Biologics in IBD. Brian P. Bosworth, MD, NYSGEF Associate Professor of Medicine Weill Cornell Medical College

Biologics in IBD Brian P. Bosworth, MD, NYSGEF Associate Professor of Medicine Weill Cornell Medical College

Case 30 year old man diagnosed with ulcerative proctitis diagnosed in 2003 Had been maintained on various 5-ASA compounds oral and rectal at doses of 1.2-4.8 g/day 2010 after taking ibuprofen for some minor aches, began experiencing bloody diarrhea about 8-10 episodes daily with associated rectal urgency and pelvic cramping

Colonoscopy Next steps?? Next step?

Case Stopped all NSAIDs but persistent symptoms C. diff negative Cultures, O&P negative Presents for Infliximab infusion 5mg/kg Induced into remission

Case Does well on maintenance IFX 5mg/kg for 4 years then begins to have increased abdominal pain, urgency, and return of blood diarrhea

Flexible Sigmoidoscopy

Patients (%) PROGNOSTIC FACTORS: Endoscopic Severity of Disease Correlates With Colectomy 100 Severe endoscopic colitis (N=46) 100 Moderate endoscopic colitis (N=39) 0 93% Deep/ extensive ulcers 30% Mucosal detachment 26% Large mucosal abrasions 17% Well-like ulcers 0 77% Superficial ulcers 8% Deep but nonextensive ulcers 93% underwent colectomy 23% underwent colectomy Carbonnel F, Lavergne A, Lemann M. et al. Colonoscopy of acute colitis: A safe and reliable tool for assessment of severity. Dig Dis Sci. 1994;39:1550.

Anti-TNF Failures Primary failures 10-30% patients Secondary failures Initial benefit Lose response over time Cause of anti-tnf failure Absence of active inflammation (?IBS) Concurrent infection Septic complications Anti-TNF Infliximab Time to 1 o Failure After induction (wk 8-12) Adalimumab Week 12 Certolizumab Week 12 1 o anti-tnf non-responders response to 2 nd anti-tnf compared with anti-tnf naïve patients May show response to 2 nd or 3 rd agent D Haens GR, Panaccione R, Higgins PDR et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn s and Colitis Organization. Am J Gastroenterol 2011;106:199-212

Diminished/Suboptimal anti-tnf Empiric Therapy Response Switch to 2 nd anti-tnf Infliximab Adalimumab Increase dose (7.5-10mg/kg) vs Shorten dosing interval Increase to weekly dosing Fail vs Therapeutic Drug Monitoring (TDM) Switch to 2 nd drug class Anti-Drug Antibody (ADA) Levels D Haens GR, Panaccione R, Higgins PDR et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn s and Colitis Organization. Am J Gastroenterol 2011;106:199-212

Anti-TNF Drug/Antibody Levels Older assays: Solid phase detection methods (ELISA) Only detects ADA not bound to drug False negative Newer assays: Liquid phase mobility shift assays Can detect drug and ADA level from a single sample Detects drug-free and drug bound ADAs in serum Steenholdt C, Bendtzen K, Brynskov J, et al. Measurement of Infliximab and Anti-Infliximab Antibody Levels Can Help Distinguish Maintenance Versus Loss of Response. Scand J Gastroenterol. 2011;46:310-318 Vande Casteele V, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn s disease. Gut 2014;0:1-7

Scenario #1 Back to our case TDM/ADA performed IFX trough level: Low ADA: Low What is the next step?

Serum Drug Trough levels Algorithm for Drug Level/ADA Interpretation Anti-Drug Antibody (at trough) Low/ Subtherapeutic Low/ Undetectable Increase dose Decrease dosing interval High/ Detectable Change to a different anti-tnf agent High/ Therapeutic Change to treatment with different mechanism of action Unclear how to manage Colombel JF, Feagan BG, Sandborn WJ et al. Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease. Inflamm Bowel Dis 2012;18:349-358

Proportion of Patients Achieving Clinical Remission by Serum Infliximab Concentration: ACT 1 and 2 Reinisch W, et al. Long-term infliximab maintenance therapy for ulcerative colitis: The ACT-1 and -2 extension studies. Inflamm Bowel Dis. 2012;18:201-211. At weeks 8, 30 and 54, the proportion of patients achieving clinical remission increased with increasing quartiles of infliximab concentrations. Infliximab Conc. (% patients) 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile P-values Week 8 26.3% (<21.3μg/mL) 37.9% ( 21.3-<33μg/mL) 43.9% ( 33-<47.9μg/mL) 43.1% (>47.9μg/mL) P=0.0504 Week 30 14.6% (<0.11μg/mL) 25.5% ( 0.11-<2.4μg/mL) 59.6% ( 2.4-<6.8μg/mL) 52.1% (>6.8μg/mL) P<0.0001 Week 54 21.1% (<1.4μg/mL) 55.0% ( 1.4-<3.6μg/mL) 79.0% ( 3.6-<8.1μg/mL) 60.0% (>8.1μg/mL) P=0.0066

Scenario #2 Back to our case TDM/ADA performed IFX trough level: Low ADA: High What is the next step?

IFX Level and Anti-Infliximab Antibody Infliximab Drug Level <0.4 ug/ml Anti-Infliximab Antibody 1645 High ug/ml

Adding an Immunomodulator Crohn s Disease SONIC/COMMIT Trials Ulcerative Colitis UC SUCCESS Trial Combination therapy: IFX+AZA Improved clinical outcomes IFX+ MTX No improvement in clinical outcomes Colombel JF, Sandborn WJ, Reinisch W et al. Infliximab, Azathioprine, or Combination Therapy for Crohn s Disease. N Engl J Med 2010;362:1383-95 Panaccione R, Ghosh S, Middleton S, et al. Combination Therapy with Infliximab and Azathioprine is Superior to Monotherapy with Either Agent in Ulcerative Colitis. Gastroenterology 2014;146:392-400 Combination therapy: IFX+AZA More likely to achieve steroid free remission than IFX monotherapy

Addition of Immunomodulator May Reduce ATIs and Rescue Response Patient 1 Patient 2 Patient 3 Patient 4

Scenario #3 Back to our case TDM/ADA performed IFX trough level: High ADA: Low What is the next step?

Summary Anti-TNF failures present a challenge to physicians treating inflammatory bowel disease TDM/ADA levels can be used to aid in the management of anti-tnf failures Changing anti-tnf, adding an immunomodulator and switching to a treatment with a different mechanism of action are all possible ways to overcome anti-tnf failures

21-year-old, known UC pancolitis Disease for 3 years, inactive disease on colonoscopy a year ago. Baseline meds: Infliximab 5mg/kg /8 weeks Azathioprine 2.5mg/kg daily Spent Thanksgiving at home with parents in New Hampshire. Progressive onset bloody diarrhea like my previous flare, with mild left lower quadrant crampy discomfort 5-8 stools per day Visited his parent s physician who prescribed prednisone 40mg This allowed him to return to his normal baseline status for duration of his trip.

Symptoms reoccurred when prednisone tapered to 20mg daily WBC: 8.9 Hb: 12.9 Platelets 440 CRP 30 (mg/l, normal<10) ESR 35 Normal kidney and liver function Albumin 3.5 Normal stool studies, C diff.

Colonoscopy

Steroid-dependent UC No longer responding to infliximab 5mg/kg /8wks & azathioprine 2.5mg/kg Infliximab Trough: 0 no infliximab in serum Anti-bodies : + has neutralizing antibodies 6-TG: 300 (therapeutic >235) 6-MMP: 200 (non-hepatotoxic <3,500)

Next step in therapy? Adalimumab vs Golimumab? Cyclosporin infusion? Repeat steroids at 60mg orally or admission for IV? Vedolizumab?

Patients (%) GEMINI I: vedolizumab in UC Induction phase: outcomes at Week 6 Induction ITT population Primary outcome PBO (n=149) Secondary outcomes 100 80 VDZ (n=225) p<0.001 p<0.001 60 40 20 0 Mean % (95% CI) VDZ vs. PBO 47.1 p<0.001 25.5 24.8 16.9 5.4 40.9 Clinical response Clinical remission Mucosal healing 21.7 (11.6, 31.7) 11.5 (4.7, 18.3) 16.1 (6.4, 25.9) ITT, intent to treat; PBO, placebo; VDZ, vedolizumab; Mean % (95% CI) = mean percentage point difference VDZ vs. PBO (95% confidence interval) Adapted from: Feagan BG, et al. N Engl J Med 2013;369:699 710.

Patients (%) GEMINI I: vedolizumab in UC Induction phase: outcomes at Week 6 in patients with 100 prior anti-tnfα failure * 90 80 70 PBO Anti-TNFα naïve (n=229) Prior anti-tnfα failure (n=145) 60 50 VDZ 51.7 40 39.0 30 20 29.1 21.0 20.6 10 0 Mean % (95% CI) VDZ vs. PBO 7.0 9.8 3.2 Clinical response Clinical remission Clinical response Clinical remission 22.7 (10.1, 35.3) 14.0 (5.4, 22.6) 18.4 (3.9, 32.9) 6.6 ( 9.8, 22.8) *Pre-specified exploratory analysis CI, confidence interval; PBO, placebo; TNF, tumour necrosis factor; UC, ulcerative colitis; VDZ, vedolizumab

Patients who lost response to Vedolizumab Q8 weeks at the end of one year had improved response to Q4 week dosing 100 80 All Patients Prior anti-tnf Failure anti-tnf Naïve 93.8 93.8 93.8 Q 4 week 60 40 20 0 50 43.8 37.5 Week 6 12.5 12.5 9.4 6.3 6.3 0 Week 26 Week 0 Q 4 week 31.3 25 25 25 25 18.8 Week 28 Week 52 Week 6 9.4 12.5 6.3 Week 26 53.1 25 18.8 12.5 Week 0 50 Week 28 56.3 43.8 37.5 31.3 Week 52 0 0 Remission Remission 0 Response Response Adapted from Sands BE et al. Inflamm Bowel Dis 2014: 20(S1)

Summary Vedolizumab is a potent alternative to patients who have failed or are refractory to anti-tnf therapy Patients who are anti-tnf naïve are more likely to respond to VDZ Some patients who lose response to VDZ q8 weeks can be recaptured by shortening the interval to q4 weeks

Ustekinumab: anti IL-12/23 Clinical response / remission Week 8 ACG 2015

Restoring TGF-β with anti-sense to SMAD7

Mongersen (GED-0301) is Safe and Effective in Steroid Dependent or Resistant Crohn s Mongersen: Oral locally active antisense oligonucleotide that targets SMAD7 Methods Phase 2 Double-Blind RCT Steroid dependent / resistant CD Nationwide Hungarian prospective cohort study Week 12 Endpoint CDAI <150 Monteleone et al. N Engl J Med 2015; 372:1104-1113 March 19, 2015DOI: 10.1056/NEJMoa1407250 ACG 2015

Sequester T-Cells so they cannot get to the gut Ozanimod (RPC1063) Oral S1Pr modulator Roach Motel Protective immunity may be preserved because effector memory T-cells do not circulate through Lymph Nodes

Ozonimod blocks trafficking of central memory CD4+ T-cells into the Gut Methods Phase 2 RCT 8 week induction in patients with Moderate to Severe UC (n=197) Results 1mg dose effective Mucosal improvement at all doses Comparable AEs Worsening UC (4.6% vs 3.1% vs 1.5% PBO)