Regulatory Decision Summary for Zeposia

The efficacy of oral ozanimod in the treatment of relapsing-remitting multiple sclerosis (RRMS) was established on the results of two pivotal Phase 3 studies conducted in patients diagnosed with relapsing multiple sclerosis (RMS): Studies RPC01-301 and RPC01-201B. The overall safety evaluation assessed data obtained from a total of 24 clinical studies of ozanimod, including 7 Phase 2 and 3 studies and 17 clinical pharmacology studies.

Both pivotal Phase 3 studies were multi-center, randomized, double-blind, double-dummy, active-controlled (30 µg of interferon (IFN) β-1a intramuscular (IM), weekly), parallel-group studies to evaluate the efficacy and safety of ozanimod in the treatment of subjects with RRMS. The main difference between the two Phase 3 studies was the duration of treatment, which was 24 months for Study RPC01-201B, and up to approximately 22 months (mean duration of 13.6 months) for Study RPC01-301, where treatment was continued until all subjects received a minimum of 12 months of treatment. Additionally, Magnetic Resonance Imaging (MRI) assessments were conducted at Months 6 and 12 in Study RPC01-301, whereas in Study RPC01-201B, they were conducted at Months 12 and 24. Statistically significant reductions in the Annualized Relapse Rate (ARR; primary endpoint) were demonstrated for ozanimod 0.92 mg and 0.46 mg, compared with IFN β-1a. In Studies RPC01-301 and RPC01-201B, this corresponded to a 48.2% and 37.7% reduction, respectively, with ozanimod 0.92 mg compared to a 31.2% and 21% reduction, respectively, with ozanimod 0.46 mg relative to treatment with IFN β-1a. Similarly, the reduction in the mean number of new or enlarging hyperintense T2-weighted brain MRI lesions per brain scan over 12 and 24 months was 48.3% and 42.3%, respectively, with ozanimod 0.92 mg compared to 24.6% and 34.3%, respectively, with ozanimod 0.46 mg, relative to IFN β-1a. For the mean number of Gadolinium-Enhanced (GdE) T1 brain MRI lesions, the reductions were 63% and 53%, at 12 and 24 months respectively, for ozanimod 0.92 mg, compared to 33.8% and 47.2%, respectively, with ozanimod 0.46 mg, relative to IFN β-1a. In pre-specified pooled analyses, disability progression, as measured by the percent reduction in time to onset of Confirmed Disability Progression (CDP) at 3 Months and at 6 Months (CDP-3M and CDP-6M, respectively), was similar between both the ozanimod and the IFN β-1a treatment groups; no disability progression claim is sought for ozanimod.

The safety profile of oral ozanimod has been investigated in a subject population comprised mainly of participants evaluated in the RRMS clinical program. The program involved 2,787 subjects with over 7,200 person-years of follow-up, including 2,491 subjects treated with ozanimod 0.92 mg for more than 1 year, 1,069 treated for more than 2 years, and 521 treated for more than 3 years. As a result of both the integrated and trial-specific safety analyses, and the known pharmacokinetics/pharmacodynamics and mechanism of action of ozanimod, the following important risks are identified in the Product Monograph (PM):

• Heart rate reduction;
• Hepatic enzyme increased ;
• Infections (including herpetic, cryptococcal, progressive multifocal leukoencephalopathy);
• Posterior reversible encephalopathy;
• Macular edema;
• Embryofetal toxicity;
• Serotonin toxicity, due to potential interaction between the monoamine oxidase (MAO) inhibitory activity of the major metabolite and serotonergic or opioid drugs.

Risk mitigation measures have been outlined in the PM for management of these risks, including appropriate contraindications, warnings, guidance, dosage considerations, screening and monitoring measures. Nevertheless, uncertainty surrounds long-term risk of malignancies, cardiovascular morbidity and withdrawal effects following ozanimod discontinuation. These risks were considered as missing information for inclusion in the Risk Management Plan (RMP).

Phase I clinical pharmacology studies identified the interaction effects of the following agents on ozanimod and the major active metabolites:

1. Breast Cancer Resistance Protein (BCRP; increased exposure of active metabolites);
2. Strong CYP2C8 inhibitors (increased exposure of active metabolites);
3. Strong CYP2C8 inducers (reduced exposure of active metabolites);
4. Monoamine oxidase (MAO) inhibitors (co-administration can decrease active metabolite exposure since CC112273 is formed by MAO-B).

The potential for clinical interaction with MAO inhibitors has not been studied. Hence, there is uncertainty with regards to risk of non-selective MAO inhibition and consequent hypertensive crisis. Furthermore, interaction with food items containing high amounts of tyramine could cause severe hypertension due to potential risk of non-selective MAO-A inhibition in the gastrointestinal (GI) tract. Adrenergic and serotonergic agents were not identified as risks in Phase I studies. However, hypertensive crisis has occurred with Zepozia 0.92 mg alone and with co-administration of other selective and nonselective MAO inhibitors (for example, rasagiline) with sympathomimetic medications, and serotonin toxicity with concomitant use of MAO inhibitors (including selective MAO-B inhibitors) with opioid drugs and/or serotonin medications. Repeated dosing of ozanimod (7-day dose escalation followed by 0.92 mg daily for 5 days) had no effect on the single-dose pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE, 35 µg) and norethindrone (NE, 1 mg), which are substrates of cytochrome P450 (CYPs) 3A, 2C19, and 2C9. Ozanimod dosing was not long enough to attain steady state for CC112273 or CC1084037 but in vitro data showed that CC112273 or CC1084037 does not inhibit or induce CYP enzymes.

Considering the above safety issues identified during the review and the appropriate management of these risks, the Benefit-Harm-Uncertainty profile for oral ozanimod in the treatment of RRMS is favourable.