Advances in Inflammatory Bowel Disease Edward V

Advances in Inflammatory Bowel Disease Edward V. Loftus, Jr., M.D. Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, U.S.A.

©2010 MFMER | slide-1 Loftus Disclosures (last 12 months) • Research support • Consultant • AbbVie •AbbVie • UCB •UCB • Genentech •Janssen • Janssen •Takeda • Amgen •Mesoblast • Pfizer •Eli Lilly • Takeda •Amgen • Robarts Clinical Trials •Bristol-Myers Squibb • Gilead • Receptos • Celgene • Medimmune • Seres Therapeutics Overview • Existing treatment paradigms • Evolving paradigms • Risk stratification • Treating earlier in disease course • Measuring objective inflammation to base treatment • Objective treatment endpoints • Therapeutic drug monitoring • New therapies

14 12.2 100,000 100,000 12 10.2 10.2 9.2

10 10.7 years)

- 8 9.0

6 CD 6.9 6.5

person UC 4

0 Age and Sex Adjusted (per Adjusted Rates Sex and Age 1970-1979 1980-1989 1990-1999 2000-2011 Years Shivashankar R et al, Am J Gastroenterol Suppl 2014

1950 2000 Pathogenesis of IBD

Luminal antigens

IBD

Genetic Environmental susceptibility triggers

CP1169260-9 Main Susceptibility Genes for Crohn’s Disease

100 Phyla Main groups of bacteria in faecal samples. 67 Several independent studies have Deltaproteobacteria reported increased numbers of mucosa- associated 90 Proteobacteria Gammaproteobacteria E. coli with invasive properties or the presence of intra- Unclassi ed 80 Atopobium group mucosal E. coli in inflamed mucosal samples from patients with Crohn’s disease, as reviewed by Chassaing Actinobacteria Corynebacterium group

) 67 70 s Dermatophylus subgroup s and Darfeuille-Michaud in 2011. A new, potentially

T Biﬁdobacterium subgroup

c s pathogenic group was designated adherent-invasive

U 60 Unclassi ed

4 E. coli (AIEC) and has been isolated from ileal mucosal

(

F Clostridium aurantibutyricum group

)

t specimens of patients with Crohn’s disease from differ-

50 U Enteroccocus group

c 71,76

O b Sporomusa group

ent countries. The AIEC strains are able to adhere to

m Fi rmicutes

u Eubacterium cylindroides

40 1

( F intest inal epithelial cells, invade epithelial cells, survive N Clostridium aminobutyricum group and replicate within macrophages.77 AIEC can also be

s Clostridium coccoides group

30 s

)

s t found in samples from healthy individuals, although e s Clostridium leptum subgroup

o Unclassi ed

20 O it is less prevalent in healthy people than in those with

e t Anaeroﬂexus assemblage

c 3 Crohn’s disease, but does not adhere to ileal enterocytes

(

a Bacteroidetes Bacteroides distasonis subgroup

10 B 77 B Prevotella subgroup isolated from individuals without Crohn’s disease. 0 Bacteroides fragilis subgroup These findings suggest that AIEC st rains are associated Healthy Patients with specifically with the ileal phenotype of Crohn’s disease. participants Crohn’s disease The potential effect of therapeutic agents on dysbiosis in Figure 4 | Reduction of bacterial diversity in patients with Crohn’s disease based Crohn’s disease is not known. Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2012.152 on data by Manichanh et al.71 from 12 participants. Taxonomy of the dominant OTUs identified in the faecal microbiota of healthy participants and patients with Dysbiosis in pouchitis Crohn’s disease. Abbreviation: OTUs, operational taxonomic units. Restorative proctocolectomy with ileal pouch–anal anas- tomosi s has become the surgical treatment of choice for genetic background, that make it difficult to correlate spe- patients with severe ulcerative colitis who do not respond cific microbial signatures with disease. Studies with pairs to medical therapy or who develop neoplasia, and for of twins discordant for disease status might help to over- patients with familial adenomatous polyposis. Pouchitis, come such difficulties. As mentioned previously, Willing which is a relapsi ng condition characterized by bouts of and co-workers56 investigated the microbial composition inflammation of the ileal pouch mucosa, is the most of faecal samples by 16S rDNA sequencing in 40 pairs common complication of this procedure, with a preva- of twins who were concordant or discordant for Crohn’s lence rat e of 23–40%.78 Interestingly, chronic pouchi- disease or ulcerative colitis and in mucosal samples tis occurs almost exclusively in patients who undergo from a subset of the cohort. Microbial communities in procto coloctomy to treat ulcerative colitis, and is rarel y individuals with Crohn’s disease differed from those in seen in patients with familial polyposis.78 Clinical and healthy individuals and profiles from individuals with basic scientific evidence suggests that dysbiosis has Crohn’s disease that predominantly involved the ileum a key role in the initiation and progression of chronic differed from those with Crohn’s disease that predomi- inflammation in the pouch reservoir. Analyses of 16S nantly involved the colon. Changes specific to patients rRNA gene sequences extracted from ileal pouch biopsy with ileal Crohn’s disease included the dis appearance samples showed a notable increase in Proteobacteria of core genera, such as Faecalibacterium and Roseburia, (E. coli and other enter obacter ia belong to this phylum), and increased amounts of Enterobacteriaceae and as well as a marked decrease in Bacteroidetes and one Ruminococcus gnavus.56 These findings seem to be con- Firmicutes species (F. prausnitzii).79 This composi tional sistent across studies of cohorts of patients with Crohn’s pattern is found in patients who previously had ulcera- disease from differ ent countries. 24,56,68,71,73 Interestingly, tive colitis with or without pouchitis at time of study, a reduction of F. prausnitzii abundance in ileal mucosal compared with control patients with familial polyposis samples is associated with a higher risk of postoperative and no pouchitis. Bacterial diversity was considerably recurrence of ileal Crohn’s disease.24 Furthermore, in greater in pouchitis-free patients than in those with mouse models of intestinal inflammation, administration pouchitis. However, no individual species have been of F. prausnitzii resulted in anti-inflammatory effects.24 specifically associated with pouchitis.78 Counts of F. prausnitzii in faecal samples were considerably lower in patients with active Crohn’s disease than Conclusions in healthy control individuals, but samples from patients Abnormal host–microbe interactions in individual s with with infectious colitis also showed reduced counts.68 This genetic susceptibility generate intestinal inflammation later observation might suggest that decreased abundance and tissue injury in IBD. No evidence exists for conta- of F. prausnitzii could be secondary to either diarrhoea or gious transmission of ulcerative colitis or Crohn’s disease. mucosal inflammation. However, several commensal microbes with or without By contrast, a greater relative abundance i n virulence properties have been identified that could be Enterobacteriaceae, particularly E. coli species, has been involved in the induction of immunoinflammatory cas- consistently observed in patients with Crohn’s disease; cades that lead to tissue dest ruction. Hypothetically, an the change is more notable in mucosal specimens than abnormal microbial composition and/or the absence of

Oral 5-ASAs Distal • Mesalamine 1.5–4.8 g/d • Balsalazide 6.75 g/d (left-sided, proctitis) • Sulfasalazine 4–6 g/d 1st-Line and/or Rectal 5-ASA or

Rectal steroid Induction

Oral steroid 2nd- Line IV Steroid

Infliximab, Adalimumab 3rd-Line

5-ASA, AZA/6-MP, IFX/ADA Maint Kornbluth A, Sachar D. Am J Gastroenterol 2010;105:501-23. Ordas I, Eckmann L, et al. Lancet 2012;380:1606-19. Importance of Adherence: Sustained Remission of IBD

100

Adherent to 5-ASA therapy 75 *P<0.001

Nonadherent to 5-ASA therapy * 25

Patients With Quiescent UC (%) UC Quiescent With Patients 0 0 10 20 30 Time (months)

Kane S et al. Am J Med. 2003;114:39. Why Is My UC Patient Refractory? • Is 5-ASA hypersensitivity colitis a possibility? • Sulfasalazine and 5-ASA can cause a paradoxical worsening of colitis • Can mimic “steroid-dependency” • Consider trial of 5-ASA cessation • Is the patient on NSAIDs? • Consider trial of NSAID cessation • Consider switch to celecoxib

Sturgeon JB et al. Gastroenterology 1995; 108:1889-93. Sandborn WJ, et al. Clin Gastroenterol Hepatol 2006; 4:203-11. Clostridium difficile and Refractory UC: Milwaukee Increasing number of Increasing percentage of C. diff hospitalizations in IBD infections are IBD patients patients with C. diff

Issa M, et al. Clin Gastroenterol Hepatol 2007; 5: 345-51. Immediate and Prolonged Outcomes of Corticosteroid Therapy in UC—Olmsted County, MN (1970-93)

Complete Partial None 30-Day 54% 30% 16% Responses (n = 34) (n = 19) (n = 10) (n = 63)

Steroid- Prolonged 1-Year Surgery dependent Response Responses 29% (n = 63) 22% 49% (n = 14) (n = 31) (n = 18)

Faubion WA Jr., et al. Gastroenterology. 2001;121:255-260. Estimate of Efficacy of AZA for Treatment Success in UC Patients: Meta-Analysis

Pooled RR Estimate Across Five Trials

Leung Y, et al. Dig Dis Sci. 2008;53:1455-1461. Infliximab for UC: ACT 1 and ACT 2 Clinical Remission

ACT 1 ACT 2 Placebo IFX 5 mg/kg IFX 10 mg/kg Placebo IFX 5 mg/kg IFX 10 mg/kg ‡ 45 § † ‡ † § 40 39 † § 36 40 37 34 ‡ 35 ‡ 34 35 34 35 32 30 28 30 26 25 25 20 20 16 17 15 15 15 11 10 10 6

Percent of Patients Percent 5 of Patients Percent 5 0 0 8 Weeks 30 Weeks 54 Weeks 8 Weeks 30 Weeks † P  0.002 vs placebo ‡ P  0.003 vs placebo § P = 0.001 vs placebo Rutgeerts P et al. N Engl J Med 2005;353:2462-76 ACT1/2 Trials: Survival Free of Colectomy

Sandborn WJ et al, Gastroenterology 2009;137:1250-60. UC Success: AZA vs. IFX vs. AZA+IFX for Moderate to Severe UC

90% * * P < 0.05 vs AZA ** P<0.05 vs AZA and vs IFX 80% * 77% 69% * * 70% 63% 60% 55% ** 50% 50% AZA 40% 40% 37% IFX AZA + IFX 30% 24%22% 20% 10% 0% Steroid-free Response Mucosal healing remission Conclusion: IFX+AZA superior to both AZA and IFX monotherapy in inducing steroid-free remission Panaccione R et al, Gastroenterology 2014. Cyclosporine vs. Infliximab for Acute Severe UC Treatment Failure, % • 110 patients steroid 80% refractory UC 70% • Treatment failure 60% • No response day 7 • No steroid-free 50% remission day 98 40% • Relapse between days 7 and 98 30% 60% 54% • Colectomy 20% • Death 10% • Conclusion: CyA was not superior to IFX in 0% acute severe UC Infliximab Cyclosporine

Laharie D et al, Lancet 2012;380:1909-15. Adalimumab for Moderate to Severe UC: Induction/Maintenance Trial (n=494) Week 8 Endpoints Week 52 Endpoints

60% * 60% 50.4% * 50% 50% 41.1% 40% 34.6% 40% * 31.7% * Placebo 30.2% Placebo 30% * 30% * 25.0% ADA 18.3% ADA 20% 16.5% 20% 17.3% 15.4% 9.3% 8.5% 10% 10% 0% 0%

Mucosal healing Clinical remissionClinical response Mucosal healing Clinical remissionClinical response Sandborn WJ et al, Gastroenterology 2012;142:257-65. Golimumab (GLM) for Moderate to Severe Ulcerative Colitis, PURSUIT Studies

Induction of Clinical Maintenance of Clinical Response Response Among * 60 * 55 Responders 51.8 60 50 50.6 50 47.1 40 40 29.7 31.4 30 30 20 Week 6 20 Week 54 10 10 0 0

* P < 0.01 vs placebo Sandborn WJ et al, Gastroenterology 2014;146:85-95. Sandborn WJ et al, Gastroenterology 2014;14696-109. Management of Crohn’sof Management Disease Maint Induction Lichtenstein GR, AZA/MTX, Anti Hanauer Adalimumab, Prednisone, Prednisone, Budesonide Anti Baumgart AZA/6MP/MTX SB, - Natalizumab TNF (Infliximab, TNF Sandborn - pegol TNF,Natalizumab DC, Certolizumab ) Sandborn WJ. AmJ WJ. Lancet 2012;380:1590 Gastroenterol 2009;104:465 - 1605. - 83. 5-Aminosalicylate (5-ASA, Mesalamine) for Crohn’s Disease

• Widely used for induction and maintenance of response and remission in mild to moderate Crohn’s disease • Meta-analyses showed no efficacy for induction or maintenance of remission • Fortunately, use in clinical practice gradually declining Immediate and Prolonged Outcomes of Corticosteroid Therapy in Crohn’s Disease— Olmsted County, MN (1970-93)

Complete Partial None 30-Day 58% 26% 16% Responses (n=43) (n=19) (n=74) (n=12)

Steroid Prolonged 1-Year Surgery dependent response Responses 38% 32% 28% (n=74)* (n=28) (n=24) (n=21)

*One patient lost to follow-up Faubion WA Jr., et al. Gastroenterology. 2001;121:255-260. ORAL BUDESONIDE IN ACTIVE CROHN’S DISEASE Updated Meta-Analysis of AZA/6-MP for Crohn’s Disease: Benefit Is Not So Clear Induction of Remission

Prevention of Relapse

Khan KJ et al, Am J Gastroenterol 2011;106:630-42.

26 Methotrexate for Crohn’s Disease • Methotrexate 25 mg/week IM/SC (and possibly 15 mg/week orally) is effective for inducing remission in patients with steroid- dependent and steroid-refractory active CD • Methotrexate 15-25 mg/week IM/SC is effective for maintenance of remission and steroid sparing in CD • Less “lymphomagenic” than thiopurines?

3002233-27 Construct of Biologic Agents Used in Crohn’s Disease

Murine Chimeric Humanized Human Pegylated Human Recombinant Humanized D2E7 Receptor/Fc Fusion Protein

Infliximab CDP571 Etanercept CDP870 Adalimumab Natalizumab (p75) Certolizumab Golimumab Onercept (p55)

IgG1 isotype IgG4 isotype IgG4 isotype IgG1 isotype 75% human 95% human 100% human 95% human 100% human Induction of Clinical Remission at Week 4 In Crohn’s Disease: Certolizumab, Adalimumab, Infliximab

100 Certolizumab Certolizumab Pegol1 Pegol2 Adalimumab3 Infliximab4 80

60 NS NS * * * 48*

40 36 27

21 24 25 % Patients of % 20 12 7 10 4 0 n 57 60 231 243 74 75 76 25 27 28

Tx Pbo CzP Pbo CzP Pbo ADA ADA Pbo INF INF 400mg 400 80/40m 160/80 5mg/kg 10mg/k mg g mg g Delta 20 11 12 24 44 21

1. Schreiber et al. Gastroenterology. 2005 Sep;129(3):807-18 2. Sandborn et al. N Engl J Med 2007 * p<0.05 3. Hanauer et al. Gastroenterology 2006;130:323-333 NS Non-significance 4. Targan et al. N Engl J Med 1997;337:1029-1035 Net Remission at Six Months: Certolizumab, Adalimumab, Infliximab

1 Certolizumab Pegol – PRECISE 2 Infliximab – ACCENT I2 100 100 Pbo CzP Pbo IFX 80 80 64.1 58.5 60 47.9 60 39.0 40 40 28.6 30.7 22.8 18.3 21.0

20 20 12.3

% % of Patients % % of Patients 0 0 Open-label Week 26 Net Open-label Week 30 Net Induction remission remission Induction remission remission Week 6 week 26 Week 2 week 30

Certolizumab Pegol – PRECISE 14 Adalimumab - CHARM3 100.0 Pbo ADA 100 Pbo CzP 80.0 80 58.0 60.0 60 40.0 40.0 40 29.5 23.2 18.3 17.0 20.0 9.9

20 of % Patients % % of Patients 0 0.0 Net Open Label Week 26 Net remission Induction remission remission week 26 Week 4 week 26 1. Schreiber et al. New Engl J Med 2007;357:239-250 2. Hanauer et al. Lancet 2002;359:1541-49 3. Colombel et al. Gastroenterology 2007;132:52-65 4. Sandborn et al. New Engl J Med 2007;357:228-38 Mucosal Healing With Adalimumab in CD (EXTEND)

50 ADA induction (160/80 mg)/placebo ADA QOW (40 mg)

40 P=0.056, NS P<0.001 30 27.4% 24.2%

13.1% Patients (%) Patients 10 0 8/61 17/62 0/61 15/62 0 Week 12 ITT Week 52 ITT

ITT, intent-to-treat; NS, not significant Primary End Point

Rutgeerts P et al. Gastroenterology. 2012;142:1102. Natalizumab (Anti-Alpha 4 Integrin) Therapy for Crohn’s Disease

• Monoclonal antibody to alpha 4 integrin • Target molecules are VCAM-1 and MAdCAM-1 • Blocks lymphocyte trafficking from vascular space to tissues • Effective for induction and maintenance of response and remission and steroid-sparing

Villablanca EJ et al, Gastroenterology 2011;140:1776-84. ENACT-2 Natalizumab in Active Crohn’s Disease: Maintenance of Clinical Response (70 points) in Week 12 Responders 80 * 70 67 * 59 * * 60 55 55

50 Placebo 40 37 Natalizumab

Percent 30 30 24 22 20

0 At Week 36 At Week 60 At Week 36 At Week 60

*P ≤ 0.001 Response Remission Sandborn WJ et al, N Engl J Med 2005; 353:1912-25 Natalizumab-Related Progressive Multifocal Leukoencephalopathy • Reactivation of the human JC polyoma virus • Severe neurologic disability or death • Has occurred in 398 patients out of approximately 125,000 treated as of September 2013 • All but two cases occurred in MS patients (less than 2% of natalizumab use in US is for Crohn’s) • FDA mandated risk management program (TOUCH) • Risk stratified by JC virus serology (99% of PML with available pre-PML sera are anti-JCV-positive) • Use restricted to patients who have failed anti-TNF therapy • Must be administered as monotherapy (without other immunosuppressive agents) Communication with Biogen Idec, Dec 19 2013 Kleinschmidt-DeMasters BK et al, J Neuropathol Exp Neurol 2012;7:604-17. Evolving Treatment Paradigm Using Available Data for Risk Prognostication

Characteristic Hazard Ratio 95% CI P-value Male 1.6 1.02 - 2.4 0.04 Small bowel 3.4 1.9 - 6.1 <0.0001 Ileocolonic 3.3 1.8 – 5.8 <0.0001 Upper gut 4.0 1.2 – 13.8 0.03 Current 1.7 1.1 – 2.7 0.02 smoker Penetrating 2.7 1.1 – 6.7 0.02 Stricturing 1.4 0.2 – 10.4 0.74 Early steroids 1.6 1.03 – 2.5 0.04

Peyrin-Biroulet L et al, Gastroenterology Suppl 2010 (DDW) Peyrin-Biroulet L et al, Am J Gastroenterol 2012. Risk Factors Associated With Intestinal Complications: Crohn’s, Olmsted County

Characteristic Hazard 95% CI Ratio Terminal ileum 7.8 3.5 – 17.4

Ileocolonic 5.6 2.3 – 13.9

Upper GI 9.5 3.0 – 30.1

Perianal fistula 1.7 0.99 – 2.86

Thia KT et al. Gastroenterology 2010;139:1147-55. Advances in IBD Natural History: Predictors of More Severe Disease

• Crohn’s disease • Ulcerative Colitis •Young age of onset •Extensive colitis (<40 years) •Male gender •Ileal or ileocolonic •Early need for extent steroids •Fistulizing disease at •Early hospitalization diagnosis •Early need for steroids

Beaugerie L et al, Gastroenterology 2006; Seksik P et al, Gastroenterology 2007 Suppl; Ingle SB et al ACG 2007 and UEGW 2007 abstracts; Thia K et al, Gastroenterology 2010; Samuel S et al, Inflamm Bowel Dis 2013; Peyrin-Biroulet L et al, Am J Gastroenterol 2012 Evolving Treatment Paradigms Treat Earlier in the Course of Crohn’s Disease

Clinical remission (CDAI <150), off corticosteroids, and no intestinal resection

100 Step-Up Top-Down P≤0.001 P=0.006 P=0.028 P=0.797 P=0.431 80 65 60 62 60 57 50 47 45

(%) 42 36 40 33

0 Wk 14 Wk 26 Wk 52 Wk 78 Wk 104

N=133 D’Haens G et al. Lancet. 2008;371:660. SONIC: Corticosteroid-Free Clinical Remission at Week 26

Primary Endpoint 100 p<0.001 80 p=0.009 p=0.022

60 56.8 44.4 40 30.6

Proportion ofPatients (%) 52/170 75/169 96/169 0

AZA + placebo IFX + placebo IFX+ AZA

Colombel JF, et al. N Engl J Med. 2010;362:1383-1395. Infliximab Effect on Hospitalizations and Surgeries – ACCENT I

Crohn’s-related Hospitalizations Intra-abdominal Surgeries 40 38 7.4 35 8 7 30 24 6 25 23 23.5 5 20 4 3.1 2.9 15 3 2.6 10 2

5 1 Hospitalizations Per Per 100 Pts Hospitalizations 0 (%) Surgeries with Patients 0 Episodic 5 mg/kg 10 mg/kg Combined Episodic 5 mg/kg 10 mg/kgCombined

Rutgeerts P, et al. Gastroenterology. 2004;126:402-13. Evolving Treatment Paradigms Treatment Decisions Based on Objective Evidence

• Complete lack of correlation between CDAI (primarily symptom-based) and endoscopic inflammation • Symptoms and r = 0.13; p = NS signs of Crohn’s are neither sensitive nor specific

Modigliani R et al, Gastroenterology 1990 Is It Really “Loss of Response” or “Non- Response”? Are Symptoms Due to IBD? • Celiac disease • Bacterial overgrowth • Bile salt diarrhea • Irritable bowel syndrome • Hypersensitivity colitis • Short bowel syndrome • Carbohydrate malabsorption (lactose and fructose) Bacterial Overgrowth in Crohn’s Disease (n=153) • Hydrogen glucose breath test in symptomatic patients –Increased stool frequency, increased flatulence or pain • 25% had positive breath tests • Risk factors –Multiple resections –Partial colonic resection –Ileocolonic disease

Klaus J et al, BMC Gastroenterol 2009;9:61 SONIC: Corticosteroid-Free Clinical Remission at Week 26 by Baseline Endoscopy Status

100 p<0.001 p=0.927 p=0.003 p=0.003 p=0.117 p=0.372 p=0.688 p=0.139 p=0.074 80 61.3 57.1 60 50.5 40.7 40.0 38.2 40 30.4 33.3 21.4 20

35/115 50/99 68/111 6/28 16/28 Proportion ofPatients (%) 0 11/27 12/36 12/30 13/34 Lesions (n=325) No Lesions (n=93) No Endoscopy or UTD* (n=90)

AZA + placebo (n=170) IFX + placebo (n=169) IFX + AZA (n=169)

Colombel JF et al, N Engl J Med 2010 *Unable to determine Paradigm Shift for Making Treatment Decisions in Patients with Inflammatory Bowel Disease • OLD: Treat based on symptoms – But: symptoms are insensitive and non-specific for bowel inflammation • NEW: Treat based on objective markers of inflammation – Serologic (CRP reduction) – Endoscopic (mucosal healing) – Radiographic (CTE/MRE improvement) – Goal should be “mucosal healing” or absence/reduction in inflammation – This will be the only way we can hope to alter the natural history of Crohn’s disease Evolving Treatment Paradigms Treatment Endpoint Based on Objective Evidence Not Symptoms

100 …and these patients did P=0.0028 better in the next 2 yrs! 80 73 Simple endoscopic score 1–9 60 Simple endoscopic score 0 80 70.8 40 30 62.5

60 Patients (%) Patients 20 40 27.3 0 Step-up Top-down 18.2

Patients In Patients 20

Complete endoscopic (%) Remission healing at 2 years 0 Remission Off Steroids, Off Steroids No Anti-TNF

D’Haens G et al. Lancet. 2008;371:660. Baert FJ et al. Gastroenterology. 2010;138:463. CT Enterography Healing: Equivalent to Mucosal Healing at Endoscopy?

3/25/2005 10/11/2006

Resolution of intramural inflammation on maintenance infliximab

51 Bruining DH, et al. Clin Gastroenterol Hepatol 2011;9:679-83. MRI and Crohn’s Activity: MaRIA

• Index based on wall thickness, 140 relative contrast enhancement, MRI edema, and MRI ulcers 120 100 • 48 patients (29 active; 19 inactive disease) Index 80

MR 60 • Receiver operator characteristic (ROC) curve for derivation 40 r=0.837, P<0.001 (0.97) and validation (0.96) 0 10 20 30 40 compared to ileocolonoscopy CEDEIS (CDEIS) • More accurate for severe disease as opposed to active disease

MaRIA, magnetic resonance index of activity Rimola J et al. Inflamm Bowel Dis. 2011;17:1759. Implementing “Treat to Target” in IBD: Mucosal Healing as the Target • Primary target: absence of mucosal ulceration • Level of target may be influenced by comorbidities and drug-related risks • Desired target should be maintained indefinitely • Use both symptoms and objective measures of inflammation (endoscopic or radiologic) to guide treatment decisions • Assess mucosal healing every 6 months till target is achieved, then every 1-2 years after, adjust according to degree of inflammation

Bouguen G, et al. Clin Gastroenterol Hepatol 2013 (online early). 53 Doi:10.1016/j.cgh.2013.09.006. Baseline assessment of A Proposed Algorithm for Disease disease activity by Monitoring in IBD endoscopy paired with surrogate marker

3-6 months Re-assessment of disease Choice of initial therapy activity directly or with based on severity and surrogate marker prognosis of patient

Healing 6-12 Documented? months No Yes

Discussion with patient Clinical follow-up that includes treatment options assessment of disease stability

No Is patient willing to proceed with your recommendations? Clinical follow-up Yes 3-6 months Adjust If no other treatment therapy Slide compliments of David T. Rubin, MD options left Challenges to Mucosal Healing in Crohn’s Disease • It can’t be achieved in many/most patients • Unclear how much healing is really needed to affect outcomes • It is unknown what incremental healing can be achieved by dose escalation or switching therapies • We don’t know the appropriate time interval between changes in therapy and subsequent reassessment • Can surrogates of endoscopic healing be used? Dave M & Loftus EV Jr. Gastroenterol Hepatol 2012;8(1):29-38. Evolving Treatment Paradigm Therapeutic Drug Monitoring

HPRT AZA 6-MP 6-TGNs

TPMT

6-MMP TPMT Activity in 407 New Zealand Patients

Wild type

Heterozygous mutation

Homozygous mutation

Sies C et al. NZ Med J 2005;118(1210):1324-30. Meta-Analysis: Association Between 6-TGN Levels and Clinical Remission

Author & Year Patients 6TGN Fraction Fraction Odds 95% (Remission) Threshold Above Below Ratio Confidence Threshold Threshold Interval Remission Remission Dubinsky 2000 92 (30) 235 .78 .40 5.07 2.62-9.83 Gupta 2001 101 (47) 235 .56 .43 1.65 0.73-3.75 Belaiche 2001 28 (19) 230 .75 .65 1.62 0.26-10.2 Cuffari 2001 82 (47) 250 .86 .35 11.63 3.78-35.7 Goldenberg 2004 74 (15) 235 .24 .18 1.47 0.47-6.42 Achkar 2004 60 (24) 235 .51 .22 3.80 1.17-12.4 Pooled 0.62 0.36 3.27 1.71-6.27 Estimate (0.43-0.80) (0.25-0.48)

Osterman MT et al. Gastroenterology 2006:130(4);1047-1053 Effect of Trough Serum Infliximab Concentrations on Clinical Outcome at >52 Weeks

Trough serum infliximab Detectable Undetectable

Patients in remission (%) Patients with endoscopic improvement >75% (%) 100 100 88 82

p<0.001 33 p<0.001 6

0 0 Patients with CRP <5 mg/dL (%) Patients with complete endoscopic remission (%) 100 76 100

p<0.001 47 p=0.03 32 19

0 0 Maser, et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54. 60 ADA Trough Above 0.33 µg/mL Predicts Clinical Response

1.0

Log Rank: P=0.01 0.8 ADA TR>0.33 µg/mL, n=104 ADA TR<0.33 µg/mL, n=16 0.6

0.4 Clinical Response (%) Response Clinical Patients with Sustained Sustained with Patients 0.2

0.0 0 30 60 90 120 150 180 210 240 Sustained Clinical Response (weeks) Karmiris K, et al. Gastroenterology. 2009;137:1628. 61 What Factors Influence the Pharmacokinetics of TNF Antagonists?

Decreases drug clearance Increases drug clearance

Concomitant Anti-drug antibodies immunosuppressives Low serum albumin High baseline CRP High baseline TNF concentration High body mass index Male sex

CRP=C-reactive protein Ordàs I et al Clin Gastroenterol Hepatol. 2012;10:1079-1087. Treatment Algorithm in IBD Patients With Clinical Symptoms (Infliximab and HACA Concentrations)

Therapeutic IFX Subtherapeutic IFX Positive HACA concentration concentration

Active disease on Increase Change to infliximab different Change to another endoscopy/radiology? dose or anti-TNF anti-TNF agent frequency agent yes no persistent disease Change to Investigate Change to Change to different alternate different non– Change to non– anti-TNF etiologies anti-TNF anti-TNF anti-TNF agent agent agent agent

Afif W et al. Am J Gastroenterol 2010;105:1133. Active Monitoring of Anti-TNF Levels May Ensure Durability of Response

Prospectively optimized IFX trough concentrations to a target range of 5-10 μg/mL

100

Optimized 80 Not Optimized P=.0006 60

20 Probability on on Probability Infliximab

0 0 100 200 300 400 500 600 700 Weeks Vaughn B, et al. Inflamm Bowel Dis. 2014;20:1996-2003. Effect of Concomitant Azathioprine or Methotrexate on Anti-drug Antibodies

IFX levels closed squares ATI open squares Patient 1 Patient 3 Start Start 7 MTX 25 AZA 6 20 5 4 15 3 10 2 5 1

0 0

Concentration (mcg/mL) Concentration Concentration (mcg/mL) Concentration

0 10 20 30 40 50 0 10 20 30 40 50 60

Weeks Weeks

Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:444-447. New Therapies

©2010 MFMER | slide-66 Vedolizumab for Moderate to Severe UC- Induction, GEMINI I • Monoclonal antibody to alpha-4 beta-7 integrin * * • Blocks lymphocyte homing in the gut • Much more gut-specific than natalizumab— shouldn’t cause PML * • Over 3000 patients treated to date—no PML

Feagan BG et al, N Engl J Med 2013;369(8):699-710. Vedolizumab for Maintenance of Remission in UC-Week 52, GEMINI I * * * * *

Feagan B et al, N Engl J Med 2013;369(8):699-710. Vedolizumab in Moderate to Severe Crohn’s Disease-GEMINI II * * * * * *

Sandborn WJ et al, N Engl J Med 2013;369(8):711-21. Ustekinumab for Moderate to Severe Crohn’s Disease: Phase 2b, CERTIFI • Monoclonal antibody to p40 subunit of Clinical Response interleukins-12 and -23 45 * 39.7 36.6 40 34.1 • Commercially approved 35 30 for psoriasis 23.5 25 • Secondary endpoints of 20 clinical response at 15 Week 6 weeks 16, 20 and 22 10 were met 5 0 • Phase 3 trials underway

Placebo

Uste 1 mg/kgUste 3 mg/kgUste 6 mg/kg * P < 0.05 versus placebo Sandborn WJ et al, N Engl J Med 2012;367:1519-28. UNITI-2 Trial Ustekinumab in Anti-TNF-Naïve CD Patients

Clinical Response at Week 6 (≥100 point CDAI reduction) 100 P<0.001 P<0.001

80 P<0.001

60 51.7 55.5 53.6

Patients,% 28.7 20 n=209 n=209 n=209 n=418 0 Placebo 130 mg ~6 mg/kg* Combined Ustekinumab

*Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg). Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response. Feagan BG et al. UEGW 2015. UNITI-1 Trial Ustekinumab in CD Patients Failing Anti-TNF Therapy Clinical Response at Week 6 (≥100 point CDAI reduction) p=0.001

P=0.003 50 P=0.002

40 34.3 33.7 30 21.5

Subjects, % Subjects, 20

10 n=247 n=245 n=249 0 Placebo 130 mg ~6 mg/kg* Ustekinumab *Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg). Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response.

Sandborn WJ, et al. CCFA 2015. Mongersen (GED-0301): Phase 2 Trial in Steroid-dependent or -resistant CD

Clinical Remission at Week 12

P<0.001

100 P<0.001

P<0.001 80 65.1 60 55

40 Patients,%

20 9.5 12.2

0 Placebo 10 40 160 (n=42) mg/day mg/day mg/day (n=41) (n=40) (n=43)

Monteleone G et al. N Engl J Med. 2015;372:1104-1113. Mongersen Tofacitinib for Moderately to Severely Active UC- Phase 2

• Janus kinase (JAK) antagonist Week 8 • Blocks downstream 90 signaling of many pro- 78 80 inflammatory interleukins 70 61 Placebo 60 • Small molecule (oral) 48 48 0.5mg BID 50 42 41 % 3mg BID 40 32 33 • Recently approved for 10mg BID rheumatoid arthritis 30 20 1013 15mg BID (Xeljanz) 10 • Increases LDL, HDL 0 cholesterol Clinical Clinical Response Remission

Sandborn WJ et al, N Engl J Med 2012;367:616-24 Selected Pipeline Drugs for IBD Crohn’s Ulcerative Colitis • AMG181 - anti-α4β7 • AMG181 integrin adhesion molecule • Tofacitinib-small molecule Janus kinase antagonist • Ustekinumab (Stelara) - anti-IL-12/23 • Etrolizumab • PF00547659—Anti- MAdCAM-1 (adhesion molecule blocker) • Etrolizumab-anti-β7 integrin • Mongerson-oral SMAD7 antisense oligonucleotide Conclusions • Crohn’s disease and ulcerative colitis are chronic inflammatory conditions which can result in high morbidity • 5-ASA products remain the mainstay of treatment of UC • Prednisone is effective for inducing clinical response in the short term but is not effective maintenance for either UC or Crohn’s • AZA, 6-MP and MTX are steroid-sparing agents Conclusions • Anti-TNF agents are effective for inducing and maintaining response/remission in Crohn’s and UC • Anti-TNF agents can reduce need for hospitalizations and surgeries in Crohn’s and UC • Natalizumab is an option for Crohn’s disease patients who are anti-TNF refractory, but carries a risk of PML Conclusions • Use objective markers of inflammation rather than symptoms to make treatment decisions • Follow up on changes in therapy with objective markers of inflammation • Use drug monitoring when available