Ozanimod Reports Consistent Efficacy in 2-Year Extension Trial

Jeffrey A. Cohen, MD, from the Mellen Center for MS Treatment and Research at Cleveland Clinic

Jeffrey A. Cohen, MD

In a 2-year extension trial, ozanimod (formerly RPC1063) demonstrated a sustained level of efficacy in patients with multiple sclerosis (MS) who were originally on the therapy, as well as achieved similar efficacy in those who switched from placebo.

The RADIANCE phase II study, originally assessing Celgene’s investigational therapy over the course of 24 weeks, revealed reduced magnetic resonance imaging (MRI) lesion activity as well as a favorable safety profile for ozanimod. That trial period reported a mean (standard deviation) cumulative number of gadolinium-enhancing (Gd+) lesions at weeks 12 to 24 of 11.1 (29.9) with placebo compared with 1.5 (3.7) with ozanimod 0.5 mg (odds ratio, 0.16; 95% CI, 0.08 to 0.30; P <.0001) and 1.5 (3.4) with ozanimod 1 mg (odds ratio, 0.11; 95% CI, 0.06 to 0.21; P <.0001).¹

In the extension trial, which was also led by Jeffrey A. Cohen, MD, from the Mellen Center for MS Treatment and Research at Cleveland Clinic, patients that had been randomized to once daily ozanimod hydrochloride in doses of either 0.5 mg (n = 41) or 1 mg (n = 85) remained on their assigned dose, while those who had been administered placebo were re-randomized 1:1 to those same dosing options (0.5 mg, n = 42; 1 mg, n = 81) for a 2-year period.²

“Ozanimod is a selective sphingosine 1-phosphate receptor (SP1) modulator under development to treat MS,” Cohen told NeurologyLive. “The results of this extension study add to the emerging data supporting its efficacy and safety in MS. Long-term data are important to confirm that benefit is durable, and that rare or late-appearing adverse effects are not seen.”

In total, 223 of the 249 total participants completed the blinded extension period. At the 2-year period, the percentage of those free of Gd+ lesions ranged from 86.5% to 94.6%. Among those who were initially assigned to placebo, 69.0% and 58.5% of those reassigned to the 1-mg and 0.5-mg doses, respectively, were Gd+ lesion-free at entry into the extension, compared to 84.7% and 87.7% of those originally on the 0.5-mg and 1-mg doses, respectively. At the end of year 1, the percentage of those who were Gd+ lesion-free had increased to a range of 91.1% to 92.9%.

The unadjusted annualized relapse rate (ARR) during the blinded extension period was 0.32 for the 0.5-mg arm, 0.18 for the 1-mg arm, 0.30 for the placebo-to-0.5 mg arm, and 0.18 for the placebo-to-1 mg arm. The mean (standard deviation) change from baseline in Expanded Disability Status Scale (EDSS) at the 2-year mark was 0.2 (0.85) for the 0.5 mg treatment group, 0.1 (0.64) for the 1 mg group, 0.3 (0.76) for the placebo-to-0.5 mg arm, and 0.2 (0.67) for the placebo-to-1 mg arm.

“Ozanimod is a once-daily oral medication,” Cohen explained. “Based on the extensive experience with fingolimod, S1P modulation is a well-established treatment approach in MS. Like fingolimod, it has a benefit on relapses and MRI, including slowing brain atrophy. As a selective S1P modulator, ozanimod avoids some of the safety issues with fingolimod.”

With regard to safety in the extension period, the most common treatment-emergent adverse events (AEs) were nasopharyngitis, upper respiratory tract infection, and increased alanine aminotransferase (ALT). In total, 4.9% (n = 12) of participants had increases in ALT that was ≥3-times the upper limit of normal (ozanimod 0.5 mg, n = 4; ozanimod 1 mg, n = 8). Of those, 2 (1 each) had concurrent aspartate aminotransferase (AST) elevations, while a single participant, in the ozanimod 1 mg group, had an isolated AST elevation. Altogether, 4 patients discontinued treatment due to a treatment-emergent AE during the blinded extension, all of which were protocol-specified and attributable to increased transaminases—all 4 patients recovered.

Serious AEs occurred in 12 patients administered the 0.5-mg dose, including 1 instance of acute myocardial infarction, 1 instance of hepatitis. Of those receiving the 1-mg dose, 9 patients reported a serious AE, including a case of moderate pancytopenia that resolved itself sans treatment interruption.

Cohen and colleagues noted that “the use of [ozanimod] for over 2 years was well tolerated, with few participants discontinuing for side effects or safety reasons. [Treatment-emergent AEs] during the 2-year blinded extension were consistent with those seen during the placebo-controlled period, with no apparent increase over time or differences between ozanimod HCl 0.5 and 1 mg.”

It was noted that no clinically significant cardiac conduction abnormalities were observed, although those with clinically relevant cardiovascular conditions were excluded and <20% of participants had a history of cardiovascular conditions. “Additional studies will help to further define the safety profile of ozanimod,” Cohen and colleagues concluded.

Notably, though, this analysis profited from a high retention rate—88.9% and 90.2% of those initially randomized to the 0.5 mg and 1 mg dosing groups completed the 2-year period.

Thus far, 2 phase III studies of ozanimod—RADIANCE and SUNBEAM&mdash;have been completed and presented at scientific meetings.

REFERENCE

1. Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381. doi: 10.1016/S1474-4422(16)00018-1.

2. Cohen JA, Comi G, Arnold DL, et al. Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study. Mult Scler J. epub July 25, 2018. Doi: 10.1177/1352458518789884.