Double-Blinded Extension of the RADIANCE Trial Demonstrates the Efficacy and Safety of Ozanimod in Patients With Multiple Sclerosis

Background

Sphingosine 1-phosphate (S1P) is a phospholipid that is involved in many biological processes, including lymphocyte migration. Fingolimod, the first S1P receptor modulator approved for treating relapsing multiple sclerosis (MS), nonselectively targets 4 of the 5 S1P receptors: S1P₁, S1P₃, S1P₄, and S1P₅. Modulation of S1P₁ prevents immune cells from entering circulation, whereas antagonism of S1P₅ may promote neuronal protection. Ozanimod is a S1P receptor modulator that selectively targets S1P₁ and S1P₅.¹

The efficacy and safety of ozanimod in patients with relapsing MS were evaluated in the RADIANCE trial. In part A of the phase II, randomized, placebo-controlled RADIANCE trial, both doses of ozanimod (0.5 mg and 1 mg) significantly reduced the mean cumulative number of gadolinium (Gd)-enhancing lesions and new or enlarging T2-hyperintense lesions over 12 to 24 weeks compared with placebo. Dose-dependent decreases in annualized relapse rate (ARR) were also observed. There were no reports of serious cardiac events, serious infections, or macular edema during part A of the trial.¹

Methods

Patients who completed part A of the RADIANCE trial were eligible to participate in the dose-blinded extension study. During the extension phase, patients originally randomized to ozanimod continued their assigned dose; patients originally randomized to placebo were re-randomized 1:1 to receive either ozanimod 0.5 mg or ozanimod 1 mg.¹

Patients were evaluated every 12 weeks during the extension study. Magnetic resonance imaging (MRI) scans were performed at extension study entry, 6 months, 1 year, and 2 years. Efficacy end points included mean number of Gd-enhancing lesions, percentage of patients free of Gd-enhancing lesions, mean number of new or enlarging T2-hyperintense lesions on brain MRI, and unadjusted ARR. Safety was also assessed. Treatment-emergent adverse events (AEs) of special interest that were assessed in the extension study included infections, bradycardia, cardiac conduction abnormalities, abnormal pulmonary function tests, macular edema, hepatic effects, and malignancies.¹

Results

Patient Demographics

In the extension phase of the RADIANCE trial, patient demographics and disease characteristics were similar across treatment groups and similar to those observed in the placebo-controlled portion of the trial. Upon entry into the blinded extension, 58.5% to 87.7% of patients were free of Gd-enhancing lesions (84.7%, ozanimod 0.5 mg to ozanimod 0.5 mg; 87.7%, ozanimod 1 mg to ozanimod 1 mg; 58.5%, placebo to ozanimod 0.5 mg; 69%, placebo to ozanimod 1 mg).¹

During the extension phase, 126 patients received 0.5-mg doses of ozanimod and 123 patients received 1-mg doses of ozanimod. Overall, 89.6% of patients (223 of 249) completed the 2-year blinded extension.¹

Efficacy

At year 1, 91.1% to 92.9% of patients were free of Gd-enhancing lesions; at year 2, 86.5% to 94.6% of patients were free of Gd-enhancing lesions. A dose-dependent trend in reduction in the mean number of new or enlarging T2 lesions was observed with ozanimod from the start of the extension phase to year 1 and from year 1 to year 2. Unadjusted ARRs, which ranged from 0.18 to 0.32 in the extension phase, were maintained in patients who received ozanimod during both the placebo-controlled trial and the extension phase and were decreased for patients who received placebo during the placebo-controlled trial and received ozanimod during the extension phase. Mean Expanded Disability Status Scale scores remained stable.¹

Safety

During the extension phase, no unexpected safety signals were observed. The most commonly reported treatment-emergent AEs included nasopharyngitis, upper respiratory tract infections, and increased alanine aminotransferase (ALT) levels. Twelve patients experienced increases in ALT levels of at least 3 times the upper limit of normal (ozanimod 0.5 mg, n = 4; ozanimod 1 mg, n = 8). Two patients had concurrent increases in aspartate aminotransferase (AST) levels (ozanimod 0.5 mg, n = 1; ozanimod 1 mg, n = 1) and 1 patient who received ozanimod 1 mg had an isolated elevation in AST level. During the blinded extension, there were no reports of serious opportunistic infections, significant abnormalities in pulmonary function tests, macular edema, malignancies, or second-degree or higher atrioventricular block.¹

Twenty-six patients discontinued treatment before the end of the 2-year extension phase (14 patients randomized to ozanimod 0.5 mg and 12 patients randomized to ozanimod 1 mg). Reasons for discontinuation of ozanimod 0.5 mg were AEs (n = 3), physician decision (n = 4), protocol violation (n = 1), and voluntary withdrawal (n = 6). Reasons for discontinuation of ozanimod 1 mg were AEs (n = 2), lack of efficacy (n = 4), protocol violation (n = 2), and voluntary withdrawal (n = 4). Four of the discontinuations due to AEs were specified by the trial protocol and were due to increased transaminase levels. These patients recovered after ozanimod use was discontinued.¹

Conclusion

The efficacy of both doses of ozanimod (0.5 mg and 1 mg) observed in the placebo-controlled RADIANCE trial was maintained in the 2-year blinded extension. Low levels of MRI lesion activity, specifically the presence of Gd-enhancing lesions, and low unadjusted ARRs were observed during the blinded extension. Greater efficacy on both MRI and clinical disease measures was observed with ozanimod 1 mg compared with ozanimod 0.5 mg.

Reference

1. Cohen JA, Comi G, Arnold DL, et al; RADIANCE Trial Investigators. Efficacy and safety of ozanimod in multiple sclerosis: dose-blinded extension of a randomized phase II study [published online July 25, 2018]. Mult Scler. 2018:1352458518789884. doi: 10.1177/1352458518789884.