Predicting response to anti - integrin therapy: long term efficacy and roles for optimisation with vedolizumab.

Transcription

1 Predicting response to anti - integrin therapy: long term efficacy and roles for optimisation with vedolizumab. Dr Peter Irving Guy s and St Thomas Hospital, London King s College London

2 Response to vedolizumab Can we predict who will do well on an anti-integrin?

3 Who responds to anti-integrin therapy? People with IBD

4 Patients, % Vedolizumab Phase 3 UC Study (GEMINI I): Primary and Secondary Outcomes at 6 Weeks Primary Outcome Induction ITT Population* Secondary Outcomes PBO (n=149) VDZ (n=225) ** ** Clinical Response Clinical Remission Mucosal Healing Mean % vs PBO (95% CI) 21.7 ( ) 11.5 ( ) 16.1 ( ) ITT, intention-to-treat; PBO, placebo; VDZ, vedolizumab; *Included patients in Cohort 1 who were randomized to and received study drug in induction; P<.1 vs placebo **p=.1 Adapted From: Feagan et al. Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. NEJM 13; 369:699-71

5 Who responds to anti-integrin therapy? People with IBD although you might have to wait a bit longer in Crohn s disease

6 Patients, % Vedolizumab in Crohn s (GEMINI II): CDAI response at 6 weeks GEMINI II - ITT Population* P= PBO (n=148) VDZ (n=2) CDAI-1 Response Adapted From: Sandborn WJ et al. Vedolizumab as Induction and Maintenance Therapy for Crohn's disease. NEJM 13;369:

7 Percentage of patients achieving CDAI-1 response (enhanced clinical response) Vedolizumab in Crohn s (GEMINI II): Response at 1 and 14 weeks in patients who failed to show a CDAI-7 response at week Placebo 1 7 Vedolizumab 5 Week 1 Week 14 Results shown for patients who failed to demonstrate CDAI-7 response at week 6 in GEMINI II and who were retained in the study and received vedolizumab every four weeks. Adapted From: Vedolizumab Summary of Product Characteristics : Last accessed Dec 14; Sandborn WJ et al. Vedolizumab as Induction and Maintenance Therapy for Crohn's disease. NEJM 13;369:

8 % of patients with clinical remission (95% CI) Vedolizumab in Crohn s (GEMINI II and III): Induction of remission by prior TNF usage at 6 weeks Placebo Vedolizumab P=NS N=7 N=15 N=157 N=158 N=76 N=19 N=5 N=51 Anti-TNF failure Anti-TNF naïve GEMINI II GEMINI III GEMINI II GEMINI III Adapted From: Vedolizumab briefing document for the joint meeting of the gastrointestinal drugs advisory committee and drug safety and risk management advisory committee. Takeda Pharmaceuticals USA. Inc. Last accessed Nov 14

9 GEMINI 2 post hoc analysis: CDAI composite score of stool frequency and abdominal pain (change from baseline) % Change from Baseline CDAI composite score of SF score and abdominal pain Overall ITT PBO VDZ -3 Feagan B, et al. ACG 17. Abstract P Baseline Week 2 Week 4 Week 6 95% CI of n , -2.4* 215 VDZ, 141 PBO PBO (n=149) VDZ (n=225) -14.3, -1.3* 197 VDZ, 139 PBO -16.8, -2.* 7 VDZ, 139 PBO

10 ACG P1273 UEGW OP97 GEMINI 1 post hoc analysis: Rectal bleeding subscore in UC (change from baseline) % Change from Baseline Overall ITT PBO (n=149) VDZ (n=225) Baseline Week 2 Week 4 Week 6 Feagan B, et al. ACG 17. Abstract P1273. UEGW 17. Abstract OP97.

11 Who responds to anti-integrin therapy? People with IBD particularly if it is their first biologic

12 Patients, % GEMINI I Prior Anti-TNFα outcomes at week 6 Total population Anti-TNFα Failure Patients PBO VDZ Clinical Response Clinical Remission Clinical R 22.7 (1

13 % of patients achieving Clinical Remission (95% CI) Vedolizumab in Crohn s (GEMINI II and III): Induction of remission at 6 and 1 weeks 4 Overall Population TNFα Failure Population * P= # P= # P< # P= # P= P=NS Placebo Vedolizumab C137 GEMINI Week C1311 II GEMINI 6 Week C1311 III GEMINI 6 Week III 1 C137* GEMINI Week C1311* II GEMINI 6 C1311* Week III GEMINI 6 Week III1 Week 6 Week 6 Week 1 Week 6 Week 6 Week 1 # P value is for descriptive purpose only (exploratory analysis); * 48% of patients in Gemini II & 75% of patients in Gemini III Adapted From: Sandborn WJ et al. Vedolizumab as Induction and Maintenance Therapy for Crohn's disease. NEJM 13;369: & Supplementary Appendix; Sands BE et al. Effects of Vedolizumab Induction Therapy for Patients With Crohn s Disease in Whom Tumor Necrosis Factor Antagonist Treatment Had Failed. Gastroenterology 14;147:

14 Who responds to anti-integrin therapy? People with EIMs and perianal disease?

15 Probability Vedolizumab in patients with arthritis or arthralgia Post hoc analysis of GEMINI II 516 patients with small joint arthritis/arthralgia 367 VDZ induction & maintenance 71 VDZ induction & PLA maintenance 78 PLA induction & maintenance Patients at Risk: VDZ VDZ/PLA PLA Study Day VDZ VDZ/PLA PLA + Censored Feagan BG, et al. Presented at DDW. May 17. Abstract Su Sustained resolution of arthritis/arthralgia at 1 year: VDZ 51% (95%CI: 44-58%) VDZ/PLA 41% (27-56%) PLA 36% (-51%) Cox proportional hazards regression analysis: VDZ group 32% more likely to achieve sustained resolution than PLA HR 1.32 (95% CI: ) VDZ group 29% less likely to develop new occurrences than PLA HR.71 (95% CI: ) 15

16 Percentage of Patients (%) Percentage of Patients (%) Vedolizumab in patients with EIM or perianal disease Post-hoc Analysis of the OBSERVE-IBD Cohort (GETAID) Prospective, multi-center, observational study: 294 IBD (173 CD, 121 UC) Efficacy of VDZ on Inflammatory Arthralgia/Arthritis Of the 294 IBD patients included at week, 46 (15.6%) had inflammatory arthralgia/arthritis VDZ Discontinuation Partial Remission 1% 8% 6% 4% % % 2.1% 2.1% 63.8% 47.% 32.% 17.% 2.1% 31.9% W6 No Response Complete Remission 1.6% 27.7% 34.% 21.% 48.9% 57.4% 55.3% 44.7% W14 W22 W3 W54 In multivariate analysis, predictors of complete remission of inflammatory arthralgia/arthritis was the presence of clinical remission of IBD (according to HBI or partial Mayo Clinic score) Efficacy of VDZ Active Fistulizing Perianal CD Of the 173 CD patients included at week, 35 (.2%) had active fistulizing perianal disease VDZ Discontinuation Partial Remission 1% 8% 6% 4% % % 65.7% 48.6% 42.9% 5.7% 5.7% 45.7% 5.7% 2.9% 2.9%.% 34.3% 31.4% 28.6% 42.9% 48.6% 34.3% 34.3% W6 No Response Complete Remission W14 W22 W3 W54 No-response: no improvement or worsening of symptoms Partial response: reduced secretion or discomfort from fistulas or closure of one or more of the fistula Complete remission: closure of all fistulas evaluated by thumb pressure or patient announcement of no secretion Tadbiri S, et al. Presented at DDW. May 17. Abstract Sa

17 Long term efficacy of vedolizumab Zinc Job Number:UK/EYV/1412/8 Date of Preparation: December 14

18 Patients, % Vedolizumab in UC (GEMINI I): Primary and Secondary Outcomes at 52 Weeks Primary Outcome Maintenance ITT Population* Secondary Outcomes 8.7 VDZ/PBO (n=126) VDZ/VDZ Q8W (n=122) VDZ/VDZ Q4W (n=125) Mean % vs PBO Clinical Remission Durable Clinical Response Mucosal Healing Durable Clinical Remission CS-Free Remission CS, corticosteroid; ITT, intention-to-treat; PBO, placebo; VDZ, vedolizumab; *Included patients randomized and responded to VDZ induction, then randomized to and received study drug in maintenance; P<.1 vs placebo; P<.5 vs placebo Adapted From: Feagan et al. Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. NEJM 13; 369:699-71

19 Patients, % Vedolizumab in Crohn s (GEMINI II): Primary and Secondary Outcomes at 52 Weeks 5 Maintenance ITT Population* Primary Outcome Secondary Outcomes P=.5 P=.4 P=.1 P< P= P= VDZ/PBO (n=153) VDZ/VDZ Q8W (n=154) VDZ/VDZ Q4W (n=154) P= NS P= NS Clinical Remission CDAI-1 Response CS-Free Remission Durable Remission CDAI, Crohn s Disease Activity Index; CS, corticosteroid; ITT, intention-to-treat; PBO, placebo; VDZ, vedolizumab; *Included patients randomized and responded to VDZ induction, then randomized to and received study drug in maintenance; P<.1 vs placebo; P<.5 vs placebo; CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved Adapted From: Sandborn WJ et al. Vedolizumab as Induction and Maintenance Therapy for Crohn's disease. NEJM 13;369:

20 GEMINI LTS UAE/EYV/917/26

21 Patients, % Patients, % Patient population (VDZ/Q4W Q4W + VDZ/Q8W Q4W) Analyses 1. NRI 2. As observed Clinical response and remission rates were similar regardless of prior TNF antagonist history Efficacy with continuous VDZ based on TNF history GEMINI 1 VDZ maintenance completers GEMINI LTS GEMINI 1 GEMINI LTS Clinical response Clinical remission Weeks of exposure All TNF-failure patients, n (NRI) TNF-failure patients with data, n (as observed) All TNF-naïve patients, n (NRI) TNF-naïve patients with data, n (as observed) * Number of patients without data have not been statistically evaluated. Abbreviations: NRI, nonresponder imputation; Q4W, every 4 weeks; Q8W, every 8 weeks; TNF, tumour necrosis factor; VDZ, vedolizumab. Loftus EV, et al. Long-term efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis. 16. In press. Adapted from Figure 3. UAE/EYV/917/26 As observed * NRI As observed * NRI TNF-failure TNF-naïve TNF-failure TNF-naïve

22 Patients, % Patients, % Long-term effectiveness in UCcomparing GEMINI 1 + OLE: 5-year to. 3-year data To conduct a 5-year exploratory, interim analyses of effectiveness in patients with UC who had completed GEMINI 1 and were enrolled in the ongoing GEMINI OLE (LTS), compared to 3-year data 1 Clinical response 1 Clinical remission year data Δ=28% 5-year data year data Δ=26% 5-year data Weeks of exposure Patents, n (NRI 5 years) Patients, n (NRI 3 years) NRI analysis of 5-year data now includes patients with completed 152 week time points Increase in response (Δ=28%) and remission (Δ=26%) compared to 3-year interim analyses 2 Abbreviations: LTS, long-term study; NRI, non-responder imputation; OLE, open-label extension; UC, ulcerative colitis; VDZ, vedolizumab. 1. Loftus EV Jr, et al. DDW. 17. Su Loftus EV Jr, et al. ECCO 17 P9. 3. Loftus EV Jr, et al. J Crohns Colitis. 17;11: GLO/EYV/17-28

23 Patients, % Patients, % Efficacy with continuous VDZ based on TNF history GEMINI 2 VDZ maintenance completers GEMINI LTS Patient population VDZ/Q4W Q4W + VDZ/Q8W Q4W Analyses 1. NRI 2. As observed Clinical response rates were similar regardless of prior TNF antagonist history Rates of clinical remission were numerically higher in patients who were TNF antagonist naïve GEMINI 2 GEMINI LTS Clinical response Clinical remission Weeks of exposure All TNF-failure patients, n (NRI) TNF-failure patients with data, n (as observed) All TNF-naïve patients, n (NRI) TNF-naïve patients with data, n (as observed) *Number of patients without data have not been statistically evaluated. Abbreviations: NRI, nonresponder imputation; Q4W, every 4 weeks; Q8W, every 8 weeks; TNF, tumour necrosis factor; VDZ, vedolizumab. Vermeire S, et al. Long-term efficacy of vedolizumab for Crohn s disease. J Crohns Colitis. 16. In press. Adapted from Figure 3. UAE/EYV/917/26 As observed * * NRI As observed NRI TNF-failure TNF-naïve TNF-failure TNF-naïve

24 A variety of real world data are now published for vedolizumab Shelton, US Samaan, UK Vivio, US Baumgart, Germany Dulai, US Amiot, France

25 Real world data shows favourable response and remission rates with vedolizumab in UC Week 6 Amiot et al. Baumgart et al. Chaudrey et al. Mankongpaisarnrung et al.* Shelton et al. Week 12 Christopher et al. Dulai et al. $ Höög et al. $$ Week 14 Amiot et al. Baumgart et al. Chaparro et al. Christensen et al. Eriksson et al. Shelton et al. Vivio et al. N RESPONSE % (95% CI) REMISSION % (95% CI) (32-51) 43 (33-52) 66 (35-9) NR 45 (29-62) 83 (36-1) 16 (8-29) 5 (25-75) 57 (48-66) 61 (51-7) 71 (53-87) 5 (27-73) 4 (12-74) 54 (4-67) NR 32 (24-41) 11 (6-19) NR 71 (29-96) 15 (6-3) NR 9 (3-19) 19 (4-46) 39 (3-48) 24 (16-32) 25 (1-44) 4 (19-64) NR 29 (18-43) 55 (27-79) Week 22 Amiot et al (49-68) 41 (32-51) Week 26 Peerani et al. $ 114 Höög et al. $$ (34-53) 18 (4-46) 26 (19-35) 5 (3-8) Week 3 Amiot et al (44-63) 42 (33-52) Week 52 Amiot et al. 121 Peerani et al. $ (38-56) 83 (75-9) 43 (34-52) 72 (63-8) % 25% 5% 75% 1% % 25% 5% 75% 1% Data on file, Takeda Pharmaceuticals. Systematic analysis of published and unpublished data * 6-8 weeks ** Induction phase response/remission Poster data Median 1 weeks (range -21) $ Cumulative rate $$ 1-12 weeks

26 VEDOLIZUMAB REAL-WORLD EFFECTIVENESS: Clinical response and remission in Crohn s Disease * Median Follow-up 1 weeks (range -21 weeks) ** 8-12 weeks *** 1-14 weeks $ Cumulative rate CI, confidence interval; NR, not reported

27 % Patients High persistence rates are seen at 6 and 12 months with vedolizumab 1 6 Months Persistence 12 Months Induction Completion All patients 69% Bio-naive 81% Bio-experienced 62% 74% 76% Treatment refractory 69% 59% 84% N=42 N=16 N=26 N=8 Patel et al. N=78 Visaria et al. N=16 Hoog et al.* N=121 Amiot et al. N=45 Vivio et al. Raluy-Callado et al. US VICTORY: Baseline albumin <3 and anti-tnf exposure predicted LOR Amiot, et al. ECCO 16; Hoog et al. ECCO 16; Patel, et al. Data on File (submitted to ACG 16); Raluy-Callado, et al. ECCO 16; Visaria, et al. Data on File (submitted to ACG 16); Vivio EE, et al. J Crohns Colitis 16;1:

28 Long term optimisation Mucosal healing

29 Patients with mucosal healing* (%) Real world mucosal healing rates in UC patients on vedolizumab range from 57 69% N=29 N=114 N= NR N=14 Vivio et al Peerani et al Chaudrey et al Christensen et al At median 22 weeks At 52 weeks Time point not reported * Mucosal healing defined as Mayo endoscopic scre or 1, except Vivio colonoscopic evaluation Vivio EE, et al. J Crohn s Colitis. 16;1:42-9 Peerani, et al. DDW 16:Sa1888 Chaudrey, et al. AIBD 15:P-33 Christensen, et al. ACG 15:P35.

30 Vedolizumab Mucosal Response in CD: US VICTORY Data % Muscosal Healing Deep Remission Months 12 Months 6 Months 12 Months Endoscopic/Radiologic Assessment Endoscopic Assessment Only (n=141) (n=121) Mucosal healing Lack of ulcers and/or erosions Median time to mucosa healing 33 weeks (21-44) Dulai PS, et al. Am J Gastroenterol. 16;111:

31 Long term optimisation Retreatment after withdrawal

32 Patients, % Patients, % Patient population (VDZ/PBO Q4W) Received VDZ induction Had response at week 6 Randomised to PBO from week 6 to week 52 during maintenance Completed GEMINI 1 Received VDZ Q4W during GEMINI LTS Analyses 1. NRI Patients with up to 1 year of interrupted therapy experienced clinical benefits after retreatment Efficacy following retreatment GEMINI 1 PBO maintenance completers GEMINI LTS Abbreviations: LTS, long-term safety; NRI, nonresponder imputation; PBO, placebo; Q4W, every 4 weeks; TNF, tumour necrosis factor; VDZ, vedolizumab. Loftus EV, et al. Long-term efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis. 16. In press. Figure All PBO patients PBO with TNF failure PBO TNF naïve GEMINI 1 (VDZ/PBO) Clinical response Clinical remission TNF-failure TNF-naïve All patients PBO GEMINI LTS (VDZ/PBO Q4W) TNF-failure PBO with TNF failure TNF-naïve PBO TNF naïve Data missing for 13 total ongoing patients Data missing for 13 total ongoing patients Study week All patients, n TNF-failure patients, n TNF-naïve patients, n UAE/EYV/917/26

33 Patients, % Patients, % Efficacy following retreatment GEMINI 2 PBO maintenance early withdrawers GEMINI LTS Patient population VDZ/PBO Q4W Received VDZ induction Had response at week 6 Randomised to PBO during maintenance Withdrew early from GEMINI 2 because of sustained nonresponse, disease worsening, or the need for rescue medication Received VDZ Q4W during GEMINI LTS Analyses NRI GEMINI 2 (VDZ/PBO) Clinical response Clinical remission Total GEMINI LTS (VDZ/PBO Q4W) TNF-failure TNF-naïve Data missing for 3 total ongoing patients Data missing for 3 total ongoing patients Patients with up to 1 year of interrupted therapy experienced clinical benefits after retreatment UAE/EYV/917/26 Total TNF-failure TNF-naïve Study week All patients, n TNF-failure patients, n TNF-naïve patients, n Abbreviations: LTS, long-term safety; NRI, nonresponder imputation; PBO, placebo; Q4W, every 4 weeks; TNF, tumour necrosis factor; VDZ, vedolizumab. 22 Vermeire S, et al. Long-term efficacy of vedolizumab for Crohn s disease. J Crohns Colitis. 16. In press. Figure 6.

34 Long term optimisation Dose increase after LOR

35 Patients, % Patients, % Effects of increased VDZ dosing frequency GEMINI 1 VDZ maintenance Q8W early withdrawers GEMINI LTS Patient population (VDZ/Q8W Q4W) Received VDZ induction Had response at week 6 Randomised to VDZ Q8W during maintenance Withdrew early from GEMINI 1 because of sustained nonresponse, disease worsening, or the need for rescue medication Received VDZ Q4W during GEMINI LTS Analyses 1. NRI Results suggest a subset of patients may benefit from an increase in dosing frequency GEMINI 1 (VDZ/Q8W) All patients Q8W TNF-failure Q8W-TNF failure Q8W-TNF naïve TNF-naïve Clinical response All patients Study week All patients, n TNF-failure patients, n TNF-naïve patients, n Q8W TNF-failure TNF-naïve Q8W-TNF failure Q8W-TNF naïve Abbreviations: LTS, long-term safety; Q4W, every 4 weeks; Q8W, every 8 weeks; TNF, tumour necrosis factor; VDZ, vedolizumab. Loftus EV, et al. Long-term efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis. 16. In press. Figure 6. UAE/EYV/917/26 GEMINI LTS (VDZ/Q8W Q4W) Clinical remission Data missing for 1 total ongoing patients Data missing for 1 total ongoing patients

36 Patients, % Patients, % Effects of increased VDZ dosing frequency GEMINI 2 VDZ maintenance Q8W early withdrawers GEMINI LTS Patient population VDZ/Q8W Q4W Received VDZ induction Had response at week 6 Randomised to VDZ Q8W during maintenance Withdrew early from GEMINI 2 because of sustained nonresponse, disease worsening, or the need for rescue medication Received VDZ Q4W during GEMINI LTS Analyses NRI Results suggest a subset of patients may benefit from an increase in dosing frequency GEMINI 2 (VDZ/Q8W) Abbreviations: LTS, long-term safety; NRI, nonresponder imputation; Q4W, every 4 weeks; Q8W, every 8 weeks; TNF, tumour necrosis factor; VDZ, vedolizumab. Vermeire S, et al. Long-term efficacy of vedolizumab for Crohn s disease. J Crohns Colitis. 16. In press. Figure 7. UAE/EYV/917/26 Total GEMINI LTS (VDZ/Q8W Q4W) TNF-failure TNF-naïve Total TNF-failure TNF-naïve Data missing for total ongoing patients Clinical response Data missing for total ongoing patients Clinical remission Study week All patients, n TNF-failure patients, n TNF-naïve patients, n

37 Further opportunities to optimise Drug levels

38 Percent of Patients VDZ Concentration at Week 6 (μg/ml) High Baseline C-Reactive Protein, Low Albumin, and High Body Mass Index Lower Vedolizumab Drug Levels Aims: To understand the relation between VDZ drug exposure and efficacy Methods: ELISA for measuring serum drug levels and antibodies were developed and applied to 37 VDZ-naïve patients at trough during induction Results: Patients with baseline CRP >1 mg/l and higher BMIs had significantly lower VDZ trough concentrations at week 2 Baseline serum Alb <4 g/l associated with significantly lower VDZ trough concentration at week 6 Patients with a decrease in CRP between week and 6 had higher VDZ trough concentrations at week 6 Alb, albumin; BMI, body mass index VDZ, vedolizumab; Gils A, et al. Presented at DDW. May 16. Abstract CRP Decrease CRP Increase * p=.46 CRP Increase CRP Decrease VDZ Concentration at Week 6 (μg/ml) 16.3 >16.3 to 24.9 >24.9 to 35.1 >35.1

39 CDAI<15 CDAI>15 Week 6 vedolizumab level predicts subsequent clinical outcome 47 consecutive patients with IBD refractory to x2 anti-tnfs 3 required dose escalation within first 6 months wk1 wk14 wk18 wk wk2 wk6 wk14 Week 6 TL: <18.5 mg/ml predicts need for dose escalation in first 6 months (AUC.72). >27.5 mg/ml predicts sustained response in 9% of patients (AUC.57). <19. mg/ml predicts response to dose intensification at week 1 (AUC.72). At this time, the benefits of therapeutic drug monitoring with vedolizumab have not been established. This is an area for further clinical research. Takeda suggest dose adjustments of vedolizumab should be based on clinical response, within permitted parameters as defined in the vedolizumab approved labelling and prescribing information. AUC: area under the curve; TL: trough level. Williet N, et al. Clinical Gastroenterology and Hepatology 17 [in press]

40 Further opportunities to optimise Combo therapy?

41 Survival without development of clearing antibody Survival without development of clearing antibody Immunomodulators reduce immunogenicity to biologics Infliximab Adalimumab Baseline immunomodulator TRUE FALSE.25 HR =.37( ) p = HR =.31( ) p = Years PANTS study (unpublished) Years

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