Op#mal Therapy in IBD: Where Are We Now?

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2 Op#mal Therapy in IBD: Where Are We Now? Brian G. Feagan MD Professor of Medicine, Epidemiology and Biosta;s;cs Western University Senior Scien;fic Director, Robarts Clinical Trials, London, Ontario, Canada

3 Crohn s Disease: A Chronic Progressive Disease Progression of digestive damage and inflammatory activity in a theoretical patient with Crohn s disease Digestive damage Surgery Fistula / abscess Stricture Stricture Inflammatory activity (CDAI, CDEIS, CRP) Disease onset Diagnosis Early Disease Pre-clinical Clinical Pariente B, et al. Inflamm Bowel Dis 211;17:

4 Most Crohn s Disease Pa#ents Will Require Surgery 1 8 % Patients Years After Onset Mekhjian HS et al. Gastroenterology. 1979;77:

5 Mortality in Crohn s Disease Survival is modestly reduced (6-7% over 2 years) Females diagnosed before the age of 5 Disease- related complica;ons, gastrointes;nal cancer Jess T. et al. Gastroenterology 22;122:

6 Can Treatment Alter the Natural History of CD? Disease Complications Natural Course Induce and maintain gastrointes#nal healing Prevent strictures and penetra#ng complica#ons Prevent extra- intes#nal complica#ons Decrease hospitaliza#on/ surgery/mortality Decrease long- term cost of care Years

7 Treatment Op#miza#on 216 = Precision Medicine

8 Right Pa#ent

9 Outcomes of Cor#costeroid Therapy for CD Immediate Outcome (n=74) Complete Remission 58% (n=43) Partial Remission 26% (n=19) No Response 16% (n=12) 1-Year Outcome (n=73) Prolonged Response 32% (n=24) Steroid Dependent 28% (n=21) Surgery 38% (n=28) Faubion W et al. Gastroenterology. 21;121:

10 Predictors of Rapid Progression to Surgery Factor Odds Ra;o (95% CI) Current smoker 3.9 ( ) Abdominal pain 1.82 ( ) Nausea/vomi;ng 2.7 ( ) Ileal localiza;on only 2.22 ( ) Oral cor;costeroid use in 1 st 6months 3.79 ( ) Sands B. et al. Am J Gastroenterol 23;98:

11 Severity of Endoscopic Lesions and Long Term Outcomes in CD Development of fistulizing disease Colectomy 12% 11.3% 1% P=.2 8% 6% 4% 2% 6/53 % % No deep ulcers Deep ulcers Allez M et al. Am J Gastroenterol 22;97:

12 Risk of Progression and Posi#ve Serology 1.75 Probability of Nonprogressive CD.5.25 P=.3 N=97 N=7 All Negative (/3) > 1 of 3 positive Time to Disease Progression (months) Dubinsky MC et al. American Journal of Gastroenterology 26;11:36-367

13 The Wrong Pa;ent

14 Coinfec#on with C. difficile AGA Consensus 217 Figure 1 (A) Increasing proportion of IBD patients with C difficile (C diff) infection compared with the total number of C difficile infected patients at a single referral hospital from 2 to 25. Published with permission from Elsevier. 15 (B) C difficile infection incidence at Barnes Jewish Hospital increased from 1998 to 24; ulcerative colitis (UC) patients appear primarily to account for the increase observed in the IBD population as a whole. *P <. 1 and **P =.8 comparing the first and last 3 years of data.

15 Right Drug

16 Surgery for Crohn s Disease and Immunosuppressives 6 Use of Immunosuppressives 25 Need for Surgery Probability of Receiving Immunosuppressives # Resections per 1 Patients Cosnes J, et al. Gut. 25:54:

17 AZTEC/GETAID The Death of AZA Monotherapy

18 AZTEC Mean CDAI P=.7 5 P<.1 25 % patients Sustained remission up to month 18 LOCF p=.2 67,7 57,1 Visit number % patients 1 NRI p= ,1 38,1 25 AZA Placebo Panes et al. Gastroenterology 213

19 GETAID Azathioprine + Prednisone Versus Step Up Cosnes J. Gastroenterology 213

20 Step- Therapy in CD is Conceptually Flawed Disease severity at presentation? Severe Cyclosporine/Tacrolimus Natalizumab Anti-TNF Anti-TNF (UC)/ Thiopurine/MTX (CD) Moderate Corticosteroids Aminosalicylate (UC)/ Thiopurine/MTX (CD) Aminosalicylate Aminosalicylate Induction Maintenance Mild time

21 TOP DOWN - Remission (CDAI <15) Corticosteroid Therapy Top-Down Step-Up 8 P=<.1 P=.6 P=.3 P=.8 P=.43 6 Percent in Remission (%) 4 2 Week 14 Week 26 Week 52 Week 78 Week 14 D Haens G et al. Lancet 29

22 Complete Ulcer Disappearance % % Top Down P=.3 3% Step Up D Haens G et al Lancet 29.

23 SONIC Proportion of Patients (%) p=.9 p<.1 45 p= /17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel JF. et al. N Engl J Med. 21 Apr 15;362(15):

24 Early Mucosal Healing with IFX and Steroid Free Remission 1 8 Patients (%) (n=12) 34 1 (n=175) 11 2 (n=114) p< (n=57) Endoscopic score at Week 8 (ACT 1 & 2) Colombel JF et al. Gastroenterology 211;141:

25 Kaplan- Meier CD- Related Hospitaliza#on: CHARM n=778 randomized to adalimumab (ADA) 4 mg EOW or weekly, or placebo, through 56 weeks CD-related hospitalization risk (%) 3 3-month hospitalization risk Placebo (%) 7.3 ADA (%) 1.6 (RR reduction: 78%) 12-month hospitalization risk Placebo (%) 13.9 ADA (%) 5.9 (RR reduction: 57%) 2 1 Week 2 Placebo Adalimumab Feagan et al. Gastroenterology Days since randomization

26 EXTEND: Complete Mucosal Healing* Rates at 1 Year Patients with complete mucosal healing* (%) Placebo Adalimumab 4mg eow 13 p= /61 17/62 Week 12, ITT 13 p= /56 17/61 Week 12, per protocol p<.1 24 /61 15/62 Week 52, ITT Rutgeerts P, et al. Gastroenterol 29; 136(Suppl 1):A116

27 Hospitaliza#on in Pa#ents With Deep Remission at Week 12 All hospitalization (%) All-cause hospitalization through Week /11 9/53 Deep remission* No deep remission* CD-related hospitalization (%) CD-related hospitalization through Week 52 9 /11 5/53 Deep remission* No deep remission* *Deep remission defined as clinical remission (CDAI <15) and complete mucosal healing Colombel JF, et al. Gut 21;59(Suppl 3):A8: OP371 at UEGW 21

28 REACT: Study Design Cluster randomized controlled trial Gastroenterology prac;ces randomized to either implement a treatment algorithm or to con;nue with their usual care for the management of CD 4 prac;ces randomized in a 1:1 ra;o using a minimiza;on procedure to balance treatment alloca;on for country and number of CD pa;ents seen annually at the prac;ce (<1 or 1) Prac;ces recruited from Canada (34) and Belgium (6) Khanna R, et al. Lancet. 215 Nov 7;386(16):

29 REACT: Therapeu#c Algorithm for Crohn s Disease Without fistula GCS (bud vs pred depending on disease activity and localization) Evaluate in 4 wks * remission? (HBS 4) Yes No Taper GCS Add adalimumab + AZA or MTX Yes With fistula Complex fistula MRI, US, EUA to rule out abscess No Antibiotics / fistulotomy * For patients in Belgium, evaluate in 12 wks. Yes No Adalimumab + AZA or MTX (GCS as needed) Re-evaluate in 12 wks remission? Yes Yes No Taper GCS, re-evaluate in 12 wks remission? Increase adalimumab to weekly dose Yes Yes Re-evaluate in 12 wks remission? No Switch antimetabolite Re-evaluate in 12 wks remission? No Switch TNF blocker Re-evaluate in 12 wks remission? No Consider resection Drainage / seton + antibiotics Yes Yes Abscess present? Re-evaluate in 4 wks - improved? Follow algorithm for active luminal CD without fistula No Surgical reassessment No Khanna R, et al. Lancet. 215 Nov 7;386(16):

30 REACT: Time to Ini#a#on of Treatment 4 Corticosteroids 4 Antimetabolites Pa#ents (%) p =.777 Pa#ents (%) p <.1 Early combined immunosuppression Conventional management Time (months) Time (months) Pa#ents (%) p <.1 TNF antagonists Pa#ents (%) Antimetabolites and TNF antagonist p <.1 11% increase Time (months) Time (months) Khanna R, et al. Lancet. 215 Nov 7;386(16):

31 REACT: Symptoma#c Remission Harvey Bradshaw Index 4 and No Cor#costeroids Pa#ents (%) Conventional management Early combined immunosuppression p =.79 p =.498 p =.389 p =.25 Baseline Month 6 Month 12 Month 18 Month 24 Khanna R, et al. Lancet. 215 Nov 7;386(16):

32 REACT: Time to First Hospitaliza#on, Surgery or Complica#on 4 HR (95% CI) =.73 (.62,.86), p <.1 Hospitalisation, surgery or complications (%) Conventional management Early combined immunosuppression 34.7% 27.4% Time (months) Khanna R, et al. Lancet. 215 Nov 7;386(16):

33 REACT: Serious Disease and Drug- Related Complica#ons and Mortality Worsening Crohn s disease Abscess 32 (3.) 33 (3.7).36 Fistula 29 (2.7) 39 (4.3).3 Stricture/bowel obstruc;on 67 (6.2) 82 (9.1).1 Serious worsening disease 98 (9.) 96 (1.7).65 Serious extra- intes;nal manifesta;ons 47 (4.3) 5 (5.6).37 Serious drug- related complica;ons 1 (.9) 1 (1.1).84 Deaths Cardiovascular 2 (.2) 5 (.5) Thromboembolic 1 (.1) 1 (.1) Cancer 3 (.3) 2 (.2) Infec;on 1 (.1) 1 (.1) Other (.) 1 (.1) Total Mortality 7 (.7) 1 (1.1).33 b Khanna R, et al. Lancet. 215 Nov 7;386(16):

34 Right Pa#ent: REACT the Unanswered Ques#ons What would the benefit be in high risk pa;ents? What would the impact be in pa;ents naïve to IMM and TNF antagonists/early disease? What if decisions were made on objec;ve markers of inflamma;on rather than symptoms?

35 Right Drug: Better Therapies are coming

36 Vedolizumab: Background Ligand for α4β7 is MAdCAM Animal models show that ACT- 1 selec;vely blocks trafficking of α4β7 posi;ve lymphocytes to the gut Raises possibility of gut specific immune modula;on Striking benefit in cojon- top tamarin model MAdCAM -1 Alpha 4 Beta 7 ACT -1 Hesterberg PE et al. Gastroenterology 1996;111: Podolsky et al. JCI 1993;92:372-8

37 Primary and Secondary Outcomes at 52 Weeks Primary Outcome Secondary Outcomes VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W Patients, % Mean Δ% vs VDZ/PBO P<.1 vs placebo; P<.5 vs placebo Sandborn WJ. et al. New Eng J Med 213.

38 Ustekinumab Background 3 8 p4 IL-12 p35 ustekinumab NK or T cell membrane p19 No IL-12 or IL-23 Intracellular signal IL-23 p4 IL-12 & IL-23 are key cytokines in the pathogenic immune cascade of Crohn s disease Ustekinumab is a fully human IgG1k monoclonal antibody binding the p4 subunit of Interleukins-12 & 23 Inhibits IL-12- and IL-23-mediated signaling, cellular activation, and downstream cytokine production Approved for moderate to severe psoriasis and psoriatic arthritis Induction efficacy recently demonstrated in a broad CD population in UNITI-1 1 and UNITI Sandborn W, et al. Oral presentation. CCFA 215 and Rutgeerts P, et al. Oral presentation. ECCO Feagan B, et al. Oral presentation. ACG and UEGW 215.

39 Overall UNITI Phase 3 Crohn s Program 3 9 Two Induction Studies One Maintenance Study UNITI-1: anti-tnf Failure Population R Placebo IV* Stelara 13 mg IV* Stelara ~6 mg/kg IV* Responders IM-UNITI Randomized Withdrawal Maintenance Study UNITI-2: Failed Convent. Therapy Stelara 13 mg IV* R Stelara ~6 mg/kg IV* 9 mg SC q8 wks R 9 mg SC q12 wks Placebo SC Responders 44 Week maintenance study: Followed by (up to) 4 yr LTE Placebo IV* Feagan B., et al. New England J Med 216.

40 Clinical Response and Remission Through Week 8 4 (anti-tnf Failure) Clinical Response (Conv. Failure) (anti-tnf Failure) Clinical Remission UNITI-2 (Conv. Failure) Feagan., B et al. New Eng J Med 216.

41 Primary Endpoint: Clinical Remission at Week Proportion of Subjects (%) Number of Subjects in Clinical Remission **, at Week 44; Randomized Subjects Excluding Those Enrolled Prior to Study Re-start 35.9 Placebo SC* (N=131) p=.4 p=.5 Δ 12.9% Δ 17.2% mg SC q12w (N=129) Ustekinumab mg SC q8w (N=128) Feagan B et al New Eng J Med 216..

42 Summary of Key Safety Events Through Week 44 in the Randomized Popula#on 42 Treated subjects who were randomized (n) Avg. duration of follow-up (weeks) Ustekinumab Placebo SC* 9 mg SC q12w 9 mg SC q8w Combined Subjects with (%) Death % % % % AEs 83.5% 8.3% 81.7% 81.% SAEs 15.% 12.1% 9.9% 11.% Infections 49.6% 46.2% 48.1% 47.1% Serious infections 2.3% 5.3% 2.3% 3.8% Discontinuation due to AE 6.% 7.6% 3.1% 5.3% Malignancies.8% %.8% % MACE % % % % 42 Feagan B et al New Eng J Med 216.

43 Risankizumab Monoclonal Against P19 The IL- 23 pathway has been implicated gene;cally and biologically in the pathogenesis of Crohn s disease (CD) 1,2 Ustekinumab is a humanised mab that targets the p4 subunit, common to IL- 12 and IL- 23, with proven efficacy in Crohn s Disease 3 5 Risankizumab is a humanized mab that targets the p19 subunit, specific to IL In chronic plaque psoriasis, a head- to- head trial demonstrated superior efficacy of risankizumab over ustekinumab 7

44 Study Design Period 1 Blinded iv therapy Period 2 Open label iv therapy/washout N=41 Risankizumab 6 mg iv q4w No Risankizumab 6 mg iv q4w Randomised 1:1:1 N=41 Risankizumab 2 mg iv q4w N=39 Placebo iv Week 12 Deep remission? Yes Flare* Wash out Period 3 Open label sc therapy Dosing Day 1 Wk 12 Primary endpoint: Clinical remission at Week 12 Wk 14 Wk 26 *p<.5, **p<.5, ***p<.1, all comparisons vs placebo; Feagan B, et al. Lancet 217

45 Period 1: Induc#on Treatment Clinical remission over time Endoscopic endpoints Week 12 4 * * 36.6 Propor;on of pa;ents (%) * 17.1 ** 24.4 *** * 3.5 Propor;on of pa;ents (%) * 26.8 * 14.6 * Week 4 Week 8 Week 12 Placebo 2 mg risankizumab Endosc. Response Endosc. Remission 2.4 Deep remission 6 mg risankizumab Pooled risankizumab Placebo 2 mg risankizumab 6 mg risankizumab *p<.5, **p<.5, ***p<.1, all comparisons vs placebo; Feagan B, et al. Lancet 217

46 Right Target : What is the Role of Endoscopy? van Dulleman H et al. Gastroenterology1995 Jul;19(1):129-35

47 Mucosal Healing and Resec#on in CD IBSEN Study: risk of future surgery in patients with mucosal healing at 1 year (n=146) 1. Proportion of patients not resected No mucosal healing Mucosal healing HR =.42, 95% CI.2.89; p=.27 Adjusted for age and disease extent at diagnosis 83% 69% Time in years after 1-year visit 9 Solberg IC et al. Clin Gastroenterol Hepatol. 27;5:143-8.

48 Early Mucosal Healing: Long- Term Remission EXTEND: Endoscopic response at week 12 and 1 year remission Patients (%) p< (n=31) >5 (n=31) Clinical remission defined as a CDAI score <15 EXTEND subanalysis; primary endpoint was complete mucosal healing at Week 12 (p=.56); all patients received adalimumab induction therapy from Week, before being randomised to placebo or adalimumab maintenance therapy at Week 4 Rutgeerts P et al. Gastroenterology. 212 May;142(5): SES-CD score at Week 12

49 UC :Early Response to Steroids 5- year Outcomes Clinical & endoscopic remission Clinical no endoscopic remission No Remission 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % # * # * # * * Relapse Hospitaliza;on Immunosup. Colectomy *p<.5 vs. Clinical and endoacopic remission # p<.5 vs. Clinical remission (+ /- endoscopic remission) Ardizzone S, et al. Clin Gastroenterol Hepatol. 211;9:483-9

50 CALM: Study Design Prednisone burst & taper Early randomization* Randomization 1:1 CM (n=122): escalation driven by CDAI, prednisone use Treatment escalation: ADA 16/8 mg, ADA 4 mg EW + No treatment ADA 4 mg EW 4 mg EOW AZA 2.5 mg/kg/day ADA 4 mg EOW De-escalation ADA 4 mg EOW+AZA T2T (n=122): escalation driven by CDAI, FC, CRP, prednisone use Weeks Rescue group** (escalation needed before next visit) Final visit *CDAI >22 AND one of the following: steroid therapy > 4 weeks and best to taper per investigator assessment, intolerant/contraindication for steroid therapy, best interest of the patient per investigator assessment. ** CDAI >3 for 2 consecutive visits 7 days apart or per investigator discretion (elevated CRP/FC, ulceration taken into consideration); moved to T2T group. AZA: azathioprine; ADA: adalimumab; CM: clinical management; CDAI: Crohn's Disease Activity Index; CRP: C-reactive protein; FC: fecal calprotectin; T2T: Treat to target

51 CALM: Results n=244 (122 in CM arm, 122 in T2T arm) Mean age±sd 31.6±11.7 years Mean CD dura;on±sd.95±1.98 years Baseline characteris;cs similar between groups Primary endpoint: CDEIS <4, no deep ulcers CM 3.3% vs T2T 45.9% (p=.1) T2T was superior for all secondary endpoints (all p<.5) No new safety signals with an;- drug an;bodies were observed Patients (%) Primary endpoint at 48 weeks CDEIS <4, no deep ulcers 3.3% 37/122 56/122 Clinical management p= % Treat to target

52 Peyrin-Birolet et al. Am J Gastro

53 Crohn s: What is the Consensus Target? Peyrin-Birolet et al. Am J Gastro

54 Right Dose: Progressive LOR to An#- TNF Primary non responder rate ; 2% Therapy in CD 1. Chaparro M et al. IBD doi:1.21/ibd Chaparro M et al. Clin Gastro 211;

55 Variables Affec#ng TNF- α Inhibitor Concentra#ons Immunosuppressant Usage An;body forma;on Drug concentra;on Drug clearance An;- drug an;bodies Drug concentra;on Drug clearance Male Gender Drug clearance Low serum albumin (marker for protein losing colopathy?) Drug clearance TNF- α inhibitor levels High baseline CRP Drug clearance High BMI Drug clearance High baseline TNF concentra;on Drug clearance Ordás I, et al. Clin Gastroenterol Hepatol. 212 Oct;1(1):179.

56 Anti-TNF Drug Concentrations Correlate with Mucosal Healing p<.1 p<.1 p<.1 Mucosal healing (%) < >6. Adalimumab trough concentration (µg/ml) 56 Infliximab concentration at Week 54 (µg/ml) n= No Yes No Yes No Yes Clinical response Mucosal healing Clinical remission Roblin X, et al. Clin Gastroenterol Hepatol 214;12:8 84 Adedokum OJ, Gastroenterology

57 The Evolving Paradigm Drug < threshold Antibody Increase dose Antibody+ Switch (high) or Dose optimize (low) Drug threshold Switch Class???

58 What Goes Wrong The Top 5 Hits 1. Failure to introduce highly effec;ve therapy in high risk pa;ents 2. Switching without op;miza;on 3. Use of monotherapy in pa;ents at risk of sensi;za;on 4. Failure to treat to any specific target 5. Clinging to yesterday s drugs when bejer op;ons are available

59 Conclusions: Op#mal Therapy in CD 217 Several highly effec;ve therapies have been iden;fied Bejer prognos;c models are needed to iden;fy high risk pa;ents A more robust treatment target incorpora;ng endoscopy has been endorsed We are on the cusp of developing treatment algorithms that can change the natural history of CD