Ozanimod Effective, Durable in Patients with Ulcerative Colitis Naive to Advanced Therapy

Findings from a post hoc analysis of the phase 3 True North study and its open-label extension are highlighting ozanimod’s efficacy and durability in patients with ulcerative colitis (UC) who are naive to advanced therapy and whose UC is inadequately controlled by conventional therapies.¹

Results showed ozanimod’s rapid onset of action, with symptomatic response and remission in numerically greater proportions of patients versus placebo as early as 2 weeks after treatment initiation. Compared with findings in the total population, the advanced therapy-naive subgroup experienced significant improvements with ozanimod numerically similar or slightly greater across all clinical and mucosal efficacy endpoints at weeks 10 and 52.¹

An oral, highly selective sphingosine 1-phosphate receptor modulator, ozanimod is approved in multiple countries for the treatment of moderately to severely active UC and relapsing forms of multiple sclerosis. Findings from the randomized, double-blind, placebo-controlled, phase 3 True North study were used to support its US Food and Drug Administration approval in 2021 and showed ozanimod is an effective, durable, and well-tolerated oral therapy for advanced therapy-naive UC patients, but its use as a first-line treatment merits further exploration.^1,2

“Given the favorable benefit–risk ratio, ozanimod may be considered as a first-line treatment after conventional therapies,” Bruce Sands, MD, Dr Burrill B Crohn Professor of Medicine at Mount Sinai, and colleagues wrote.¹

True North included a 10-week induction period and a 42-week maintenance period. Patients in cohort 1 were randomly assigned in a 2:1 ratio to receive double-blind ozanimod 0.92 mg or placebo once daily in the induction period through week 10, while patients in cohort 2 received open-label ozanimod 0.92 mg once daily.¹

All patients treated with ozanimod who achieved clinical response at week 10 were re-randomized in a 1:1 ratio to receive double-blind ozanimod 0.92 mg or placebo once daily in the maintenance period through week 52. Patients who received ozanimod and achieved clinical response at week 52 could continue ozanimod in the ongoing open-label extension and will be evaluated through week 94.¹

The present post hoc analysis assessed ozanimod during True North and the ongoing open-label extension in patients with active disease who were exposed to conventional therapies but naive to advanced therapies. Clinical, endoscopic, and mucosal outcomes were evaluated at the end of induction and maintenance as well as at predefined open-label extension time points (week 46 and week 94).¹

Of the 1012 patients enrolled in True North, 616 (60.9%) were advanced therapy-naive (placebo, n = 137; ozanimod cohort 1, n = 287; ozanimod cohort 2, n = 192). Investigators noted demographic and clinical characteristics were similar across the induction treatment groups in advanced therapy-naive patients.¹

At the end of induction, 62% of advanced therapy-naive patients on ozanimod from cohorts 1 and 2 achieved clinical response and were rerandomized to receive placebo (n = 152) or ozanimod (n = 145) in the maintenance period. At week 52, 82 advanced therapy-naive patients maintained clinical response while on continuous ozanimod treatment during the induction period and maintenance period and subsequently entered the open-label extension. A total of 122 advanced therapy-naive patients who did not achieve a clinical response to ozanimod at week 10 subsequently entered the open-label extension.¹

By week 2, numerically greater proportions of patients receiving ozanimod than placebo achieved symptomatic response (39% vs 29%; 95% CI, –0.1 to 18.8), with significant differences (56% vs 39%; 95% CI, 6.3 to 26.3) achieved by week 4. Investigators observed similar trends when looking at rates of symptomatic remission with ozanimod.¹

At week 10, clinical remission was achieved by a significantly greater proportion of advanced therapy-naive patients who received ozanimod in cohort 1 compared with placebo (23.0% vs 6.6%; P <.0001). Significant improvements with ozanimod compared with placebo were also observed for secondary endpoints in the advanced therapy-naive population, as well as in subgroups based on prior mesalamine and immunomodulator exposure and baseline endoscopic severity.¹

In advanced therapy-naive patients who entered the open-label extension in clinical response after 52 weeks of ozanimod treatment in True North, investigators pointed out 90.9% maintained clinical response after an additional 2 years of ozanimod at open-label extension week 94. Clinical remission, endoscopic improvement, mucosal healing, and corticosteroid-free remission were achieved by 70.9%, 73.7%, 57.1%, and 69.1% of patients, respectively.¹

In advanced therapy-naive patients who failed to achieve a clinical response after 10 weeks of ozanimod induction therapy, 53.5% and 62.4% were able to achieve symptomatic response with an additional 5 and 10 weeks of ozanimod treatment in the open-label extension, respectively, and 18.4% and 23.9% achieved symptomatic remission at open-label extension weeks 5 and 10, respectively.¹

Investigators noted safety outcomes in advanced therapy-naive patients were consistent with the total True North population. Although a single death occurred in a patient receiving ozanimod during the induction period, the patient had a history of ischemic cardiomyopathy and prolonged tobacco use and developed influenza and acute respiratory distress syndrome. Otherwise, incidences of bradycardia, cancer, herpes zoster, serious infections, and macular edema were low with ozanimod (≤1.6%).¹

Investigators noted several potential limitations to these findings, including True North’s lack of power to investigate patient subpopulations, the lack of control of groups and blinding in the open-label extension, and the lack of generalizability of the study population to the broader advanced therapy-naive population in clinical settings.¹

“This analysis of advanced therapy-naive patients demonstrated that ozanimod has rapid onset of high and durable efficacy rates across clinical and mucosal outcomes and a favorable safety profile,” investigators concluded.¹ “These data inform the early use of ozanimod in patients who require an advanced therapy and suggest that ozanimod may be optimally positioned after or in combination with mesalamine and before corticosteroids, particularly in those with moderate endoscopic disease.”

References

1. ^{Sands BE, D’Haens G, Panaccione R, et al. Ozanimod in Patients With Moderate to Severe Ulcerative Colitis Naive to Advanced Therapies. Clinical Gastroenterology and Hepatology. https://doi.org/10.1016/j.cgh.2024.03.042}
2. ^{Walter, K. FDA Approves Ozanimod for Adults with Ulcerative Colitis. HCPLive. May 27, 2021. Accessed June 27, 2024. https://www.hcplive.com/view/fda-ozanimod-adults-ulcerative-colitis}