*3.3. Ozanimod*

Ozanimod, a S1PR1 and S1PR5 modulator, that has been studied in two phase III clinical trials, RADIANCE Part B and SUNBEAM, the most recent agen<sup>t</sup> in this class to receive regulatory approval. Each of these trials was a randomized, double-blind, double-dummy, parallel group, active-controlled study, evaluating the efficacy and safety of daily oral OZM 0.5 mg or 1 mg versus weekly IFNβ-1a 30 μg IM in patients with RRMS. Following its ingestion, OZM is partly transformed into 2 primary metabolites, CC112273 and CC1084037, which account for the bulk of OZM pharmacological effects, each with a t1/2 elimination of approximately 11 days, compared to 19–22 h for OZM itself [85].

### 3.3.1. RADIANCE Part B

RADIANCE Part B [98], a 24 month trial, included 1,313 patients with RRMS randomized to daily oral OZM 0.5 mg (*n* = 439), OZM 1 mg (*n* = 433) or weekly IFN β-1a 30 μg IM (*n* = 441). Inclusion criteria were ages 18–55 years, EDSS 0.0–5.0, diagnosis of RRMS, and evidence of active disease over the prior 24 months. Exclusion criteria included recent myocardial infarction, TIA, stroke, prolonged QTc interval, resting heart rate < 55 bpm, Type I diabetes, or uncontrolled Type II diabetes.

The primary endpoint in RADIANCE Part B was ARR at each OZM dose versus interferon β-1a over 24 months of treatment. Key secondary endpoints included number of new or enlarging T2 brain lesions, number of Gd+ brain lesions, and time to three-month CDP. Other secondary endpoints included relative rate of whole brain volume loss. Exploratory outcomes included relative changes in cortical grey matter and thalamic volumes over the 2 years of observation. Because of its superior efficacy, regulatory approval was only given the 1.0 mg dose. The 0.5 mg data are not presented. ARR at two years was 0.172 for OZM and 0.276 for IFN β-1a, a relative reduction of 38% favoring OZM (*p* < 0.0001). There was a 42% relative reduction in new and enlarging T2 lesions with OZM treatment compared to IFNβ-1a (*p* < 0.001). The relative reduction in number of Gd+ enhancing brain lesions at two years was 53% in OZM-treated patients (*p* = 0.0006) compared to patients treated with IFNβ-1a. There were no statistically significant di fferences between OZM and IFNβ-1a treatment in time to three-month CDP. Relative reduction in brain volume loss at 2 years was 27% less in OZM (*p* < 0.0001) than in IFNβ-1a treated patients. Relative cortical gray volume loss was reduced by 58% in patients treated with OZM (*p* < 0.0001) and relative thalamic volume loss at 2 years was reduced by 32% (*p* < 0.0001) in patients receiving OZM.
