IBD Updates. Themes in IBD IBD management journey. New tools for therapeutic monitoring. First-line treatment in IBD

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1 IBD Updates Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida Themes in IBD 213 First-line treatment in IBD New tools for therapeutic monitoring Biologic therapy for CD and UC New targets and new drugs IBD management journey Induction of remission Maintenance of remission Maintenance of remission off steroids and / or mucosal healing (histology)

2 Impact of Vitamin D on Risk for Surgery and Hospitalization in IBD One-third of patients were deficient (25[OH]D <2 ng/ml) and 27% were insufficient In CD patients, plasma 25[OH]D <2 ng/ml was associated with: Increased risk for surgery (OR 1.76; 95% CI ) Increased risk for hospitalization (OR 2.7; 95% CI ) Similar associations were seen for UC In CD patients, normalization of vitamin D status was associated with reduced likelihood of surgery (OR.48; 95% CI.32-.7) and hospitalization (OR.51; 95% CI ) Normalization of vitamin D status was associated with lower median CRP levels Ananthakrishnan AN et al. Abstract Budesonide MMX for UC: Primary Endpoint Combined Clinical and Endoscopic Remission 2 * ** *** % of Patients N=12 N=8 1 9 Asa.= Asacol Ent.= Entocort B-MMX= Budesonide MMX N=21 N=12 3 N=1 9 N=23 2 N=121 N=19 N=23 N=124 N=13 Placebo B-MMX 9 mg B-MMX 6 mg Asa./Ent. Sandborn WJ et al. Gastroenterology 212 Nov;143(5): Travis,S et al. Gut. 213 Feb 22. *p=.143 **p=.47 ***p=.2 Biologics, combo therapy and other management issues Anti-TNFs in UC Infliximab versus Cyclo Post-op prevention of CD Discontinuing biologics

3 Biologics in IBD Infliximab cover Gastro 1995; NEJM 1997 (ca2) Adalimumab for Crohn s disease (22) Certolizumab Pegol for Crohn s disease (28) Adalimumab for UC (212) Infliximab approved for Crohn s disease 1998 Infliximab for ulcerative colitis (25) Natalizumab for Crohn s disease (28) Golimumab for UC (213) SONIC Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint Proportion of Patients (%) 1 p<.1 8 p=.9 p= /17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel, J.F., et al., N Engl J Med. 362(15): p IBD has common genetic origins NOD2 PTPN22 CD genes 3 CD specific loci 11 IBD loci Common pathways: Leprosy Mycobacterial susceptibility Other immunemediated disease UC genes 23 UC specific loci MHC Genes in common Jostins, L. et al. Nature 491, (1 November 212)

4 UC SUCCESS Moderate-to-severe UC failing steroids Naive to azathioprine or had stopped 3 months prior to entry Excluded intermediate TPMT activity AZA 2.5mg/kg IFX 5mg/kg IFX + AZA 1 endpoint: Steroid-free remission at week 16 (total Mayo score 2) 2 endpoint: mucosal healing Panaccione R et al. DDW 211; Abstract 835 UC SUCCESS study Patients (%) * *P<.5 compared to IFX; #P<.5 compared to AZA Panaccione R et al. DDW 211; Abstract 835 Adalimumab in UC 4% of patients in trial were previously anti TNF exposed Week 8 Week 52 Weeks 8 and 52 P< P= Placebo Adalimumab (n=248) Patients (%) P= P< P< P<.1 25 P<.5 P< P= Sandborn WJ et al. Gastroenterology. 212 Feb;142(2):257-65

5 Proportion of patients (%) Golimumab in UC (PURSUIT-SC): Clinical Response at Week 6 Randomized Patients in Phase p<.1 p< * * Placebo (n=256) 2 mg 1 mg (n=257) 4 mg 2 mg (n=258) Defined as a decrease from baseline in the Mayo score by 3% and 3 points, with either a decrease from baseline in the rectal bleeding subscore of 1 or a rectal bleeding subscore of or 1 W Sandborn et al. Gastroenterology. 213 Jun 1. Golimumab in UC (PURSUIT-SC): Maintenance of Clinical Response Through Week 54 Proportion of patients (%) Randomized Patients in Clinical Response to Golimumab Induction 31.4 Placebo (n=156) p=.1 p<.1 Defined as a decrease from Week of the induction studies in the Mayo score by 3% and 3 points, with either a decrease from baseline in the rectal bleeding subscore of 1 or a rectal bleeding subscore of or GLM 5 mg (n=153) 5.6 GLM 1 mg (n=154) Rutgeerts P, et al. UEGW 212 CsA vs IFX in IV Steroid- Refractory UC: The CYSIF Study Colectomy-free survival Time to Colectomy p=.66 Day 7 response rates: CsA = 84%; IFX = 86% (P=.76) Colectomy rate Cys: 18 ± 5% (n=1) IFX: 21± 5% (n=13) CsA n=55 IFX n= Days since randomisation % of patients at risk Laharie D et al. Lancet. 212 Dec 1;38(9857):

6 Comparative Efficacy of Adalimumab vs Immunomodulators and 5-ASA in Preventing Postoperative Recurrence of CD Patients (N=51) with CD who had undergone ileocolonic resection Randomized to receive adalimumab, azathioprine, or mesalamine 2 weeks after surgery Patients followed for 2 years Quality of life higher in adalimumab group Savarino E et al. Abstract 92 Genoa Italy Can we ever stop biologics? Usually continue indefinitely but may be subset of patients on immunomodulators that can stop Maintaining remission on antimetabolites after stopping infliximab in Crohn s disease: a prospective cohort study STORI Kaplan-Meier Curve of Relapse n=52 relapses/115 patients Median follow-up 28+/- 2 months Median time to relapse: 16.4 months Louis E, et al. Gastroenterology. 212 Jan;142(1):63-7

7 Predictive Model for Time-to-Relapse Kaplan Meier time-to-relapse curves according to multivariate models and scores generated through Cox model using multiple imputations Proportion without relapse Deleterious factors were: No previous surgery method No. of deleterious factors 1..8 < > Months since infliximab withdrawal Steroid use within 12-6 months before infliximab withdrawal Male gender Haemoglobin 14.5 g/dl Louis E, et al. Gastroenterology. 212 Jan;142(1):63-7 leukocyte count >6 1 9 /l hscrp 5 mg/l faecal calprotectin 3 µg/g CDEIS > infliximab trough 2 mg/l Tools for guiding therapy Emerging concept: more inflammation requires more anti-tnf Higher drug levels correlate with mucosal healing Clinical Outcomes at >52 Weeks According to Trough Infliximab Concentration Clinical Remission C-reactive Protein Endoscopic Change *P<.1 * *P<.1 *P<.1 * * Undetectable 2. ug/ml Undetectable 2. ug/ml Undetectable 2. ug/ml Maser EA et al. Clin Gastroenterol Hepatol. 26;4:

8 SONIC: IFX Trough Levels at Week 3* are Higher with Concomitant AZA Median Serum Trough Levels (mg/ml) (N=97) (N=19) * Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis Sandborn, W. et al. NEJM, 21 Trough Concentration of Infliximab is Higher With Concurrent Methotrexate 6.35 Infliximab plus µg/l 3.75 Feagan B et al. DDW 28. Abs no. 682C. Benefit of Immunomodulators with anti-tnf on Antibody Formation Infliximab 1 (CD 5 mg/kg) (CD 1 mg/kg) Infliximab 2 (UC 5 mg/kg) (UC 1 mg/kg) Patients, % Episodic Maintenance Scheduled Maintenance IMS- IMS+ IMS- IMS+ 38% 16% 11% 8% 7% 4% No data 19% 9% 2% 4% Certolizumab 3 (PRECiSE I) 1% 4% Certolizumab 4 (PRECiSE II) 24% 8% 12% 2% Adalimumab 5 (RA, all doses) 12% 1% No data Adalimumab 6 (CLASSIC II) 4% % IMS, immunosuppressant; RA, rheumatoid arthritis; UC, ulcerative colitis 1. Hanauer et al. Clin Gastroenterol Hepatol. 24;2(7): Sandborn WJ, et al. Presented at DDW; May 19 24, 27. Abstract T Sandborn WJ, et al. N Engl J Med. 27;357: Schreiber S, et al. N Engl J Med. 27;357: Summary of Product Characteristics for adalimumab. Abbott Laboratories. July Sandborn WJ, et al. Gut. 27;56:1232.

9 Detectable Serum Trough IFX Concentration is Associated with Higher Remission Rate and Endoscopic Improvement in UC Patients % of patients P<.1 Undetectable serum IFX predicted an increased risk for colectomy (55% vs 7%; p<.1) Seow CH et al. Gut 21;59:49-54 Adalimumab in UC: Remission associated with higher adalimumab levels Sandborn WJ, et al Gastro 212;142:257 Management of Secondary Infliximab Failure Based on Serum Levels of Infliximab and Antibodies to Infiximab Patients with secondary infliximab failure (N=46) randomized to infliximab q4w or interventions based on combined infliximab and anti-infliximab serum concentrations Patients with anti-infliximab antibodies and low infliximab levels switched to adalimumab Patients without anti-infliximab antibodies and low infliximab levels were dose escalated Response rate 58% in algorithm group vs 53% in dose-escalation group v Algorithm p=.13 IFX q4 p<.1 p<.1 Steenholdt C et al. Abstract 94

10 Methods Prevalence and Impact of Antibodies to Adalimumab (UCSF) Antibodies to adalimumab (ATA), serum levels of adalimumab, symptoms, and CRP levels measured in 54 female IBD patients (2 with UC) Results Prevalence of detectable ATA was 22.2% Prevalence of detectable adalimumab concentration was 9.7% Serum concentration of <5 µg/ml of adalimumab associated with elevated CRP More active disease demonstrated in patients with low drug concentrations (<5 µg/ml) and/or detectable ATA (P=.1) Velayos FS et al. Abstract 49 Adalimumab levels correlate with mucosal healing Yarur AJ et al. Abstract Tu1147 Is Fecal Loss of Infliximab a Cause of Lack of Response to Treatment? Background Infliximab may be lost through leaky gut that is characteristic of the denuded and ulcerated mucosa in severe CD and UC Methods Repeated fecal samples collected from IBD patients within first 14 days of therapy Infliximab levels quantified in samples Patients Severe IBD (N=9; 3 with CD, 6 with UC) Results Infliximab could be detected in the feces of all patients Highest concentrations were measured in the first days after initiation of therapy In nonresponders (3/9), the amount of drug detected in the stool at the first day after infusion was significantly higher than in patients who had a clinical response (P=.24) Conclusion Non-response to infliximab associated with rapid clearance through stool (and high inflammatory burden) Brandse JF et al. Abstract 157

11 New targets and treatments SONIC: Corticosteroid-Free Clinical Remission at Week 26 Proportion of Patients (%) Primary Endpoint P<.1 P=.6 P= % 52/17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel J-F et al. N Engl J Med. 21 Apr 15;362(15): Ustekinumab for Crohn s disease: blocks IL-12/IL Clinical Response and Remission at Weeks 6 and 8 Placebo UST 1 mg/kg UST 3 mg/kg UST 6 mg/kg UST combined 2 1 Clinical Response Week 6 Clinical Response Week 8 Clinical Remission Week 6 Clinical Remission Week 8 (primary end point) *P<.5 Sandborn W, et al. N Engl J Med. 212 Oct 18;367(16):

12 Vedomizumab in UC: Clinical Response, Remission, Mucosal Healing at 6 Weeks % P< % CI: 11.6, 31.7 Feagan B, et al. DDW212 Induction ITT Population Placebo Vedolizumab P= P= Clinical Response Clinical Remission Mucosal Healing , , % Vedolizumab in UC: Primary and Secondary Outcomes Through 52 Weeks, Maintenance ITT Population 15.9 *** *** Clinical Response 23.8 *** 56.6 *** 56. *** 52. *** 51.6 Durable Clinical Response 19.8 Mucosal Healing 8.7 ** ** Durable Clinical Remission 13.9 Placebo VDZ Q8 wks VDZ Q4 wks * 31.4 *** 45.2 CS Free Remissions n: *P<.5 **P<.1 ***P<.1 Feagan B, et al. DDW212 Janus Kinase Pathway Janus kinase inhibitor Targets a specific intracellular signaling cascade-jak/stat pathway The JAK family binds multiple cytokine receptors including: IL2/IL4/IL7/IL9/IL12 (JAK3) IFNs Tofacitinib is JAK3 inhibitor used for psoriasis and rheumatoid arthritis. TNF, tumor necrosis factor; RA, rheumatoid arthritis Shuai K et al. Nat Rev Immunol. 23;11:9.

13 Phase 2 Study of Tofacitinib (CP-69,55), an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis Week 8 Sandborn W et al. N Engl J Med 212 Positioning New and Established Medications for IBD Induction of Remission/ Active Disease Maintenance of Remission Cyclosporine Vedolizumab Ustekinumab (CD) Anti-TNFs Tofacitinib Corticosteroids Vedolizumab Anti-TNFs MTX 6-MP/AZA