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. 2025 Jan 8;120(10):2339-2349.
doi: 10.14309/ajg.0000000000003310. Online ahead of print.

Impact of Prior Biologic Exposure on Ozanimod Efficacy and Safety in the Phase 3 True North Clinical Trial

Bruce E Sands  1 , David T Rubin  2 , Edward V Loftus Jr  3 , Douglas C Wolf  4 , Remo Panaccione  5 , Jean-Frederic Colombel  1 , Axel Dignass  6 , Miguel Regueiro  7 , Severine Vermeire  8 , Anita Afzali  9 , Garrett Lawlor  10 , Harris A Ahmad  10 , Hsiuanlin Wu  10 , Mark T Osterman  10 , Anjali Jain  10 , Geert D'Haens  11
Affiliations

Impact of Prior Biologic Exposure on Ozanimod Efficacy and Safety in the Phase 3 True North Clinical Trial

Bruce E Sands et al. Am J Gastroenterol. .

Abstract

Introduction: Patients with ulcerative colitis (UC) and prior biologic failure may have reduced or delayed efficacy with subsequent advanced therapies. This analysis evaluated the efficacy and safety of ozanimod during the True North (TN) study and its open-label extension (OLE) in biologic-exposed patients with UC.

Methods: TN was a randomized, placebo-controlled 52-week trial (10-week induction, 42-week maintenance period). Eligible patients could enter the OLE. Clinical outcomes were assessed at TN week (W) 10 and W52 and OLE W46 and W94. Symptomatic efficacy was evaluated through induction and in the OLE until W94. Safety was assessed.

Results: This analysis included 376 biologic-exposed patients. In the placebo-controlled cohort, more ozanimod-treated patients achieved clinical response than placebo at W10 regardless of the number or type of prior biologics; patients who used 1 vs ≥2 prior biologics achieved higher efficacy rates. Efficacy rates were higher at W52 than W10 and were similar across subgroups regardless of the number or type of prior biologics. Significantly greater proportions of ozanimod vs placebo patients achieved symptomatic response by W5 ( P = 0.0173) and symptomatic remission by W10 ( P = 0.0207). Among biologic-exposed TN W10 ozanimod nonresponders who entered the OLE, 61% achieved symptomatic response with an extra 10 weeks of ozanimod treatment. Ozanimod efficacy was durable for ∼3 years of continuous treatment in biologic-exposed W52 clinical responders who entered the OLE. No new safety signals were observed.

Discussion: Ozanimod was effective and safe in biologic-exposed patients with UC, but these patients may require more time to respond to treatment. Clinical trial registry website and trial numbers: ClinicalTrials.gov , numbers NCT02435992 and NCT02531126.

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Conflict of interest statement

Guarantor of the article: Bruce E. Sands, MD, MS, FACG.

Specific author contributions: B.E.S., D.T.R., E.V.L., D.C.W., R.P., J.F.C., A.D., M.R., S.V., A.A., and G.D.: data interpretation and approval of the final draft. G.L. and A.J.: conceptualization, data analysis, data interpretation, and approval of final draft. H.A.A. and M.T.O.: conceptualization, data interpretation, and approval of final draft. H.W.: data acquisition, data analysis, and approval of final draft.

Financial support: This work was supported by Bristol Myers Squibb, Princeton, NJ, USA.

Potential competing interests: B.E.S.: received consulting fees from AbbVie, Adiso Therapeutics, AgoMab, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fresenius Kabi, Fiat, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sanofi, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, UNION Therapeutics, and Ventyx; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Eli Lilly; research grants, consulting and speaking fees, and other support from Bristol Myers Squibb, Janssen, Pfizer, and Takeda; research grants and consulting fees from Theravance Biopharma; stock/stock options from Ventyx. D.T.R.: received grant support from Takeda; served as a consultant for AbbVie, AltruBio, Apex Pharma, Avalo Therapeutics, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect Biopharma, Eli Lilly, Intouch Group, Iterative Health, Janssen, Pfizer, Samsung NeuroLogica, and Takeda; serves on the board of trustees for the Crohn's & Colitis Foundation and on the board of directors for Cornerstones Health. E.V.L.: received consulting fees from AbbVie, Alvotech, Amgen, Arena, Astellas, Avalo Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota Biosciences, Iterative Health, Janssen, Merck, Morphic, Ono Pharma, Protagonist, Sun Pharma, Surrozen, Takeda, TR1X Bio, and UCB; received research support from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Gossamer Bio, Janssen, Receptos, Takeda, Theravance, and UCB; shareholder of Exact Sciences. D.C.W.: received research funding from AbbVie, Arena/Pfizer, Celgene/Bristol Myers Squibb, Genentech, and Janssen; lectured for AbbVie, Bristol Myers Squibb, Janssen, and Takeda; consulted for AbbVie, Arena/Pfizer, Celgene/Bristol Myers Squibb, Eli Lilly, Janssen, and Takeda. R.P.: received consulting fees from Abbott, AbbVie, Abivax, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, BioJAMP, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Therapeutics, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, UCB, Ventyx, and Viatris; received speaker fees from AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; served on an advisory board for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, BioJAMP, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Ventyx. J.F.C.: received research grants from AbbVie, Janssen, and Takeda; received payment for lectures from AbbVie, Amgen, Allergan, Bristol Myers Squibb, Ferring, Shire, and Takeda; received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Enterome, Ferring, Genentech, Gilead, Immunic, Imtbio, Inotrem, Ipsen, Iterative Scopes, Janssen, Landos, LimmaTech Biologics AG, MedImmune, Merck, Novartis, OMass, Otsuka, Pfizer, Shire, Takeda, TiGenix, and Viela Bio; holds stock options in Intestinal Biotech Development. A.D.: received fees for participation in clinical trials and review activities (i.e., data monitoring boards, statistical analysis, and endpoint committees) from AbbVie, Abivax, Bristol Myers Squibb, Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; received consultancy fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene/Bristol Myers Squibb, Celltrion, Eli Lilly, Falk, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead, Janssen, Johnson & Johnson, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Tillotts, Vifor, and Zeria; received payment for lectures, including service on speaker bureaus, from AbbVie, Alfasigma, Eli Lilly, Falk Foundation, Ferring Pharmaceuticals, Galapagos, Janssen, MSD, Pfizer, Takeda, Tillotts, and Vifor; received payment for development of educational presentations from Ferring Pharmaceuticals and Tillotts. M.R.: served on advisory boards or as a consultant for AbbVie, Alfasigma, Allergan, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Miraca Labs, Pfizer, Prometheus, Salix, Seres, Takeda, Target PharmaSolutions, and UCB. S.V.: received grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda; received consultancy and/or speaker fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena, AstraZeneca, Celgene, CVasThera, Cytoki Pharma, Dr. Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, IMIDomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, and Zealand. A.A.: served as a consultant for AbbVie, Bristol Myers Squibb, DiaSorin, Eli Lilly, Gilead, Janssen, Pfizer, Takeda, and TLL Pharmaceuticals; received speaker fees from AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Takeda. G.L., H.A.A., H.W., M.T.O., and A.J.: employees and/or shareholders of Bristol Myers Squibb. G.D.: served as an advisor for AbbVie, Agomab Therapeutics, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Exeliom Biosciences, Ferring, Galapagos, GlaxoSmithKline, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Ventyx; received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.

Writing support: Support for third-party writing assistance for this manuscript was provided by Anny Wu, PharmD, and Julie Ko, PharmD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.

Data transparency statement: Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. Deidentified individual patient data will not be shared.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Efficacy of ozanimod vs placebo by the number of prior biologics in biologic-exposed patients. (a) Efficacy at week 10 of the IP by 1 biologic and ≥2 biologics. (b) Efficacy at week 52 of the MP by 1 biologic and ≥2 biologics. “Δ” represents the difference between ozanimod and placebo in cohort 1 of the IP and between ozanimod (ozanimod/ozanimod) and placebo (ozanimod/placebo) in the MP. CI, confidence interval; IP, induction period; MP, maintenance period.
Figure 2.
Figure 2.
Ozanimod efficacy by prior biologic type. (a) Week 10 efficacy outcomes in patients previously exposed to anti-TNFs, vedolizumab, or both. (b) Week 52 efficacy outcomes in patients previously exposed to anti-TNFs, vedolizumab, or both. “Δ” represents the difference between ozanimod and placebo in cohort 1 of the IP and between ozanimod (ozanimod/ozanimod) and placebo (ozanimod/placebo) in the MP. CI, confidence interval; CS, corticosteroid; IP, induction period; MP, maintenance period; NE, not estimable; TNF, tumor necrosis factor.
Figure 3.
Figure 3.
Onset of action. (a) Symptomatic response and (b) symptomatic remission during the IP of True North. Shading represents the 1-week dose titration of ozanimod. IP, induction period.
Figure 4.
Figure 4.
Symptomatic efficacy from OLE week 5 to week 94 in biologic-exposed patients who were TN week 10 ozanimod clinical nonresponders and subsequently entered the OLE for extended induction treatment with ozanimod. (a) OC and (b) NRI analyses. Denominators for the OC (n) analyses were based on the numbers of patients who completed the OLE timepoint and had data available for the endpoints in question. Denominators for the NRI analyses (n) were based on the numbers of patients who completed the OLE timepoint or discontinued ozanimod. NRI, nonresponder imputation; OC, observed case; OLE, open-label extension; TN, True North; W, week.
Figure 5.
Figure 5.
Efficacy at OLE weeks 46 and 94 in biologic-exposed patients who were TN week 10 ozanimod clinical nonresponders and subsequently entered the OLE for extended induction treatment with ozanimod. (a) OC and (b) NRI analyses. Denominators for the OC analyses were based on the numbers of patients who completed OLE weeks 46 or 94 and had data available for the endpoints in question. Denominators for the NRI analyses were based on the numbers of patients who completed OLE week 46, completed OLE week 94, or discontinued ozanimod treatment. CS, corticosteroid; NRI, nonresponder imputation; OC, observed case; OLE, open-label extension; TN, True North; W, week.
Figure 6.
Figure 6.
Efficacy at OLE weeks 46 and 94 in biologic-exposed patients who were TN week 52 ozanimod clinical responders and subsequently entered the OLE. (a) OC and (b) NRI analyses. CS, corticosteroid; NRI, nonresponder imputation; OC, observed case; OLE, open-label extension; TN, True North.
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