Ozanimod Is Superior to Interferon in Relapsing-Remitting MS

PARIS—Ozanimod is superior to interferon beta-1a on clinical and MRI measures in patients with relapsing-remitting multiple sclerosis (MS), according to the results of two studies presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug could become a safe and effective oral medication for this population, said the investigators.

Scientists at the Scripps Research Institute developed ozanimod, a selective sphingosine 1-phosphate 1 and 5 receptor modulator. “Receptor specificity for subtypes 1 and 5 is anticipated to preserve efficacy, but to lessen off-target treatment effects, as compared to nonselective sphingosine 1-phosphate receptor modulators,” said Jeffrey Cohen, MD, a neurologist at the Cleveland Clinic and an investigator on both of the studies.

Jeffrey Cohen, MD

The SUNBEAM Study

SUNBEAM was the first of the two trials of ozanimod to be presented at the meeting. Eligible participants were between ages 18 and 55, had relapsing-remitting MS, had had at least one documented relapse in the previous year, had not had a relapse in the previous 30 days, and had no history of cardiac conditions. The trial randomized participants to 0.5 mg/day of oral ozanimod, 1 mg/day of oral ozanimod, or weekly intramuscular injections of interferon beta-1a (30 µg). Patients in the ozanimod groups underwent a seven-day dose escalation as an initiation.

The trial’s primary end point was annualized relapse rate. Among the secondary end points were new and enlarging T2 lesions from baseline to month 12 and T1, gadolinium-enhancing lesions at month 12. The investigators carried out a prespecified evaluation of disability progression, based on Expanded Disability Status Scale (EDSS), using a pooled analysis of SUNBEAM and RADIANCE, the other phase III study.

The researchers enrolled 1,346 patients in 20 countries. The treatment groups were well balanced at baseline. Participants’ mean age was 36, and 66% of the population was female. Mean EDSS score at baseline was 2.6, mean number of relapses in the prior year was 1.3, and 47% of participants had gadolinium-enhancing lesions. In addition, 31% of participants previously had been treated with disease-modifying therapy.

The mean treatment duration in SUNBEAM was 13.6 months. The annualized relapse rate was reduced by 31% with 0.5 mg/day of ozanimod and by 48% with 1 mg/day of ozanimod, compared with interferon beta-1a. Overall, ozanimod reduced MRI activity by 63%, compared with interferon beta-1a. The number of new or enlarging T2 lesions and the adjusted mean number of gadolinium-enhancing lesions at month 12 were significantly reduced in the ozanimod groups, compared with the interferon group. The investigators observed a consistent dose response to ozanimod for all efficacy end points.

The majority of treatment-emergent adverse events were mild, and serious adverse events were uncommon. The rate of adverse events was similar for all treatment groups. The rate of discontinuation due to adverse events also was low and similar between treatment groups. The researchers observed no first-dose, clinically relevant cases of bradycardia.

The RADIANCE Trial

The eligibility criteria for the RADIANCE trial were the same as those of the SUNBEAM study. Participants were randomized to 0.5-mg/day or 1-mg/day doses of ozanimod or to 30 µg/week of interferon beta-1a. The primary end point in RADIANCE was annualized relapse rate at two years. Secondary end points included measures of MRI lesion activity, brain volume loss over two years, and a pooled analysis of confirmed disability worsening. Disability was assessed during a clinical evaluation every three months and at the time of potential relapse.

The investigators enrolled 1,313 patients into the study, and their baseline characteristics were similar across treatment groups. Participants’ mean age was 36, and 67% of the population was female. Mean EDSS score at baseline was 2.5, and mean number of relapses in the prior year was 1.3. About 43% of patients had gadolinium-enhancing lesions at baseline, and 29% previously had received disease-modifying therapy. Overall, 86% of the participants completed the trial, and the discontinuation rate was similar in all treatment arms.

The 0.5-mg dose of ozanimod was associated with a 21% reduction in annualized relapse rate, compared with interferon, and the 1-mg dose of ozanimod was associated with a 38% reduction in this measure. The adjusted mean number of new or enlarging T2 lesions per scan was reduced by 42% with ozanimod 1 mg and by 35% with 0.5 mg of ozanimod, compared with interferon. The adjusted mean number of gadolinium-enhancing lesions at 24 months also was reduced by 53% with 1 mg of ozanimod and by 47% with 0.5 mg of ozanimod, compared with interferon.

In addition, the study demonstrated an approximately 25% reduction in whole-brain volume loss in the two ozanimod arms, compared with the interferon group. Ozanimod also reduced segmented cortical gray volume loss and segmented thalamic volume loss to a similar extent, compared with interferon.

In the pooled analysis of both trials, the rate of confirmed disability worsening was low. The investigators did not observe any difference in this outcome between the three treatment arms.

Ozanimod was well tolerated. Liver enzyme elevations associated with the drug tended to be mild and resolved despite continuation of study drug. The drug was associated with a minimal change in heart rate, and the researchers observed no cases of second-degree or higher heart block. “It appears that the first-dose escalation protocol effectively mitigated cardiac effects,” said Dr. Cohen.

Celgene, the company developing the drug, expects to submit the compound for FDA approval and introduce it to the market by the end of 2018, according to a press release.