Regulatory Decision Summary for Zeposia

This SNDS was filed to add an indication for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, loss of response, or were intolerant to either conventional therapy or a biologic agent. The proposed indication was supported by a phase 3 pivotal trial (RPC01-3101) that was composed of two sub-studies evaluating the Induction of remission and Maintenance of remission, respectively, a supportive phase 2 trial (RPC01-202), and an open label extension trial (RPC01-3102).

Study RPC01-3101 was composed of two multicenter, randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of ozanimod in the Induction of remission (referred to as TRUENORTH-I in the Product Monograph) and Maintenance of remission (referred to as TRUENORTH-M). Adult patients with active moderate to severe UC were eligible to enroll if they had a previously inadequate response, loss of response, or were intolerant to either conventional therapy or biologic agents. Additionally, patients were required to be taking concomitant 5-aminosalysilic acids (5-ASA; also known as mesalazine) for the duration of the trial and/or oral corticosteroids until at least week 10.

In TRUENORTH-I, 429 patients were treated with Zeposia (0.92 mg) and 216 patients were treated with placebo for 10 weeks. The primary efficacy endpoint was the percentage of patients achieving clinical remission according to a validated 3-component Mayo score at week 10. Clinical remission consisted of a rectal bleeding subscore of 0, a stool frequency subscore ≤ 1 (and a decrease of ≥ 1 point from the Baseline Stool Frequency subscore) and an endoscopy subscore ≤ 1 without friability (these subscores are each assessed a score of 0-3, with 3 being most severe). Key secondary endpoints included clinical response, endoscopic improvement, and mucosal healing.

Subjects who completed TRUENORTH-I and achieved clinical response or remission were eligible to enter the maintenance period in TRUENORTH-M. In this study, 230 patients were treated with Zeposia (0.92 mg) and 227 were treated with placebo. In order to provide sufficient clinical responders for the maintenance period, an open-label cohort additionally enrolled 367 patients to receive Zeposia treatment. The primary efficacy endpoint was the percentage of patients achieving clinical remission at week 52. Key secondary endpoints additionally included maintenance of remission and corticosteroid-free remission.

The results showed a statistically significant (p = < 0.0001) induction of clinical remission at week 10 in patients treated with Zeposia 0.92 mg daily (18%), compared to placebo daily (6%). Key secondary endpoints provided additional support for the superiority of Zeposia in inducing remission, including the proportion of patients achieving (i) clinical response (Zeposia 48%; placebo 26%), (ii) endoscopic improvement (Zeposia 27%; placebo 12%), and (iii) mucosal healing (Zeposia 13%; placebo 4%;). Of those who achieved induction of clinical response or remission, a statistically significant (p = < 0.0001) percentage of patients were able to meet the primary efficacy endpoint of clinical remission at week 52 (Zeposia 37%; placebo 19%). Key secondary endpoints provided additional support for the superiority of Zeposia in maintaining remission, including the proportion of induction period responders who met (i) clinical response (Zeposia 60%; placebo 41%), (ii) endoscopic improvement (Zeposia 46%; placebo 26%), (iii) mucosal healing (Zeposia 30%, placebo 14%), (iv) corticosteroid-free clinical remission (Zeposia 32%; placebo 17%), and (v) the maintenance of clinical remission at week 52 in the subset of patients in remission at week 10 (Zeposia 52%, placebo 29%).

Subgroup analysis suggested generally lower efficacy in patients ≥ 65 years of age, in those with more severe or longer-term UC, and in those with prior anti-TNF biologic usage. These groups also showed worse outcomes when treated with placebo compared to other sub-groups. Notably, comprising only 5% of enrolled subjects, patients ≥ 65 years of age had a reduced benefit of Zeposia during induction period treatment (15.8% achieved remission with Zeposia vs. 7.1% in placebo) and no benefit compared to placebo in the maintenance period (23.1% achieved remission with Zeposia vs 25% re-randomized to placebo). This disparity between induction and maintenance periods was observed across all secondary endpoints. As a result, the indication for geriatric patients was restricted to the induction period only.

In terms of safety, the results demonstrate that Zeposia has an acceptable safety profile consistent with S1P receptor modulators and risk characteristics in the multiple sclerosis treatment setting. Important potential risks include cardiac effects, hypertension, malignancies, infections, elevated hepatic enzymes, macular edema, and pulmonary effects. All of these events are adequately labelled for and were not seen at higher rates in the UC population. Furthermore, Zeposia was shown to be generally well-tolerated for up to approximately 5.5 years in subjects with moderately to severely active UC.

Health Canada considers that the benefit-harm-uncertainty profile of Zeposia (ozanimod) (0.92 mg daily) is favourable for the treatment of moderately to severely active UC who have had an inadequate response, loss of response, or were intolerant to either conventional therapy or a biologic agent.