Does the Choice of the Interferon Interfere with the SVR Response

Novel DAAs combined with PEG/RIBA

Heiner Wedemeyer Hannover Medical School Germany

1 Disclosures

Honoraria for consulting or speaking (last 5 years): Abbott, Abvie, Biolex, BMS, Boehringer Ingelheim, Gilead, ITS, JJ/Janssen, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV

Research grants: Abbott, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, Siemens

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Chronic Hepatitis C: Treatment Concepts 2014/15

PEG-IFNa + Ribavirin

PEG-IFNa + Ribavirin DAA

P-IFN+RBV DAA

DAAs/RBV DAA

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Role of PEG-IFNa/RBV-based therapies in 2014/15 ?

PEG-IFNa + Ribavirin

PEG-IFNa + Ribavirin DAA New IFN-combinations therapies: P-IFN+RBV - Less side effects DAA - Shorter therapies - Higher efficacy - less complicated (e.g. no RGT) - less expensive (???)

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Direct Acting Antivirals Against HCV

“…asvirs“ NS5A Inhibitors

“…previrs“ Nucs Non-Nucs Protease Inhibitors Polymerase Inhibitors “…buvirs“

H. Wedemeyer: 12-2013 Manns, von Hahn, Nat Rev Drug Discov 2013 Novel DAAs in combination with PEG-RIBA ….. Direct Acting Antivirals Against HCV Daclatasvir Ledipasvir Asunaprevir ABT-267 Danoprevir “…asvirs“ ABT-450/r MK-5172 NS5A Inhibitors Sovaprevir

Simeprevir ABT-333 ABT-072 Faldaprevir Deleobuvir Setrobuvir BMS-731225 Filibuvir Boceprevir Telaprevir VX-222 …. “…previrs“ Nucs Non-Nucs Protease Inhibitors Polymerase Inhibitors “…buvirs“

Sofosbuvir Mericitabine ALS-2200

H. Wedemeyer: 12-2013 Manns, von Hahn, Nat Rev Drug Discov 2013 Novel DAAs in combination with PEG-RIBA …..

Direct Acting Antivirals Against HCV Daclatasvir Combination with PEG-IFNa/Ribavirin Ledipasvir Asunaprevir ABT-267 Danoprevir “…asvirs“ ABT-450/r MK-5172 NS5A Inhibitors Sovaprevir

Sofosbuvir Mericitabine ALS-2200

H. Wedemeyer: 12-2013 Manns, von Hahn, Nat Rev Drug Discov 2013 Novel DAAs in combination with PEG-RIBA Combination of novel DAAs with PEG-IFNa/RBV

Combination with new protease inhibitors - Simeprevir - Faldaprevir

Combination with NS5A inhibitors - daclatasvir

Combination with nucleotide polymerase inhibitors - sofosbuvir

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Simeprevir + Faldaprevir PEG-IFNa + Ribavirin DAA • Response-guided Therapy • Phase 3 trials completed • Overall SVR around 80% • >80% qualify for shortened therapy • SVR in patients with RVR (eRVR; ETS….) >80% • Stopping rules already at week 4 • Less side effects (no anemia!!) • HIV-coinfected patients show similar response rates

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Simeprevir

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA QUEST- 1&2: Trial designs

Response-guided treatment

SMV 150 mg PR N=257 PR Post-therapy follow-up QD + PR Post-therapy follow-up

N=134 Placebo + PR PR PR Post-therapy follow-up

Week 0 12 24 48 72

• Patients were stratified by HCV subtype and IL28B genotype • Quest 2: 63% of patients were randomised to receive SMV or placebo + PegIFNα-2a or 2b/RBV; the remainder received PegIFNα-2a/RBV • Response-guided therapy (RGT) criteria: HCV RNA <25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12 • Primary endpoint: SVR12 (determined 12 weeks after planned end of treatment)

H. Wedemeyer: 12-2013 Manns et al oral presentation at EASL 2013 Novel DAAs in combination with PEG-RIBA QUEST-1: Sustained virological response (SVR12)

P<0.001*

100 90 80 80 70 60 50 50 40 30 20 10 Proportionpatients of (%) 210/264 65/130 0 SMV 150 mg QD + PR Placebo + PR

*Controlling for stratification factors PR, peginterferon -2a + ribavirin; SVR12, sustained virological response (HCV RNA undetectable) 12 weeks after planned treatment end.

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Jacobson et al Poster 3232 - EASL 2013 QUEST-2: Proportion of patients achieving SVR12

100 p<0.001*

81,3 % 80

60 50 %

20 Proportion of patients(%)

209/257 67/134 0 SMV/PR Placebo/PR *Statistically significant difference between the SMV and placebo groups

PR, PegIFN + ribavirin;SMV, simeprevir. *Based on the Cochran-Mantel-Haensze test controlling for type of PegIFN/ribavirin and stratification factors

H. Wedemeyer: 12-2013 Manns et al oral presentation at EASL 2013 Novel DAAs in combination with PEG-RIBA QUEST-2: RGT and SVR

SVR12 in SMV/PR 100 86%

80 91.4% (235/257) of patients met 60 RGT criteria and were eligible for 24 40 weeks of treatment 20 Proportion of patients(%)

202/235 0 202/235  8.6% (22/257) of patients did not meet RGT criteria – among them, 31.8% (7/22) achieved SVR12

PR, PegIFN + ribavirin; RGT, response-guided therapy; SMV, simeprevir. RGT criteria: HCV RNA < 25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12

H. Wedemeyer: 12-2013 Manns et al oral presentation at EASL 2013 Novel DAAs in combination with PEG-RIBA QUEST-2: SVR12 by type of PegIFN

SMV/PR p<0.001 p<0.001 p<0.001 100 Placebo/PR

88.3% 79% 80 77.5%

62.2% 60 45.7% 41.9% 40

20 Proportion of patients(%) 68/77 28/45 62/80 18/43 79/100 21/46 0 PegIFNα-2a/RBV PegIFNα-2b/RBV PegIFNα-2a/RBV, not randomised  Statistically significantly higher SVR12 rates with SMV/PR compared with placebo/PR, irrespective of the type of PegIFN used

PR, PegIFN + ribavirin; SMV, simeprevir. *Based on a logistic regression model with factors for treatment group, baseline HCV RNA, HCV geno/subtype, IL28B and type of PegIFN/RBV

H. Wedemeyer: 12-2013 Manns et al oral presentation at EASL 2013 Novel DAAs in combination with PEG-RIBA QUEST-2: SVR12 by HCV subtype

SMV/PR p<0.001 p<0.001 100 Placebo/PR

80.4% 82% 80

60 Quest 1: 71% 1a vs. 93%1b 53.2% 45.6% 40

20 Proportion of patients(%) 86/107 26/57 123/150 41/77 0 1a 1b

 Statistically significantly higher SVR12 rates with SMV/PR compared with placebo/PR, irrespective of HCV subtype

PR, PegIFN + ribavirin; SMV, simeprevir. *Based on a logistic regression model with factors for treatment group, baseline HCV RNA, HCV geno-/subtype, IL28B and type of PegIFN/RBV

H. Wedemeyer: 12-2013 Manns et al oral presentation at EASL 2013 Novel DAAs in combination with PEG-RIBA Faldaprevir

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA STARTVerso1+2: Faldaprevir in Treatment-naïve patients

H. Wedemeyer: 12-2013 Jensen et al., AASLD 2013 Novel DAAs in combination with PEG-RIBA STARTVerso1+2: Faldaprevir in Treatment-naïve patients SVR in Patients with ETS

H. Wedemeyer: 12-2013 Jensen et al., AASLD 2013 Novel DAAs in combination with PEG-RIBA STARTVerso4: Faldaprevir in HCV/HIV co-infected patients

H. Wedemeyer: 12-2013 Rockstroh et al., EACS 2013 Novel DAAs in combination with PEG-RIBA STARTVerso4: Faldaprevir in HCV/HIV co-infected patients Randomisation and Allocation

H. Wedemeyer: 12-2013 Rockstroh et al., EACS 2013 Novel DAAs in combination with PEG-RIBA STARTVerso4: Faldaprevir in HCV/HIV co-infected patients SVR

H. Wedemeyer: 12-2013 Rockstroh et al., EACS 2013 Novel DAAs in combination with PEG-RIBA Daclatasvir

• Phase 3 program is ongoing („Command Studies“) • EASL 2013: Study in Genotype 2-3 patients

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA 12-16 Weeks of Daclatasvir in Genoytpe 2/3 patients

0 12 16 24 48 Study Week

P YE 36-week follow-up 12-week cohort DCV + D S (N = 50) peg-alfa/RBV R Placebo + Adult ? NO 24-week follow-up treatment-naïve peg-alfa/RBV patients with YE P 36-week follow-up HCV GT 2 or 16-week cohort DCV + D S GT 3 infection (N = 50) peg-alfa/RBV R Placebo + ? NO peg-alfa/RBV 24-week follow-up Control: 24 weeks Placebo + (N = 51) peg-alfa/RBV 24-week follow-up Randomization stratified by HCV genotype; modified intent-to-treat analysis

■ Protocol-defined response (PDR): HCV RNA < LLOQTND or TD at Week 4 and < LLOQTND at Week 10 – DCV recipients without PDR discontinued DCV at Week 12 and received an additional 12 weeks of placebo + peg-alfa/RBV

Primary efficacy endpoint: HCV RNA < LLOQTND 24 weeks post treatment (SVR24)

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Dore GJ, et al. EASL2013, Oral 1418. COMMAND GT 2/3 12-16 Weeks of Daclatasvir in Genoytpe 2

100 100 96 96 96 91 87 88 88 88

83 83 83

71 63

mITT (% (% patients) of analysis HCV RNA Response RNA HCV

a Week 4 Week 12 End of SVR12 SVR24 Treatment

< LLOQTND < LLOQTD a DCV + peg-alfa/RBV, 12 weeks (N = 24) SVR24 observed values (excluding patients with missing post-treatment data): DCV + peg-alfa/RBV, 16 weeks (N = 23) 95% (DCV 12 weeks), 100% (DCV 16 weeks), Placebo + peg-alfa/RBV, 24 weeks (N = 24) and 83% (placebo 24 weeks).

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Dore GJ, et al. EASL2013, Oral 1418. COMMAND GT 2/3 12-16 Weeks of Daclatasvir in Genoytpe 3

96 100 96 92 89 89 85

82 78 69 69 70 59 52 48

mITT (% (% patients) of analysis HCV RNA Response RNA HCV

a Week 4 Week 12 End of SVR12 SVR24 Treatment

< LLOQTND < LLOQTD a DCV + peg-alfa/RBV, 12 weeks (N = 26) SVR24 observed values (excluding patients with missing post-treatment data): DCV + peg-alfa/RBV, 16 weeks (N = 27) 72% (DCV 12 weeks), 69% (DCV 16 weeks), Placebo + peg-alfa/RBV, 24 weeks (N = 27) and 70% (placebo 24 weeks).

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Dore GJ, et al. EASL2013, Oral 1418. COMMAND GT 2/3 Sofosbuvir

P-IFN+RBV DAA

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Sofosbuvir + PEG-IFNa + Ribavirin „The Neutrino Study“

HCV GT 1, 4, 5, 6 Follow-Up 3 Years SOF 400 mg QD + Treatment-naïve PEG-alfa-2a 180 µg/week + SVR12 SVR24 N=327 RBV 1000‒1200 mg/day

Study Week 0 12 24 No response guided therapy ♦ Primary endpoint: SVR12 – Prespecified comparison to historical SVR control rate of 60% – SVR24 was also assessed ♦ Expanded inclusion criteria – Targeted 20% enrollment of patients with cirrhosis, no upper limit to age or BMI, opiate replacement therapy permitted, platelets ≥ 90,000/mm3, neutrophils ≥ 1500/mm3 or 1000/mm3 (Blacks)

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87 Sofosbuvir + PEG-IFNa + Ribavirin „The Neutrino Study“ SOF+PEG-IFN+RBV N=327 Mean age, y (range) 52 (19‒70) Male, n (%) 209 (64) Black, n (%) 54 (17) Hispanic, n (%) 46 (14) Mean BMI, kg/m2 (range) 29 (18‒56) IL28B CC, n (%) 95 (29) GT 1, n (%) 292 (89) GT 4/5/6, n (%) 35 (11)

Mean baseline HCV RNA, log10 IU/mL (SD) 6.4 (+ 0.7) Cirrhosis, n (%) 54 (17)

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87 Sofosbuvir + PEG-IFNa + Ribavirin „The Neutrino Study“

> 91

299/327 321/325 326/327 296/327 Patients with HCV RNA

On treatment ♦ Study met primary endpoint of superiority over historical control rate of 60% (P<0.001) ♦ Relapse accounted for all virologic failures ♦ No S282T mutations observed by population or deep sequencing (1% cutoff)

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87 Sofosbuvir + PEG-IFNa + Ribavirin Response by Genotype

96 100 100 91 90

(%) 40

296/327 262/292 27/28 7/7 Patients with HCV RNA Patients with

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87 Sofosbuvir + PEG-IFNa + Ribavirin Response by Cirrhosis Status

No cirrhosis Cirrhosis

93 99 96 100 100 100 91 93 80*

Patients with HCV RNA

Week 2 Week 4 Week 12 SVR 12/24

On treatment *SVR12 GT1 = 81%

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87 Sofosbuvir + PEG-IFNa + Ribavirin Response by Fibrosis Stage

SVR12 Rates by Biopsy Fibrosis Stage SVR12 Rates by FibroTest Stage (n=232) (n=323)

F0 100 100 100 97 100 97 9696 F1–2 91 91 8989 F3 8585 7979 F4 80 7878 80

60 60 ()

40 40

SVR12 (%)

20 20

n = 16/16 124/137 34/38 32/41 n = 76/78 101/105 46/54 68/86 0 0 16/16 124/137 34/38 32/41 76/78 26/29 75/76 46/54 68/86 63/65 23/26 66/67 41/49 64/81

Treating at earlier stages of fibrosis is associated with higher response

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Patel K, et al. AASLD 2013. Washington, DC. #1093 Sofosbuvir + PEG-IFNa + Ribavirin response by pre-specified subgroups

SSV V R R 1 1 2 2 R RA a T t E e , % (9 5 % CI ) Ov e r a l l SO F + P E G - I F N + R B V 1 (1 a , 1b , 1a / b ) 1a HC V GT 1b 4, 5, 6 No Ci r r h o s i s Ye s Bl ac k Ra c e No n - b l ac k

<6 lo g 1 0 IU / mL HC V RN A le v e l ≥6 lo g 1 0 IU / m L CC IL 2 8 B No n - C C

60 70 80 90 10 0 Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Sofosbuvir + PEG-IFNa/RBV in genotype 2/3

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Sofosbuvir + PEG-IFNa + Ribavirin Genotype 2/3 Open-label, Phase 2 study of the efficacy of SOF + pegylated interferon (PegIFN) + RBV for 12 weeks in treatment-experienced patients with GT 2 or 3

GT 2/3 TE SOF + PegIFN + RBV 1000–1200 mg SVR12 N=47 12 24 Study Week 0 No response guided therapy Mean age (range), y 56 (39‒72) Male, n (%) 32 (68) White, n (%) 45 (96) Hispanic, n (%) 21 (45) Mean BMI (range), kg/m2 31 (21‒53) IL28B CC, n (%) 17 (36) HCV GT 3, n (%) 24 (51)

Mean BL HCV RNA (range), log10 IU/mL 6 (4‒7) Cirrhosis, n (%) 26 (55) Prior relapse/breakthrough, n (%) 40 (85)

H. Wedemeyer: 12-2013 Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4 36 Novel DAAs in combination with PEG-RIBA Sofosbuvir + PEG-IFNa + Ribavirin Genotype 2

96 100 93 100

SVR12 (%) SVR12 40

22/23 9/9 13/14* 0 Overall Non-cirrhotic Cirrhotic GT2

* The 1 cirrhotic patient who did not achieve SVR prematurely discontinued therapy without

H. Wedemeyer: 12-2013 Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4 37 Novel DAAs in combination with PEG-RIBA Sofosbuvir + PEG-IFNa + Ribavirin Genotype 3

83 83 100 83

SVR12 (%) SVR12 40

20/24* 10/12 10/12 0 Overall Non-cirrhotic Cirrhotic GT3

*2 relapses; 2 lost to follow-up H. Wedemeyer: 12-2013 38 Novel DAAsLawitz in combination E, et al. with AASLD PEG- 2013.RIBA Washington, DC. Oral #LB-4 Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4 Safety of DAAs + PEG-IFNa/RBV

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Brain Kidney

Direct Pancreas Toxicity of Drugs Liver

Heart Bone Marrow

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA QUEST-2: Incidence of AEs

SMV/PR Placebo/PR Patients, % (N=257) (N=134) Grade 1 or 2 AE 70.0 73.1 Grade 3 or 4 AE 25.7 23.9 Serious AE 2.3 1.5 AE leading to discontinuation of SMV* 1.6 0.7 Most common AEs (≥25% in SMV arm) Headache 37.0 33.6 Pyrexia 30.4 35.8 Fatigue 34.6 38.8 Influenza-like illness 25.7 25.4 Other AEs of interest Rash (any type) 23.7 11.2 Anaemia 13.6 15.7 Pruritus 18.7 14.9 Photosensitivity conditions 3.9 0.7

 Data for the first 12 weeks of treatment are shown  The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2 *Without regard to PegIFN and ribavarin. AE, adverse event; PR, PegIFN + ribavirin; SMV, simeprevir

H. Wedemeyer: 12-2013 Manns et al oral presentation at EASL 2013 Novel DAAs in combination with PEG-RIBA QUEST-2: Changes in laboratory parameters

SMV/PR Placebo/PR Bilirubin Haemoglobin Entire treatment phase – bilirubin (µmol/L) Entire treatment phase – haemoglobin (µmol/L)

30 200 180 ± SE) 20 ± SE) 160 140 10 120 Mean values values ( Mean 0 values ( Mean 100 0 2 4 8 12 16 20 24 36 48 0 2 4 8 12 16 20 24 36 48 Weeks Weeks

No. of subjects No. of subjects Placebo 134 131 132 130 124 110 111 87 80 Placebo 134 131 131 130 121 111 110 88 81 TMC435 257 262 251 248 248 242 238 8 7 TMC435 257 252 251 247 247 242 237 8 7

H. Wedemeyer: 12-2013 Manns et al oral presentation at EASL 2013 Novel DAAs in combination with PEG-RIBA Sofosbuvir + PEG-IFNa + Ribavirin Safety

SOF+PEG-IFN+RBV N=327 AEs, n (%) 310 (95) Overall Grade 3‒4 AEs, n (%) 48 (15) safety Serious AEs, n (%) 4 (1) Treatment D/C due to AEs, n (%) 5 (< 2) Grade 3-4 laboratory abnormality, n (%) 159 (49) Hemoglobin < 10 g/dL, n (%) 74 (23) Hematologic Hemoglobin < 8.5 g/dL, n (%) 8 (2) abnormalities Absolute neutrophil count < 750/mm3, n (%) 66 (20) Platelets < 50,000/mm3, n (%) 1 (< 1) ♦ SOF was well tolerated without any additive effects to the expected safety profile of PEG-IFN+RBV ♦ Most common AEs were fatigue (59%), headache (36%), nausea (34%), and insomnia (25%) ♦ A total of 5/327 (1.5%) of patients D/C due to an AE

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87 Direct Toxicity of Drugs Liver

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Bilirubin Direct Increases Toxicity of Liver Drugs Disease Drug-Drug other infections Interactions other drugs “Immune-mediated Fatty Liver Disease mechanisms”

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Bilirubin Direct Increases Toxicity of Liver

Drug-DrugDrugs Diseaseother infections Interactions “Immune-mediated other drugs mechanisms” Fatty Liver Disease

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA Role of PEG-IFNa in Future Treatment of Hepatitis C

Shortening of Therapy – Cost Saving (?)

Increasing Efficacy in Genotype 3

H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA H. Wedemeyer: 12-2013 Novel DAAs in combination with PEG-RIBA