2nd Nottingham IBD Masterclass, 2017

Transcription

1 2nd Nottingham IBD Masterclass, 217 Positioning IL12/IL23 blockade in the Crohn s disease treatment algorithm Prof James Lindsay, Consultant Gastroenterologist, Barts Health NHS Trust Professor in Inflammatory Bowel Disease Barts and The London School of Medicine Queen Mary University of London

2 Speaker Declarations This presenter has the following declarations of relationship with industry Served as consultant and an advisory board participant for AbbVie, Actavis (Warner Chilcott), Atlantic Healthcare, Celtrion, Ferring, Jansen, MSD, Napp, Pfizer, Shire, Takeda and Vifor Pharma Received speaker fees and sponsorship to attend academic meetings from AbbVie, Actavis (Warner Chilcott), Ferring, MSD, Shire and Tillott s and Takeda Received investigator led research grants from Hospira, Shire and Takeda [November 217]

3 Managing Crohn s disease in 217 Our therapeutic choices are increasing Tumour necrosis factor antagonists (anti-tnfs) Initial report 5ASA, Steroids, Azathioprine Methotrexate, ciclosporin Vedolizumab Biosimilars Ustekinumab Rizankizumab Surgery With choice comes responsibility. Choose correct drug at the correct time Monitor patient to ensure response Modify therapy as appropriate Reflection...

4 Positioning IL12/IL23 blockade in Crohn s disease What I am aiming to cover Why do we need new drugs for Crohn s disease Introducing the IL-12 / IL-23 pathway Clinical data supporting efficacy of drugs that target this pathway Practical questions for ustekinumab.

5 Why do we need new therapies? Treatment goals have changed to improve outcome Symptomatic benefit Steroid-free remission Mucosal healing Histological remission Prevent hospitalisation and surgery Early Induce disease remission (B1) Later Maintain disease remission (B2 / B3) Prevent Post complications surgery end Enhance stage QOL disease

6 Percentage of patients Why do we need new therapies? Optimal use of current therapies does not work in all patients anti TNF using treat to target approach in Crohn s disease: CALM 1 1 o Endpoint: mucosal healing (CDEIS <4) and no deep ulcerations 8 p=.1 Therapeutic Gap /122 56/122 Clinical management Tight control Endoscopic scoring is based on site read. Cochran-Mantel-Haenszel test stratified by smoking status (yes/no) and weight (<7/ 7 kg) at screening. NRI analysis. CDEIS: Crohn s disease endoscopic index of severity; NRI: non-responder imputation. Colombel JF, et al. Gastroenterology 217;152(Suppl 1):S155; Colombel JF, et al. Lancet

7 Why do we need new therapies? Current therapies do not work in all: secondary loss of response PANTS data courtesy G Heap and T Ahmad

8 Why do we need new therapies? Some patients develop adverse reactions to current therapies Distribution of skin lesion in the 29% of patients 264/917 (29%) patients treated with anti-tnf developed skin lesions In 28/264 patients (11%) skin lesions were a reason to stop therapy 3.8% 5.3% 26.2% 3.6% 1.6% 23.5% Psoriasiform eczema Eczema Xerosis cutis Palmoplantar pustulosis Psoriasis Other Cleynen I, et al. Ann Intern Med. 216;164:1-22.

9 Remission at weeks 4-8 (%) Remission at weeks (%) Why do we need new therapies? Switching drugs in class are less effective in non responders 1 Efficacy of adalimumab after failure of infliximab in Crohn s: Meta analysis Primary N/R Secondary N/R Intolerance Primary N/R Secondary N/R Intolerance Gisbert JP, et al. Aliment Pharmacol Ther. 215;41:613-23

10 Patients, % Patients, % Why do we need new therapies? Switching drugs out of class is less effective. GEMINI II: Vedolizumab is less effective in anti TNF refractory Crohn s disease Induction of Remission Week 6 Anti-TNF naïve/failure: 5/5 Maintenance of Remission Week 52 1 Patients With Anti- TNFα Failure (n=175) Patients Without Anti-TNFα Failure (n=193) 1 Patients With Prior Anti- TNFα Failure (n=237) Patients Without Prior Anti- TNFα Failure (n=224) PBO VDZ VDZ/PBO VDZ Q8W VDZ Q4W Clinical Remission CDAI-1 Response Clinical Remission CDAI-1 Response Clinical Remission CDAI-1 Response Clinical Remission CDAI-1 Response Adapted from: Sands BE et al. Presentation at: UEGW 2th Annual Meeting 212.

11 Positioning IL12/IL23 blockade in Crohn s disease What I am aiming to cover Why do we need new drugs for Crohn s disease Anti TNF therapies are effective and induce mucosa healing Even with treat to target approach 5% have active disease Progressive loss of response due to ADA formation Second line anti TNFs are less effective Vedolizumab less effective in anti TNF exposed.

12 Y Introducing the IL-12 / IL23 pathway A role in IBD pathogenesis. Lumen DC TLR IFN-g, TNF-a, MMP Lamina propria apoptosis APC IL-1 Th1 YYTh1/17 Treg TGF-b Th1 Treg Chemokines Th1/17 Endothelium DC T cell Th17 IL-12, IL-23 Th1 Mesenteric LN adhesion molecules

13 Introducing the IL-12 / IL23 pathway Two new drugs for Crohn s disease Anti P4 Ustekinumab : Phase III induction and maintenance in CD Anti P19 Risankizumab: Phase II induction in CD Ustekinumab

14 Ustekinumab for Crohn s disease Phase III clinical trial data: Uniti UNITI-1: TNF-α failure population R Placebo IV (N=247) UST 13 mg IV (N=245) IM-UNITI 44-week randomised withdrawal maintenance study IM-UNITI LTE Up to 4-year study extension UST ~6 mg/kg IV (N=249) UNITI-2: Failed conventional therapy R Placebo IV (N=29) UST 13 mg IV (N=21) UST ~6 mg/kg IV (N=29) Responders 9 mg SC q8 wks (N=132) R 9 mg SC q12 wks (N=132) Placebo SC (N=133) Responders 75% (298/397) of randomised subjects who started maintenance entered LTE 56% (718/1281) of all subjects who started maintenance continued in LTE IV, intravenous; LTE, long-term extension; SC, subcutaneous; TNF-α, tumor necrosis factor α; UST, ustekinumab Feagan BG, et al. N Engl J Med. 216;375:

15 Patients (%) Patients (%) Ustekinumab for Crohn s disease Phase III clinical trial data: induction data 1 Clinical response (a decrease of 1 points from BL in CDAI score or a CDAI score < 15 points) a UNITI-1 TNF antagonist failure Primary endpoint 1 UNITI-2 failed conventional Primary endpoint 8 p =.1 p =.3 8 p <.1 p =.1 p <.1 p <.1 6 p =.49 p = Week 3 Week 6 Week 3 Week 6 Placebo UST 13 mg UST ~6 mg/kg a ITT, 2-sided Cochran-Mantel-Haenszel chi-square test at a significance level of.5. BL, baseline; CDAI, Crohn s Disease Activity Index. Feagan BG, et al. N Engl J Med. 216;375:

16 Daily score change (mean) Ustekinumab for Crohn s disease Phase III clinical trial data: induction data Early symptomatic improvement in PRO Mean change of soft/liquid stools from baseline (number per day) Mean change of abdominal pain from baseline (rated 3) Mean change of general wellbeing from baseline (rated 4) Time (days) Time (days) Time (days) * * * ** ** * * * ** ** * ** ** * ** ** * * ** * * * * ** ** ** ** ** ** ** * * * * * ** ** ** ** ** 1.4 * ** ** **.6.6 PBO (n = 191) UST 13 mg (n = 188) UST ~6 mg/kg (n = 184) * p <.5 for UST 13 mg vs placebo. ** p <.5 for UST ~6 mg/kg vs placebo. PBO, placebo. Adapted from Sandborn WJ, et al. Presented at ACG 217; P2145.

17 Patients (%) Ustekinumab for Crohn s disease Phase III clinical trial data: maintenance data Primary and major secondary endpoints in IM-UNITI at Week Placebo UST 9 mg q12w UST 9 mg q8w p =.2 p =.7 p =.5 p =.3 p =.19 p = p =.4 p = n = Clinical remission Clinical response Remission among those in remission at IM-UNITI week Glucocorticoid -free remission Feagan BG, et al. N Engl J Med. 216;375:

18 Patients (%) Ustekinumab for Crohn s disease Phase III clinical trial data: maintenance data Remission in UNITI-1 and UNITI-2 subgroups in IM-UNITI Placebo UST 9 mg q12w UST 9 mg q8w p =.1 p =.14 p =.2 p = n = UNITI-1 population (TNF antagonist failure) UNITI-2 population (failed conventional) Feagan BG, et al. N Engl J Med. 216;375:

19 Mean SES- CD Reduction (from Induction Baseline) Proportion of Subjects Ustekinumab for Crohn s disease Phase III clinical trial data: Endoscopic data at week (P=.54) 3.8 5% 4% 21.1% (P=.17) 48.6% 2.1% P=.12 Placebo (n=51) UST q12w (n=47) UST q8wk (n=74) (P=.758) 1.5 3% 2% 29.8% 27.5% 17.% 33.8% 11.8% P= % % 13.7% 9.8% 12.8%. Placebo (n=51) UST q12w (n=47) Improvement in SES-CD *Subjects with eligible SES-CD and ulcerations at baseline UST q8w (n=74) % SES-CD 3-pt Reduction Endoscopic Response Mucosal Healing Endoscopic Response (5% SES-CD improvement) Endoscopic Remission (SES-CD <2) Rutgeerts P, et al. UEGW 216. Presentation 14.

20 Ustekinumab for Crohn s disease Phase III clinical trial data: safety data 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 % % % % *Subjects 2 who were in clinical response to ustekinumab IV induction dosing and were randomized to placebo SC on entry to this maintenance study Malignancies 2 were both Basal cell skin cancers, 1 each in the Placebo and q8w groups Sandborn W.J., et al. DDW 216. Presentation 768.

21 Subject in clinical remission (%) Ustekinumab for Crohn s disease Phase III clinical trial data: Uniti long term extension Clinical remission was well maintained over time No new safety signals identified in LTE ITT analysis % 77.4% 74.4% 72.6% 4 2 UST 9 mg q12w (n = 84) UST 9 mg q8w (n = 82) ITT, intent-to-treat population. Time (weeks) Sandborn WJ, et al. Poster presented at ECCO 217; #OP1.

22 New therapies in IBD: what does the future hold? Drugs that IL-23 signalling: anti P19 Risankizumab Anti P4 Ustekinumab : Phase III induction and maintenance in CD Anti P19 Risankizumab: Phase II induction and OLE in CD Ustekinumab

23 Randomised 1:1:1 Drugs that target IL-23: what does the future hold? anti P19 Risankizumab phase II data 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 N=41 Risankizumab 2 mg iv q4w Week 12 Deep remission? Period 3 Open label sc therapy N=39 Placebo iv Yes Flare* Wash out Dosing Day 1 Wk 12 Primary endpoint: Clinical remission at Week 12 Wk 14 Wk 26 Clinical remission defined as a CDAI <15. Deep remission is defined as clinical remission and endoscopic remission (CDEIS of 4; for patients with isolated ileitis of CDEIS 2). *If CDEIS score >4 (or above 2 for patients with initial isolated ileitis), patients to receive open-label iv induction therapy (6 mg risankizumab x 3 q4w). ClinicalTrials.gov identifier, NCT CDAI, Crohn s Disease Activity Index; CDEIS, Crohn s Disease Endoscopic Index of Severity

24 Drugs that target IL-23: what does the future hold? anti P19 Risankizumab phase II data Methods: Phase 2, placebo-controlled, double-blind, 12-week induction trial (3 doses) Results: Endoscopies at baseline and at week 12 assessed by blinded central reader 94.2% were anti-tnf experienced; 56-59% had >2 prior anti-tnfs Week 12 Efficacy (primary endpoint): Clinical remission at week 12 Endoscopic response at week 12 Feagan BG, et al. Presented at DDW. May 216. Abstract 768. Endoscopic response > 5% fall in CDEIS

25 Proportion of patients (%) Drugs that target IL-23: what does the future hold? anti P19 Risankizumab phase II data Period 1 induction regimen Placebo Risankizumab 2 mg 6 mg Patients entering period Patients in deep remission entering wash out 1 5 Patients receiving 6 mg risankizumab Clinical remission 8 7 Week 12 (after randomised blinded therapy) Week 26 (after OL 6 mg risankizumab therapy or wash out) n/n 6/39 1/41 15/41 18/39 22/41 22/41 Week 12 Week 26 Placebo 2 mg Risankizumab 6 mg Risankizumab

26 Positioning IL12/IL23 blockade in Crohn s disease Practical questions for ustekinumab Does it work in the real world Should you persist if no response to IV dose Should I use it in combination with azathioprine Does it heal perianal disease Should I measure drug levels Is it safe outside of clinical trials?

27 Practical questions for ustekinumab Does it work in the real world? Retrospective Cohort Study 167 UST Treated CD Patients Primary outcome: clinical & objective response & remission at 3, 6 & 12 months Clinical response: HBI fall of 3 points, clinical remission: HBI 4 points Objective remission: improvement in endoscopic or radiographic (CT/MRE) Ma C, et al. Presented at DDW. May 217. Abstract Sa1967.

28 Proportion of Subjects (%) Practical questions for ustekinumab Should you persist if no response to iv dose? Delayed responders: clinical response and remission 8 weeks after first SC dose 1 Non-responders to 13mg or 6mg/kg IV 8 6 Response 5.5 N=467 Remission * Subjects who were in clinical response to ustekinumab IV induction dosing and were randomised to placebo SC on entry to this maintenance study ** Includes data up to Week 44 Note: Only maintenance Week 8 responders continued to receive UST (n=251) Subjects who had insufficient data to calculate the CDAI score at the designated analysis timepoint are considered not to be in clinical remission Sands BE, et al. UEGW 216. Presentation 5.

29 Patients in clinical remission (%) Practical questions for ustekinumab Should you persist if no response to iv dose? Clinical remission through Week 44: delayed responders group from induction 1 8 Randomized 9 mg SC q8w (N = 128) Non-responders to UST IV induction (given 9 mg SC q8w; N = 251) % 53.7% 53.4% 5.2% Time (weeks) Of 467 patients given induction treatment at week, 251 were in clinical response and continued to receive 9 mg SC q8w in the maintenance study These data provide clinical rationale for providing at least 1 SC maintenance dose of UST irrespective of clinical response 8 weeks after IV induction, as described in the EU SmPC SmPC, summary of product characteristics. Adapted from Colombel J-F, et al. Presented at ACG 217; P2133. Ustekinumab SmPC, EMA, date of implementation: October 217.

30 Proportion of Patients (%) Proportion of Patients (%) Practical questions for ustekinumab Does it heal perianal disease? Methods A combined post-hoc analysis of UNITI-1, UNITI-2 and CERTIFI Results 12.3% had active perianal fistula (161 patients) Fistula Resolution (1% Reduction) at Week 8 Among Randomized Patients with Open, Draining Fistulas at Baseline in Pooled Data from CERTIFI, UNITI-1 and UNITI Placebo P=.134 P=.52 P= /71 16/66 18/65 37/15 1 mg/kg and 13 mg 6 mg/kg and ~6 mg/kg Ustekinumab All UST Doses Combined Patients in Fistula Response ( 5% Reduction) in Primary Population Through Week 44 (52 Weeks Post-Induction) in IM-UNITI UST Induction Week 8 Clinical Responders with Open, Draining Fistulas at Baseline Randomized to SC Ustekinumab or Placebo in IM-UNITI at Each Visit Through Week n=21 n=21 n=21 n=13 n=13 n=13 Placebo SC n=2 n=13 n=17 n=17 n=13 n=13 n=17 n=13 Combined SC UST n=16* n=16* n=15* n=12 n=12 n=12 n=15* n=15 n=12 n= Weeks Post Maintenance *P<.5 Sands et al. Presented at DDW. May

31 Median serum UST concentration (μg/l) Practical questions for ustekinumab Should I use in combination with azathioprine? No difference in response rates in Phase III clinical trials Retrospective French cohort of 122 anti TNF refractory patients showed response of 65% at 3/12: IM at baseline increased OR of clinical response 5.45 (95%CI ; p=.3) Median serum UST concentrations in IM-UNITI UST 6 mg/kg IV (I) 9 mg SC q8w (M) Receiving AZA, 6-MP, or MTX Not receiving AZA, 6-MP, or MTX MP, 6-mercaptopurine; AZA, azathioprine; MTX, methotrexate. Adapted from Adedokun OJ, et al. Presented at ACG 217; P2163.

32 Practical questions for ustekinumab Should I measure drug levels? Simple answer currently not available! Clinical remission at week 24 Based on ROC analyses, trough concentrations of μg/ml or greater were associated clinical remission CRP normalisation at week 24

33 Number of TB Cases per 1 Patient-Years Practical questions for ustekinumab Is it safe? Lower Rates of Active TB with ustekinumab than anti-tnf Agents Compared safety data in Phase 2/3 trials for ustekinumab, infliximab and golimumab across all indications Active TB cases were significantly lower with ustekinumab compared to anti-tnf therapy (n=2, <.1% vs. n=58,.5%) Frequency (%) (Drug vs. Comparator) Ustekinumab (n=6,581) Anti-TNF (11,839) <.1 vs...5 vs. <.1 Active TB Cases 2 58 Exposure in Patient Years 12,122 2,538 Active TB cases per 1 patient-years % Confidence Intervals Active TB Cases Per 1 Patient-Years in the All Trial Populations (95% CI=.21,.37) (95% CI= 1..,.6) Anti-TNF All Trial Anti-IL12/23 All Trial 1,2 3 Population Population Exposure in Patient Years Loftus EV, et al. Presented at DDW. May 217. Abstract

34 Events per 1 patient-years Practical questions for ustekinumab Is it safe? 4 Cumulative incidence rates of serious infections of interest per 1 patient-years (PY) in PSOLAR registry Ustekinumab* Infliximab* Adalimumab* Cohort Overall population* Adapted from Kalb R et al Study limitations inherent to observational studies including treatment selection and patient participation biases due to the lack of randomisation. Limitations specific to the PSOLAR study include: some differences were noted in patient characteristics across biologic cohorts at entry into the registry; statistical significance may not necessarily connote clinical relevance. Error bars are representative of 95% CI. 1 All products have specific benefits and risks, please see each product's Summary of Product Characteristics for full details. *Data are shown by treatment cohort in the overall population. The overall population includes patients who received a biologic agent before (prevalent population) or after (incident population) enrolling in the registry Kalb R, et al. JAMA Dermatol. 215; 151:

35 Positioning IL12/IL23 blockade in Crohn s disease Factors that drive biologic treatment decisions Disease phenotype Disease activity / perianal disease / EIM Patient comorbidity Age / previous malignancy / risk of infection Previous treatment history Therapeutic drug monitoring with anti TNF agents Adverse events Cost biosimilar revolution Patient preference Route of administration

36 Positioning IL12/IL23 blockade in Crohn s disease Conclusions: IL-12/23 blockade is a third class of biologic therapy Ustekinumab is licensed for use in the UK Efficacy in anti TNF failures as well as naïve NICE approved for first and second line use Rizankizumab is in phase III trial development No head to head trials to compare efficacy Treatment decisions relate to patient factors / cost Increasing options should drive careful patient monitoring to allow therapy to be optimised