Phase 3 Ozanimod Trials Show Good Efficacy and Tolerability at 2 Years for Relapsing MS

Once-daily oral ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator, was well tolerated and resulted in significantly lower relapse rates than weekly intramuscular interferon beta-1a therapy in two large international phase 3 trials involving patients with relapsing multiple sclerosis (MS).

Results from the trials — SUNBEAM and RADIANCE — were published online Sept. 3, 2019, in The Lancet Neurology.

An approval decision is expected from the FDA by late March 2020 for use of the drug in treating relapsing forms of MS. If approved, ozanimod will join two other S1P receptor modulators — fingolimod (FDA-approved in September 2010) and siponimod (approved in March 2019) — for this indication.

“In the phase 2 and phase 3 experience we now have with ozanimod, it compared favorably with the other two available drugs in its class,” says Jeffrey A. Cohen, MD, senior author of the SUNBEAM trial and lead author of the RADIANCE trial. “If approved, ozanimod is expected to offer an important new treatment option for relapsing MS.” Dr. Cohen is Director of Experimental Therapeutics in Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research.

Trial designs and results

Both trials were double-blind, double-dummy, active-control phase 3 investigations that compared ozanimod (1.0 mg or 0.5 mg daily) to interferon beta-1a (30 μg weekly). SUNBEAM enrolled 1,346 participants across 152 sites and provided at least 12 months of treatment (mean, 13.6 months). RADIANCE, with 1,320 participants at 147 sites, lasted 24 months.

Key findings from the trials included:

• Lower annualized relapse rates with ozanimod compared with interferon beta-1a, with the higher ozanimod dosage conferring the greatest benefit.
• Reduced new or enlarging T2 and gadolinium-enhancing lesion counts on brain MRI in the ozanimod groups compared with the interferon beta-1a groups, with the higher ozanimod dosage again conferring the most benefit.
• Reduced brain volume loss — including whole brain, cortical gray matter and thalamic volumes — in the ozanimod groups compared with the interferon beta-1a groups.

The slowing of thalamic volume loss is a particularly promising finding, according to Dr. Cohen, who believes this is the first time such a finding has been reported in phase 3 testing of an MS drug.

“Neurologists regard the thalamus as a kind of thermostat for brain damage, as so many neural pathways pass through it,” he explains. “Reduced volume loss suggests that ozanimod might offer some protection against structural harm associated with MS progression.”

Greater selectivity fine-tunes therapy

Five subtypes of S1P receptors have been described. While fingolimod is nonselective, both siponimod and ozanimod interact with receptor subtypes 1 and 5 with high affinity, which is believed to account for efficacy.

“The results met our higher expectations for a selective S1P receptor modulator,” says Dr. Cohen. “Good efficacy was combined with reduction of most of the safety concerns sometimes seen with this drug class.”

Investigators particularly looked out for the following:

• Cardiac conduction problems. No clinically significant bradycardia or second- or third-degree atrioventricular block occurred in the ozanimod groups, indicating that the first-dose monitoring required with fingolimod (and with siponimod for patients with specific cardiac abnormalities) may not be needed for ozanimod treatment initiation.
• In RADIANCE, lymphopenia occurred in 4.2% of patients taking ozanimod 1.0 mg and 0.9% taking 0.5 mg. In SUNBEAM, it occurred in 2.5% of the 1.0-mg group and none of the 0.5-mg group. In comparison, lymphopenia was observed in 7% of patients in a siponimod trial and 18% in a fingolimod trial.
• Opportunistic infections. No serious opportunistic infections occurred in the RADIANCE or SUNBEAM studies.
• Because of the risk of hepatotoxicity, CYP2C9 genotyping is required before siponimod treatment can be initiated, to determine whether the patient has a haplotype that is contraindicated or requires dose adjustment. Ozanimod is also metabolized in the liver via CYP enzymes. A small percentage of patients in both phase 3 trials of ozanimod developed hepatobiliary dysfunction that led to drug discontinuation.
• Macular edema. Macular edema is a complication associated with S1P receptor modulator therapy. Patients with a history of macular edema were not excluded from enrollment in SUNBEAM or RADIANCE; a low incidence of cases occurred in both trials, with similar numbers in the ozanimod and interferon beta-1a groups.

A promising new treatment option

Editorialists in an accompanying Lancet Neurology commentary noted: “If ozanimod attains regulatory approval without requiring universal first-dose observation of CYP2C9 genotyping, it might improve start-up feasibility, particularly in resource-poor areas.”

Dr. Cohen says that if ozanimod is approved, it would be reasonable to use it as first-line therapy for patients recently diagnosed with relapsing MS and as an alternative for those who failed other treatments because of relapse or adverse effects.

“The availability of multiple treatment options enables us to better personalize medicine and find a drug that best suits each patient,” he adds.