Ozanimod, an oral modulator of the sphingosine1-phosphate (S1P) receptor, was effective up to 72 weeks in a blinded extension of the phase 2/3 RADIANCE clinical trial that included patients with relapsing forms of multiple sclerosis (MS).
“Both doses of ozanimod demonstrated efficacy on MRI [magnetic resonance imaging], and clinical measures of MS disease activity in patients continuing ozanimod and in those switching from placebo at week 24,” said Jeffrey A. Cohen, MD, Director, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, OH.
The FDA approved fingolimod, a nonselective S1P receptor agonist, for the treatment of patients with relapsing forms of MS, but there are concerns about its safety, especially its cardiovascular effects. Although the heart rate–lowering effect of fingolimod usually occurs within 6 hours of the first dose, the maximum effect may occur as much as 20 hours later. Fingolimod is therefore contraindicated in patients with certain cardiovascular conditions, and strict monitoring of patients using the drug is recommended.
According to Dr Cohen, a more selective S1P receptor modulator may carry less potential for cardiac effects. The question is whether ozanimod, a more selective S1P subtype, is as effective as fingolimod.
“It turns out that with this selective drug, we can recapitulate much of the efficacy” seen with the nonselective S1P receptor agonist, Dr Cohen said at the 2016 ACTRIMS (Americas Committee for Treatment and Research in Multiple Sclerosis) Forum.
“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.”
With this drug class, the stimulation of the S1P receptor on lymphocytes ultimately results in the sequestration of lymphocytes, reducing their presence in the circulation.
RADIANCE Study Results
The phase 2/3 RADIANCE clinical trial enrolled patients with relapsing forms of MS who had an Expanded Disability Status Scale score of 0 to 5.0, and ≥1 relapses in the past 12 months, or ≥1 relapses in the past 24 months plus ≥1 gadolinium-enhancing lesions on MRI in the past 12 months.
Overall, 258 patients were assigned to ozanimod (0.5 mg or 1 mg) or to placebo once daily for 24 weeks. Ozanimod was slowly uptitrated for 8 days to attenuate first-dose cardiac effects.
Ozanimod significantly reduced MRI lesion activity at 24 weeks, with a favorable safety profile. The mean cumulative number of gadolinium-enhancing lesions at weeks 12 to 24 was 11.1 with placebo versus 1.5 with ozanimod 0.5 mg (odds ratio [OR], 0.16; P <.0001) and 1.5 with ozanimod 1 mg (OR, 0.11; P <.0001).
No serious cardiac adverse events were reported, including no first-dose cardiac effects and no evidence of atrioventricular block or sinus pause.
Benefits Continue to Week 72
The 48-week extension (72 weeks total treatment) of the RADIANCE study evaluated the long-term safety of both doses of ozanimod, as well as the drug’s efficacy in patients who switched from placebo.
In this phase of the RADIANCE study, 154 patients completed another 48 weeks of treatment with ozanimod (low or high dose), and 76 patients who had been receiving placebo crossed over to ozanimod at week 24 and completed 48 weeks of treatment.
“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.
The mean number of lesions at week 72 was 0.4 with low-dose ozanimod and 0.2 with high-dose ozanimod. The proportion of patients free of enhancing lesions was 73% and 88%, respectively. The unadjusted annualized relapse rate dropped from 0.43 at week 24 to 0.26 at week 72 in patients receiving low-dose ozanimod, and from 0.26 to 0.15, respectively, for those receiving high-dose ozanimod. No evidence of disease activity was observed in 44% of patients receiving low-dose ozanimod and in 63% of patients receiving high-dose ozanimod.
According to the investigators, 0.15 annual relapses shown with this oral, small molecule is in line with the efficacy of the most robust available treatments, and it has a good safety profile.
Patients crossing over from the placebo arm to the ozanimod arm also demonstrated striking benefit. The mean number of gadolinium-enhancing lesions was 0.4 at week 72 with low-dose ozanimod, and 0.1 with high-dose ozanimod, representing reductions of 91% and 95%, respectively, from week 24.
Good Safety Record
Ozanimod was well-tolerated. No cardiac effects were observed, and liver toxicity was also minimal. Alanine aminotransferase ≥3 times the upper limit of normal occurred in 3.2% of patients.
Dr Cohen commented that with dose titration, the first-dose cardiac effect can be avoided; he noted that hepatotoxicity appears quite low compared with other S1P modulators in development. “To me, this drug looks like the safest in the class,” Dr Cohen said.