P1659 - The Evolution of Clinical Trial Design in Ulcerative Colitis: Interpreting Future Endpoints Based on Post-Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1

Monday, October 25, 2021

10:30 AM – 4:15 PM PT

Location: Shoreline Exhibit Hall

Has Audio

Presenting Author(s)

William J. Sandborn, MD

University of California San Diego
San Diego, CA, United States

William J. Sandborn, MD¹, Bruce E. Sands, MD, MS², Sharif Uddin, ³, Karen Lasch, MD³, Rana Qasim Khan, MD, CPM³
¹University of California San Diego, San Diego, CA; ²Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY; ³Takeda Pharmaceuticals USA, Inc., Lexington, MA

Introduction: Ulcerative colitis (UC) is a chronic, relapsing disease characterized by inflammation of the colon. In UC clinical trials, the Mayo score is used to assess outcomes. The 12-point total Mayo (t-Mayo) score incorporates measures of stool frequency, rectal bleeding, endoscopic findings, and a Physician Global Assessment (PGA) of disease activity. However, because the PGA may not fully capture improvements across all signs and symptoms associated with UC, in 2016 the US Food and Drug Administration (FDA) issued guidance advising removal of the PGA in favor of a broader patient- or observer-reported outcome instrument for future trials.¹We examined how endpoints in UC trials have evolved in response to FDA guidance and conducted a post hoc analysis of two vedolizumab trials, GEMINI 1 and VISIBLE 1, to understand how use of a 9-point modified Mayo (m-Mayo) score, excluding PGA, compares with the t-Mayo score.

Methods: Endpoint definitions of clinical remission in phase 3 trials of biologic maintenance treatment were extracted from published literature and ClinicalTrials.gov. For post hoc analysis of data from GEMINI 1 and VISIBLE 1, we measured the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 according to a range of four selected endpoint definitions of differing stringency (Figure 1).

Results: Phase 3 UC trials completed up to the end of 2019 used the t-Mayo score to assess the endpoint of clinical remission. Trials that began in 2015 or later and were completed or estimated to be completed in 2020 or later used m-Mayo scores that excluded the PGA (Table 1). Post hoc analysis of GEMINI 1 and VISIBLE 1 data revealed a trend of increasing %Δ values as the stringency of endpoint definition decreased. The second-least stringent definition produced %Δ values most like those reported for GEMINI 1 and VISIBLE 1 using the t-Mayo score (Figure 1).

Discussion: Endpoint definitions for UC clinical trials have evolved following FDA guidance to remove the subjective PGA. Our post hoc analysis of GEMINI 1 and VISIBLE 1 reveals that the effectiveness of vedolizumab, measured using endpoint definitions like those used in recent UC trials (Figure 1, definitions C and D), was comparable to that previously reported using the t-Mayo score.

1. US FDA. 2016. Available from: www.fda.gov/regulatory-information/search-fda-guidance-documents/ulcerative-colitis-clinical-trial-endpoints-guidance-industry

Figure: Figure 1. Difference between the proportion of patients achieving clinical remission with vedolizumab versus placebo at week 52 in the GEMINI 1 and VISIBLE 1 trials according to each of four endpoint definitions of differing stringency and the primary analysis definition.

*Patients received intravenous vedolizumab once every 8 weeks. † Patients received subcutaneous vedolizumab once every 2 weeks. ǂNew definitions are based on most (A) to least (D) stringent criteria.
(A) RBS = 0, ES = 0, and ≥ 1-point decrease in SFS from baseline to achieve a subscore of 0 or 1
(B) RBS = 0, ES = 0, SFS ≤ 1 (0 or 1)
(C) RBS = 0, ES ≤ 1 (0 or 1), and ≥ 1-point decrease in SFS from baseline to achieve a subscore of 0 or 1
(D) RBS = 0, ES ≤ 1 (0 or 1), SFS ≤ 1 (0 or 1)
(E) Total Mayo score at week 52 ≤ 2 with no individual subscore > 1
CI, confidence interval; ES, endoscopic subscore; RBS, rectal bleeding subscore; SFS, stool frequency subscore.
1. Feagan BG et al. New Engl J Med 2013;369:699–710. 2. Sandborn WJ et al. Gastroenterology 2020;158:562–72.

Biologic name	Phase 3 UC trial [ClinicalTrials.gov number]	Trial completion date	Primary endpoint definition (clinical remission, maintenance phase)*
Risankizumab	M16-066 [NCT03398135]	Estimated May 2024	Modified Mayo score at week 52
Upadacitinib	U-ACHIEVE [NCT02819635]	Estimated June 2022	Modified Mayo score^† at week 52. SFS ≤ 1 and not greater than baseline, RBS = 0, and ES ≤ 1
Ustekinumab	UNIFI [NCT02407236]	Estimated November 2021	Total Mayo score^ǂ at week 52 ≤ 2 and no individual subscore > 1. Alternative primary endpoint: modified Mayo score^† at week 52. Absolute stool number ≤ 3, RBS = 0, and ES ≤1
Ozanimod	True North [NCT02435992]	June 2020	Modified Mayo score^† at week 52. RBS = 0 , SFS ≤ 1 (and a decrease of ≥ 1 point from baseline SFS), and ES ≤ 1
Filgotinib	SELECTION [NCT02914522]	March 2020	EBS score^† at week 58. ES ≤ 1, RBS = 0, and ≥ 1-point decrease in stool frequency from baseline to achieve a subscore ≤ 1
Vedolizumab	VARSITY [NCT02497469]	January 2019	Total Mayo score^ǂ at week 52 ≤ 2 and no individual subscore > 1
Vedolizumab	VISIBLE 1 [NCT02611830]	August 2018	Total Mayo score^ǂ at week 52 ≤ 2 and no individual subscore > 1
Vedolizumab	GEMINI 1 [NCT00783718]	March 2012	Total Mayo score^ǂ at week 52 ≤ 2 and no individual subscore > 1
Adalimumab	ULTRA 2 [NCT00408629]	March 2010	Total Mayo score^ǂ at week 52 ≤ 2 and no individual subscore > 1
Infliximab	ACT 1 [NCT00036439]	January 2007	Total Mayo score^ǂ at week 54 ≤ 2 and no individual subscore > 1

Table: Table 1. Endpoint definitions for clinical remission during maintenance treatment in phase 3 UC trials.

*For the ACT1 infliximab trial, the primary endpoint was clinical response and clinical remission was a secondary endpoint. †Excludes Physician Global Assessment. ǂIncludes Physician Global Assessment.
EBS, endoscopy/bleeding/stool frequency; ES, endoscopic subscore; RBS, rectal bleeding subscore; SFS, stool frequency subscore; UC, ulcerative colitis.

Disclosures:

William Sandborn: Abbvie – Consultant, Grant/Research Support. Abivax – Consultant, Grant/Research Support. Admirx – Consultant. Alfasigma – Consultant. Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust) – Consultant. Alivio Therapeutics – Consultant. Allakos – Consultant. Allakos – Stockholder/Ownership Interest (excluding diversified mutual funds). Amgen – Consultant. Applied Molecular Transport – Consultant. Arena Pharmaceuticals – Consultant, Grant/Research Support. Bausch Health (Salix) – Consultant. Beigene – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Bellatrix Pharmaceuticals – Consultant. Boehringer Ingelheim – Consultant, Grant/Research Support. Boston Pharmaceuticals – Consultant. Bristol Meyers Squibb – Consultant. Celgene – Consultant, Grant/Research Support. Celltrion – Consultant. Cellularity – Consultant. Cosmo Pharmaceuticals – Consultant. Equillium – Consultant. Escalier Biosciences – Consultant. Genentech/Roche – Consultant, Grant/Research Support. Gilead Sciences – Consultant, Grant/Research Support. Glaxo Smith Kline – Grant/Research Support. Glenmark Pharmaceuticals – Consultant. Gossamer Bio – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Immunic (Vital Therapies) – Consultant. Index Pharmaceuticals – Consultant. Intact Therapeutics – Consultant. Janssen – Consultant, Grant/Research Support. Kyverna Therapeutics – Consultant. Landos Biopharma – Consultant. Lilly – Consultant, Grant/Research Support. Oppilan Pharma – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Otsuka – Consultant. Pandion Therapeutics – Consultant. Pfizer – Consultant, Grant/Research Support. Progenity – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Prometheus Biosciences – Consultant, Grant/Research Support, Stockholder/Ownership Interest (excluding diversified mutual funds). Prometheus Laboratories – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Protagonists Therapeutics – Consultant. Provention Bio – Consultant. Reistone Biopharma – Consultant. Seres Therapeutics – Consultant, Grant/Research Support. Shanghai Pharma Biotherapeutics – Consultant. Shire – Consultant, Grant/Research Support. Shoreline Biosciences – Consultant, Employee, Stockholder/Ownership Interest (excluding diversified mutual funds). Sublimity Therapeutics – Consultant. Surrozen – Consultant. Takeda – Consultant, Grant/Research Support. Theravance Biopharma – Consultant, Grant/Research Support. Thetis Pharmaceuticals – Consultant. Tillotts Pharma – Consultant. UCB – Consultant. Vendata Biosciences – Consultant. Ventyx Biosciences – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Vimalan Biosciences – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Vivelix Pharmaceuticals – Consultant. Vivreon Biosciences – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Zealand Pharma – Consultant.

Bruce Sands: AbbVie – Consultant. Abivax – Consultant. Alimentiv – Consultant. Allergan – Consultant. Amgen – Consultant. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant. Bacainn Therapeutics – Consultant. Baxalta Biosciences India – Consultant. Boehringer-Ingelheim – Consultant. Boston Pharmaceuticals – Consultant. Calibr – Consultant. Capella Bioscience – Consultant. Celgene – Consultant. Celltrion Healthcare – Consultant. ClostraBio – Consultant. F.Hoffmann-La Roche – Consultant. Galapagos – Consultant. Gilead – Consultant. Gossamer Bio – Consultant. Immunic – Consultant. Index Pharmaceuticals – Consultant. Innovation Pharmaceuticals – Consultant. Ironwood Pharmaceuticals – Consultant. Janssen – Consultant. Johnson & Johnson – Consultant. Lilly – Consultant. Morphic Therapeutic – Consultant. Oppilan Pharma – Consultant. OSE Immunotherapeutics – Consultant. Otsuka – Consultant. Pfizer – Consultant. Progenity – Consultant. Prometheus Biosciences – Consultant. Prometheus Laboratories – Consultant. Protagonist Therapeutics – Consultant. Q32 Bio – Consultant. Redhill Biopharma – Consultant. Rheos Medicines – Consultant. Salix Pharmaceuticals – Consultant. Seres Therapeutics – Consultant. Shire – Consultant. Surrozen – Consultant. Takeda – Consultant. Target RWE – Consultant. Theravance Biopharma R&D – Consultant. USWM Enterprises – Consultant. Vivelix Pharmaceuticals – Consultant.

Sharif Uddin: Takeda Pharmaceuticals U.S.A., Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Karen Lasch: Takeda Pharmaceuticals U.S.A., Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Rana Qasim Khan: Takeda Pharmaceuticals U.S.A., Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

William J. Sandborn, MD¹, Bruce E. Sands, MD, MS², Sharif Uddin, ³, Karen Lasch, MD³, Rana Qasim Khan, MD, CPM³. P1659 - The Evolution of Clinical Trial Design in Ulcerative Colitis: Interpreting Future Endpoints Based on Post-Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.