table below. Details of Alofisel’s global pivotal Phase III study in Crohn’s disease are yet to be announced.

Table 71: Alofisel Phase III data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

Table 71: Alofisel Phase III data in Crohn’s disease

**Clinical remission = closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed.

ITT = intent-to-treat; mITT = modified intent-to-treat; MRI = magnetic resonance imaging; TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Marketed Drugs: Crohn's Disease 302

The table below summarizes the design of the international Phase III study.

Table 72: Alofisel Phase III trial in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Primary endpoints Start date/primary completion date

TNF = tumor necrosis factor

Source: Trialtrove; ClinicalTrials.gov Disease Coverage | Marketed Drugs: Crohn's Disease 304

OTHER TRIALS

Phase I/II efficacy data for Alofisel in Crohn’s disease are summarized in the table below.

Table 73: Alofisel Phase I/II data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

MRI = magnetic resonance imaging

Source: see above Disease Coverage | Marketed Drugs: Crohn's Disease 306

SWOT ANALYSIS Figure 70: Alofisel for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

Figure 71: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

Source: Datamonitor Healthcare

Figure 72: Datamonitor Healthcare’s drug assessment summary of Alofisel in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Alofisel compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Alofisel for Crohn’s disease:

REGULATORY

• Datamonitor Healthcare does not forecast Alofisel to launch in Japan as no evidence of the drug’s clinical development in Japanese Crohn’s disease patients has been found.

COMPETITION

US key opinion leader

“Alofisel will be used as needed to help heal the fistula tracks, but patients will continue whatever therapies they were on for their luminal Crohn’s disease.”

US key opinion leader

EU key opinion leader

US key opinion leader

DOSING

• Datamonitor Healthcare has assumed dosing of 120 million cells administered by a single intralesional injection, as described in the prescribing information (EMA, 2018).

PRICING

• Please view the accompanying datapack for a full table of drug costs per patient per year.

ALOFISEL FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Alofisel in Crohn’s disease, by country, over 2016–25.

Figure 73: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 74: Alofisel sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US ------26.6 61.9 120.6 177.8

France - - - 1.3 4.0 8.9 13.7 18.3 23.0 27.0

Germany - - 2.6 8.2 18.3 27.9 37.2 46.4 54.1 59.7

Italy - - - 0.7 2.1 4.7 7.2 9.7 12.2 14.3

Spain - - - 0.6 2.0 4.6 7.1 9.5 12.0 14.2

UK - - 0.5 1.5 3.3 5.1 6.8 8.6 10.2 11.3

Total - - 3.1 12.2 29.6 51.1 98.6 154.4 232.0 304.3

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Marketed Drugs: Crohn's Disease 313

EMA (2009) Public summary of opinion on orphan designation. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006230.pdf [Accessed 12 June 2017].

EMA (2018) Alofisel prescribing information. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/004258/WC500246474.pdf [Accessed 25 April 2018].

Panes J, Garcia-Olmo D, Van Assche GA, Colombel JF, Reinisch W, et al. (2017) CX601, ALLOGENEIC EXPANDED ADIPOSE-DERIVED MESENCHYMAL STEM CELLS (EASC), FOR COMPLEX PERIANAL FISTULAS IN CROHN'S DISEASE: LONG-TERM RESULTS FROM A PHASE III RANDOMIZED CONTROLLED TRIAL. Presented at the 2017 Digestive Disease Week Annual Meeting, 6–9 May 2017, Chicago, Illinois, US; Abstract 985.

PRODUCT PROFILE: CIMZIA

PRODUCT PROFILE

ANALYST OUTLOOK

DRUG OVERVIEW

Table 75: Cimzia drug profile

Molecule certolizumab pegol

Mechanism of action TNF inhibitor

Originator Celltech (now UCB)

Marketing company UCB, Astellas

Formulation SC

Alternative names n/a

SC = subcutaneous; TNF = tumor necrosis factor

Source: Biomedtracker; Medtrack; Pharmaprojects

DEVELOPMENT OVERVIEW

PIVOTAL TRIAL DATA

Pivotal Phase III trial data that supported the approval of Cimzia in the US are summarized in the table below.

Table 76: Cimzia pivotal trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

*Clinical response = ≥100-point decrease in CDAI score from baseline. Disease Coverage | Marketed Drugs: Crohn's Disease 317

Table 76: Cimzia pivotal trial data in Crohn’s disease

**Clinical remission = CDAI score ≤150 points.

CDAI = Crohn’s Disease Activity Index

Source: various (see above) Disease Coverage | Marketed Drugs: Crohn's Disease 318

OTHER LATE-PHASE TRIALS

Additional late-phase trial data for Cimzia in Crohn’s disease are summarized in the table below.

Table 77: Cimzia late-phase trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and duration Results Reference

*Clinical remission calculated using the Harvey-Bradshaw index. Disease Coverage | Marketed Drugs: Crohn's Disease 320

Table 77: Cimzia late-phase trial data in Crohn’s disease

TNF = tumor necrosis factor

Source: various (see above) Disease Coverage | Marketed Drugs: Crohn's Disease 321

SWOT ANALYSIS Figure 74: Cimzia for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

Figure 75: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

Source: Datamonitor Healthcare

Figure 76: Datamonitor Healthcare’s drug assessment summary of Cimzia in Crohn’s disease

Source: Datamonitor Healthcare

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Cimzia in Crohn’s disease:

REGULATORY

• Cimzia was approved and launched in the US for the treatment of Crohn’s disease in April 2008 (FDA, 2008).

COMPETITION

• Datamonitor Healthcare’s 2016 survey indicates that there is a small amount of off-label prescribing of Cimzia in Japan and

Spain.

“Entyvio is mostly used in later lines in patients who are refractory to anti-TNFs, and only in a few biologic-naïve patients.”

EU key opinion leader

DOSING

• Datamonitor Healthcare has assumed dosing of 400mg every four weeks, as described in Cimzia’s prescribing information (FDA, 2017).

PRICING

• Based on discussions with key opinion leaders, Datamonitor Healthcare assumes that Cimzia’s net price in the US is 30% lower than the list price due to discounts and rebates.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

CIMZIA FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Cimzia in Crohn’s disease, by country, over 2016–25.

Figure 77: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country, 2016–25

Source: Datamonitor Healthcare

Table 78: Cimzia sales for Crohn’s disease across the US, Japan, and Spain, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 334.0 345.7 352.5 360.7 372.9 389.4 405.1 418.8 432.0 443.6

Japan 2.0 2.0 1.9 1.8 1.7 1.7 1.6 1.5 1.5 1.4

Spain 6.6 6.6 6.4 6.2 6.1 6.0 6.0 5.9 5.8 5.6

Total 342.6 354.3 360.8 368.7 380.7 397.1 412.6 426.2 439.3 450.6

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Marketed Drugs: Crohn's Disease 327

BIBLIOGRAPHY

FDA (2008) Cimzia’s approval. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/125160s000ltr.pdf [Accessed 12 June 2017].

FDA (2014) FDA approves Entyvio to treat ulcerative colitis and Crohn's disease. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398065.htm [Accessed 12 June 2017].

FDA (2017) Cimzia prescribing information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125160s270lbl.pdf [Accessed 23 March 2018].

Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, et al. (2007) Certolizumab pegol for the treatment of Crohn's disease. The New England Journal of Medicine, 357(3), 228–38.

Takeda (2017) Results for FY2016: DATA BOOK. Available from: http://infopub.sgx.com/FileOpen/qr2016_q4_d_en.ashx?App=Announcement&FileID=452899 [Accessed 12 June 2017].

PRODUCT PROFILE: ENTYVIO

PRODUCT PROFILE

ANALYST OUTLOOK

DRUG OVERVIEW

Table 79: Entyvio drug profile

Molecule vedolizumab

Mechanism of action MAb against alpha-4-beta-7 integrin receptor

Originator Millennium Pharmaceuticals (now Takeda Oncology)

Marketing company Takeda

Formulation IV

Alternative names n/a

IV = intravenous; MAb = monoclonal antibody

Source: Biomedtracker; Medtrack; Pharmaprojects; Entyvio prescribing information, 2018

DEVELOPMENT OVERVIEW

In January 2014, Takeda initiated a Phase III program for IV Entyvio in Crohn’s disease in Japan (Biomedtracker, 2017).

A subcutaneous (SC) formulation of Entyvio is also being assessed in a Phase III program, and is forecast to launch in the US, Japan, and Europe from 2021 (Takeda, 2017).

PIVOTAL TRIAL DATA

Pivotal Phase III trial data that supported approvals of Entyvio in the US and EU are summarized in the table below.

Table 80: Entyvio pivotal trial data in Crohn’s disease

Trial Sample size Target patients Study design Dosing tested and Results Reference duration

Table 80: Entyvio pivotal trial data in Crohn’s disease

*Corticosteroid-free remission = proportion of patients that discontinued corticosteroids and were in clinical remission.

**Clinical remission = CDAI score ≤150.

***Clinical response = decrease of ≥70 points in CDAI score from baseline.

CDAI = Crohn’s Disease Activity Index; IV = intravenous; TNF = tumor necrosis factor

Source: see above Disease Coverage | Marketed Drugs: Crohn's Disease 332

ONGOING LATE-PHASE TRIALS

Ongoing late-phase trials for Entyvio in Crohn’s disease are summarized in the table below.

Table 81: Entyvio ongoing late-phase trials in Crohn’s disease

Trial Sample size Target patients Study design Dosing Primary Study start/primary endpoints/results completion date

Table 81: Entyvio ongoing late-phase trials in Crohn’s disease

*Clinical remission = CDAI score ≤150.

CDAI = Crohn's Disease Activity Index; ECG = electrocardiogram; IV = intravenous; SC = subcutaneous

Source: : Biomedtracker; Trialtrove; ClinicalTrials.gov; Vermeire et al., 2017 Disease Coverage | Marketed Drugs: Crohn's Disease 336

SWOT ANALYSIS Figure 78: Entyvio for Crohn’s disease – SWOT analysis

Source: Datamonitor Healthcare

CLINICAL AND COMMERCIAL ATTRACTIVENESS

Figure 79: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

Source: Datamonitor Healthcare

Figure 80: Datamonitor Healthcare’s drug assessment summary of Entyvio in Crohn’s disease

Source: Datamonitor Healthcare

For more information about how Entyvio compares to other marketed drugs and pipeline agents for Crohn’s disease, please refer to the Market Dynamics chapter of the Crohn’s disease forecast.

PATIENT BASED FORECAST

Datamonitor Healthcare makes the following assumptions in its forecast of Entyvio for Crohn’s disease:

REGULATORY

• Entyvio launched in the US and Europe in June and July 2014, respectively (Takeda, 2014; Biomedtracker, 2017).

COMPETITION

US key opinion leader

“The safety profile of vedolizumab (Entyvio) is very good, and I think it is better than the safety profile of anti-TNFs. Entyvio doesn’t have a black box warning.”

US key opinion leader

• In Japan, Entyvio is forecast to capture 5% of first-line patient share from immunomodulators.

“Entyvio is mostly used in later lines in patients who are refractory to anti-TNFs, and only in a few biologic-naïve patients.”

EU key opinion leader

• In Japan, Entyvio is forecast to capture 8% of Humira, Remicade, and Cimzia’s first- and second-line patient shares, and 12% of

their third-line and later patient shares.

• In the US, Entyvio is forecast to capture up to an additional 8% of patient share from Tysabri, across all lines of therapy.

“To begin with, there were very few patients on Tysabri because of the PML [progressive multifocal leukoencephalopathy] risk. When Entyvio came out we started prescribing Tysabri even less….”

US key opinion leader

“I believe Entyvio is a little bit less effective than an anti-TNF and Stelara. The speed of action and the effect rates are a bit lower, but in the long term the effects are superimposable.”

EU key opinion leader

• Entyvio is forecast to lose up to 7% of its patient share to the IL-23 inhibitor risankizumab (AbbVie/Boehringer Ingelheim) across all lines of therapy following its anticipated launch in 2021.

DOSING

• Datamonitor Healthcare has assumed dosing of 300mg every eight weeks, as described in Entyvio’s prescribing information (FDA, 2018; EMA, 2018).

PRICING

• Datamonitor Healthcare assumes that SC Entyvio will be priced at the average annual cost per patient of available biologic therapies in Crohn’s disease.

• Please view the accompanying datapack for a full table of drug costs per patient per year.

ENTYVIO FORECAST, 2016–25

The figure and table below show Datamonitor Healthcare’s forecast of Entyvio in Crohn’s disease, by country, over 2016–25.

Figure 81: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country, 2016–25

Source: Datamonitor Healthcare

Table 82: Entyvio sales for Crohn’s disease across the US, Japan, and five major EU markets, by country ($m), 2016–25

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 422.9 527.2 656.9 769.0 827.5 847.3 852.9 848.4 838.1 820.8

Japan - - - - <0.1 0.8 3.1 5.6 8.3 11.3

France 29.2 37.5 48.7 57.8 61.6 62.1 61.8 60.3 58.7 57.2

Germany 45.5 52.6 61.5 67.4 69.2 69.6 69.7 69.7 69.5 69.5

Italy 11.0 13.9 17.6 20.7 22.2 22.5 22.6 22.4 22.2 22.1

Spain 14.9 20.9 28.9 35.7 39.0 39.7 39.5 38.0 36.2 34.6

UK 11.3 16.1 22.6 28.0 30.5 30.9 30.4 29.6 28.9 28.2

Total 534.8 668.3 836.2 978.6 1,049.9 1,072.9 1,080.0 1,073.9 1,061.9 1,043.7

Note: totals may not sum due to rounding.

Source: Datamonitor Healthcare Disease Coverage | Marketed Drugs: Crohn's Disease 344