Caroline Helwick

February 20, 2016

NEW ORLEANS — In patients with relapsing multiple sclerosis (MS), ozanimod, an oral modulator of the sphingosine1-phosphate (S1P) receptor, demonstrated efficacy over the course of 72 weeks in a blinded extension of the phase 2/3 RADIANCE trial.

"Both doses of ozanimod demonstrated efficacy on [magnetic resonance imaging (MRI)] and clinical measures of MS disease activity in patients continuing ozanimod and in those switching from placebo at week 24," said RADIANCE principal investigator Jeffrey A. Cohen, MD, director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Research in Ohio.

The therapeutic potential of S1P receptor modulation has been demonstrated with fingolimod (Gilenya, Novartis), a nonselective S1P receptor agonist already approved for relapsing MS, but there have been concerns about safety, especially in terms of cardiovascular effects, he said.

An advisory from the US Food and Drug Administration stated that the administration "remains concerned about the cardiovascular effects of Gilenya after the first dose. Data show that, although the maximum heart rate lowering effect of Gilenya usually occurs within 6 hours of the first dose, the maximum effect may occur as late as 20 hours after the first dose in some patients."

Fingolimod is therefore contraindicated in patients with certain cardiovascular conditions, and a strict monitoring protocol is recommended.

A more selective SP1 receptor modulator may carry less potential for cardiac effects, according to Dr Cohen, who presented the RADIANCE results here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016, a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.

"But we also know that fingolimod interacts with four of the five S1P receptor subtypes, so our question initially was whether those other subtypes mediate the benefit in MS," he said. "It turns out that with this selective drug, we can recapitulate much of the efficacy" seen with the nonselective SP1 receptor agonist, he added.

"Our sense was that by adjusting the dose to target specific lymphocyte depletion, the effects we got are pretty comparable to the clinical efficacy [of fingolimod] on MRI lesions," Dr Cohen said in an interview with Medscape Medical News.

With this drug class, the stimulation of the S1P receptor on lymphocytes ultimately results in sequestration of lymphocytes, reducing their presence in the circulation.

Ozanimod is also showing promise for the treatment of inflammatory bowel disease.

RADIANCE Main Results

The global placebo-controlled phase 2/3 RADIANCE trial enrolled patients with relapsing MS who had an Expanded Disability Status Scale score of between 0 and 5.0, and who had either one or more relapses in the previous 12 months or one or more relapses in the past 24 months plus one or more gadolinium-enhancing lesions on MRI in the previous 12 months before screening.

The 258 participants were assigned to ozanimod (0.5 or 1 mg) or placebo once daily for 24 weeks. To attenuate first-dose cardiac effects, ozanimod was up-titrated from 0.25 to 0.5 mg or 1 mg over the course of 8 days. The primary endpoint was the cumulative number of total gadolinium-enhancing MRI lesions 12 to 24 weeks after treatment initiation.

The 24-week analysis of the phase 2 trial was recently published in Lancet Neurology. The 2-year phase 3 trial is ongoing.

Ozanimod significantly reduced MRI lesion activity, with a favorable safety profile, over a period of 24 weeks. The mean cumulative number of gadolinium-enhancing lesions at weeks 12 to 24 was 11.1 with placebo compared with 1.5 with ozanimod 0.5 mg (odds ratio, 0.16; 95% confidence interval, 0.08 - 0.30; P < .0001) and 1.5 with ozanimod 1 mg (odds ratio, 0.11; 95% confidence interval, 0.06 - 0.21; P < .0001).

"We saw a robust suppression of enhancing lesions at week 24, and significantly more patients free of enhancement, vs placebo," Dr Cohen said.

Importantly, no serious cardiac adverse events were reported. The maximum reduction in mean heart rate by Holter monitoring during the first 6 hours in ozanimod-treated participants was less than 2 beats per min (bpm) compared with baseline, and no patient had a minimum hourly heart rate lower than 45 bpm. Electrocardiograms and 24-hour Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod.

48-Week Blinded Extension

Here at ACTRIMS Forum 2016, Dr Cohen presented the results of a 48-week blinded extension phase of RADIANCE that evaluated the long-term efficacy and safety of both doses of ozanimod, as well as the drug's efficacy in patients who switched from placebo.

Patients originally randomly assigned to ozanimod continued the assigned dose they received for 24 weeks in the initial study; 76 completed another 48 weeks of treatment with the low dose and 78 completed high-dose treatment. Patients receiving placebo were randomly assigned to cross over to ozanimod after 24 weeks; 38 of them completed treatment with 0.5 mg and 38 with the 1.0-mg high dose.

"We found that the benefit of patients maintained on ozanimod continued to week 72, and when patients switched from placebo to ozanimod, we saw recapitulation of the benefit, with no new safety issues," Dr Cohen reported.

In patients continuing treatment with the low and high doses of ozanimod, the mean number of lesions was 0.4 and 0.2, respectively, at week 72, which was essentially stable from week 24. The proportion of patients free of enhancing lesions was 73% and 88%, respectively, at study's end.

The unadjusted annualized relapse rate dropped from 0.43 at week 24 to 0.26 at week 72 in patients receiving the low dose, and from 0.26 to 0.15, respectively, in the high-dose group.

No evidence of disease activity (no new/enlarging T2 lesions at week 72, no relapse, no increase in disability) was observed in 44% of patients continuing the low dose and 63% receiving the high dose.

Paul A. Frohna, MD, vice president of Clinical Development and Translational Medicine for Receptos Services, LLC, the study's sponsor, commented on this magnitude of benefit in an interview with Medscape Medical News.

"The reduction in relapses significantly dropped when you got out to 72 weeks. At 72 weeks, the relapse rate is down to 0.15, which approaches the best numbers that are out there, and this is with an oral small molecular that has good safety profile. You are gaining additional clinical benefit the longer you are on the drug," he said.

A striking difference was observed among patients crossing over from placebo. In the low-dose group, the mean number of gadolinium-enhancing lesions dropped from 4.5 at week 24 to 0.4 at week 72, and in the high-dose group, the numbers dropped from 1.9 to 0.1, representing reductions of 91% and 95%, respectively. The proportion of patients free of enhancing lesions at week 72 was 85% and 79%, respectively.

Mirroring patients treated for the full 72 weeks, patients crossing over from placebo also had substantial reductions in unadjusted annualized relapse rate, and no evidence of disease activity was achieved in 42% and 57% of patients in the low-dose and high-dose groups, respectively.

Good Safety Profile, Cardiac Included

Ozanimod was well tolerated, with the most common adverse events being minor infections and headache. Maximum first-dose reductions in mean hourly heart rate were less than 1 bpm from baseline, and only one patient had a minimum hourly heart rate lower than 45 bpm, which was transient. Alanine aminotransferase levels three or more times the upper limit of normal occurred in 3.2% of patients.

"We think with dose titration we can largely avoid the first-dose cardiac effect," Dr Frohna said. "We think there are some potential advantages of this drug over some of the other selective S1P agents in development, especially the very low rate of hepatotoxicity," he said. "To me, this drug looks like the safest in the class."

Dr Frohna cited another potential benefit, which is a relatively short half-life. "Ozanimod is almost completely eliminated in about 5 days," he said, "which is beneficial in situations such as accidental pregnancy or serious infection."

Jennifer Graves, MD, PhD, assistant professor of neurology at the University of California, San Francisco, School of Medicine, commented on the potential value of having a safer drug in the S1P receptor modulator class.

"I am concerned about cardiac safety effects, particularly in certain patient populations at higher risk. If the research can demonstrate a lower rate of cardiac effects with this medication, it could have advantages," Dr Graves told Medscape Medical News, although she cautioned, "It's challenging, especially when side effects are rare, to establish in early phase trials whether there are differences between agents."

Dr Graves also saw the attractiveness of an agent that can be eliminated quickly, noting that with fingolimod, the recommended washout time is 2 months. "A faster washout would be good," she said.

The study was funded by Receptos Services, LLC. Dr Cohen reported relationships with Receptos, EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex. Dr Frohna is employed by Receptos. Dr Graves has disclosed no relevant financial relationships.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016: Abstract LBA158. Presented February 19, 2016.

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