P0200 Mirikizumab, guselkumab, and risankizumab did not differ in remission efficacy adjusting for imbalanced treatment discontinuation in network meta-analysis of treat-through trials for Crohn’s disease

Abstract Background Traditional Crohn’s disease (CD) trials used a re-randomisation design, but more recent trials, including trials with the interleukin (IL)-23p19 inhibitors mirikizumab, guselkumab, and risankizumab, used a treat-through design vs a direct comparator ustekinumab; however, there were clinically relevant different trial settings. The U.S. Food and Drug Administration raised concerns on the reliability of network meta-analysis (NMA) results with such limitations. This study developed an adjustment method to address the heterogeneity of these trials using the imbalanced discontinuation rates and to test the impact of the proposed bias adjustments in NMA. Methods The studies VIVID-1, GALAXI 2-3, and SEQUENCE were identified for this NMA and only patients with a previous failure of a biologic were considered. While VIVID-1 and GALAXI 2-3 had a similar design, SEQUENCE was open label and presented an uncommon heterogeneous discontinuation rate between the study arms (9.8% for risankizumab vs 27.2% for ustekinumab). We developed a method and applied in 3 scenarios to adjust the risk difference based on a clinical assumption about the outcomes of the excess discontinuers in the ustekinumab arm and incorporated it into an NMA. Scenario one assumed that the higher amount of non-completers in the ustekinumab arm would respond like the completers, if they had not discontinued the study. For the second and third scenarios, different downgrade factors were applied to mitigate the strength of the assumption. The outcomes presented are clinical remission and endoscopic remission at 48/52 weeks. Results The data included only bio-failed patients that presented comparable values regarding age, sex, SES-CD, and CDAI across the studies. After the three adjustments, clinical remission achievement rates for ustekinumab in the study SEQUENCE were 50.5%, 49.5%, and 47.8%, respectively, compared to the unadjusted 40.8%. Endoscopic remission achievement rates for ustekinumab in the study SEQUENCE were 20.1%, 19.7%, and 19.0% compared to the unadjusted 16.2%. The NMA showed comparable efficacy across the IL-23s in all three situations. Conclusion Across different approaches, this study explored the impact of different adjustments for discontinuation bias in an NMA of CD IL-23p19 treat-through trials. Consistent results were observed across adjusted approaches compared to the unadjusted NMA. No difference in remission efficacy was observed across mirikizumab, guselkumab, and risankizumab. Conflict of interest: Dr. Mckenzie, Robert: I work full time for Eli Lilly and a shareholder Sands, Bruce E: Grant: Janssen Personal Fees: Abivax SA Abbvie Adiso Therapeutics Agomab Therapeutics Alimentiv Amgen AnaptysBio AstraZeneca Biora Therapeutics Boehringer-Ingeleim Bristol Myers Squibb Celltrion, Inc. ClostraBio Cytoki Pharma EcoR1 Capital Eli Lilly and Company Enthera Equilium, Inc. Ensho Therapeutics Evommune Ferring Galapagos Genentech, Inc. Gilead Sciences GlaxoSmithKline Gossamer Bio Imhotex Immunyx Pharma Ltd. Index Pharmaceuticals Innovation Pharmaceuticals Janssen Janssen Biotech Janssen Pharmaceutica NV Janssen Research & Development, LLC Janssen Scientific Affairs, LLC Janssen-Cilag PTY, Ltd. Johnson & Johnson Kaleido Kallyope Kyowa Kirin, Inc. Merck & Co. Microba Microbiotica Limited Mirador Therapeutics Morphic Therapeutic MRM Health NV Palisade Therapeutics Pfizer, Inc. Prometheus Biosciences Prometheus Laboratories Protagonist Therapeutics, Inc. Q32 Bio Sanofi Sorriso Therapeutics Surrozen Takeda Target RWE Teva TLL Pharmaceutical Tr1x Union Therapeutics Ventyx Biosciences Non-financial Support: Janssen, Pfizer, Lilly, Takeda, Bristol Myers Squibb Other: Stock/Stock Options from Ventyx Biosciences Dignass, Axel: Personal Fees: AbbVie, Alfasigma, CED Service GmbH, Celltrion, Dr. Falk Pharma, Falk Foundation, Ferring, Fresenius Kabi, Gilead, High5MD, J & J, Lilly, Materia Prima, MSD, Pfizer, Pharmacosmos, Sandoz, Stada, Streamed-Up, Takeda, Tillotts, Vifor Pharma Grant Abbvie, J & J, Takeda Non-financial support Abbvie, J & J, Takeda Other: Abivax, AbbVie, Alfasigma, Dr Falk Pharma, Fewrring, J & J, Pfizer Hisamatsu, Tadakazu: Grant support: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd. Consulting: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax, MSD, Chugai. Lecture fee: Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Kissei Pharmaceutical Co. Ltd. Panni, Tommaso: I am a full time employee by Eli Lilly and a shareholder tarafder, abdul_masud: I am a full time employee at Eli Lilly and a shareholder Richards, Melissa: work for Eli Lilly and Co, pharmaceutical company De La Torre Ortega, Inmaculada: Lilly employee Fewster, Harriet: No conflict of interest Moss, Joe: No conflict of interest