Caroline Helwick

May 31, 2017

NEW ORLEANS — The oral investigational agent ozanimod demonstrated continued efficacy on measures of disease activity among patients with relapsing multiple sclerosis (RMS), in a blinded extension study of the phase 2 RADIANCE Part A trial.

The unadjusted annualized relapse rate was only 0.17, Brett E. Skolnick, PhD, from Receptos, a subsidiary of Celgene, reported here at the Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting. Dr Skolnick stepped in for lead investigator, Giancarlo Comi, MD, from  Vita-Salute San Raffaele University in Milan, Italy, who had to cancel his trip to the conference.

On May 22, Celgene Corp announced topline results of the phase 3 RADIANCE trial, involving 1313 patients with RMS, showing the trial met its primary endpoint, a reduction in annualized release rate compared with weekly interferon (IFN) β-1a (Avonex) with both 0.5- and 1-mg doses. Reductions were also seen in the secondary endpoints of the number of new or enlarging T2 MRI lesions and number of gadolinium-enhancing lesions over 24 months.

The statement also noted that in a prespecified pooled analysis of the phase 3 RADIANCE and SUNBEAM trials, the time to confirmed disability progression was "very low" across all treatment groups, and treatment with ozanimod was not statistically significantly different from IFNβ-1a.

However, both doses of ozanimod showed a statistically significant reduction in brain atrophy compared with IFNβ-1a in both the SUNBEAM and RADIANCE trials, the company noted. Safety and tolerability in RADIANCE was "consistent" with that seen in SUNBEAM and previous phase 2 trials

Further analyses of the RADIANCE trial are ongoing, the company writes. "In February 2017, Celgene announced positive top-line results from the second active comparator phase 3, SUNBEAM, in RMS," the statement said. "Detailed results from the RADIANCE and SUNBEAM trials will be presented at an upcoming medical congress."

A New Drug Application submission to the US Food and Drug Administration, based on the combined SUNBEAM and RADIANCE trials for RMS, is expected by the end of 2017.

Therapeutic Potential

Ozanimod is an oral, selective sphingosine-1 phosphate (S1P) receptor-1 (S1P1R) and receptor-5 (S1P5R) modulator in the development for RMS.  The increased receptor selectivity of ozanimod and additional pharmaceutical properties are predicted to result in a more favorable safety profile compared with other nonselective and selective S1P receptor modulators.

The therapeutic potential of S1P receptor modulation was demonstrated with fingolimod (Gilenya, Novartis), a nonselective S1P receptor agonist approved for relapsing MS, but there have been concerns about safety, especially in terms of cardiovascular effects, according to experts in the field.

At the CMSC meeting, Dr Skolnick presented data from the 96-week blinded extension portion of the phase 2 RADIANCE Part A trial, which is part of a phase 2/3 clinical trial of ozanimod in adults with RMS.

Results of the 24-week placebo-controlled phase 2 core treatment period demonstrated strong efficacy and favorable safety and tolerability profile (Lancet Neurol. 2016;15:373-381).

The global placebo-controlled RADIANCE trial enrolled patients with relapsing MS who had an Expanded Disability Status Scale score of 0 to 5.0 and had (1) one or more relapses in the previous 12 months or (2) one or more relapses in the past 24 months plus one or more gadolinium-enhancing lesions on MRI in the 12 months before screening.

In phase 2 of the trial, 258 participants were assigned to ozanimod (0.5 mg or 1 mg) or placebo once daily for 24 weeks. The study met its primary endpoint, a reduction in the cumulative number of total gadolinium-enhancing MRI lesions 12 to 24 weeks after treatment initiation.

The mean cumulative number of gadolinium-enhancing lesions at weeks 12 to 24 was 11.1 with placebo vs 1.5 with ozanimod 0.5 mg (odds ratio, 0.16; P < .0001) and 1.5 with ozanimod 1 mg (odds ratio, 0.11; P < .0001). No serious cardiac adverse events were reported.

Two-Year Extension Period, Part A

Dr Skolnick reported the drug's continued efficacy on MRI and clinical measures of MS disease activity over the 2-plus years of the blinded extension period and noted that ozanimod 1.0 mg was more effective than the 0.5-mg dose.

In the extension period, patients who began receiving ozanimod in the core treatment continued to receive 0.5 mg (n = 85) or 1.0 mg (n = 81) or, if initially on placebo, received ozanimod 0.5 mg (n = 41) or 1.0 mg (n = 42) for the first time. Ozanimod was dose-escalated over 7 days to attenuate first-dose effects (ie, to assure cardiac safety). Completing 96 weeks of treatment were 112 patients (88.9%) receiving ozanimod 0.5 mg and 111 (90.2%) receiving ozanimod 1.0 mg. 

At the conclusion of the blinded extension phase, approximately 90% of patients were free of gadolinium-enhancing lesions, and the unadjusted annualized relapse rates were 0.38 with ozanimod 0.5 mg and 0.17 with ozanimod 1.0 mg. In the core study, the rate of 0.24 with ozanimod 1.0 mg in the core study represented a 50% reduction vs the placebo group, and the rate for this group fell further to 0.17, he noted.

MRI and clinical outcomes after 24 weeks of treatment in the core study and after the blinded extension study are shown below.

Table. Outcomes With Ozanimod After 24 Weeks and 2+ Years

Outcome Measure Placebo-Ozanimod 0.5 mg (Core/Extension) Placebo-Ozanimod 1.0 mg (Core/Extension) Ozanimod-Ozanimod 0.5 mg (Core/Extension) Ozanimod-Ozanimod 1.0 mg (Core/Extension)
Mean number of new gadolinium-positive lesions 4.5/0.4 1.9/0.1 0.4/0.4 0.2/0.2
Number of new or enlarging T2 lesions 10.8/3.2 7.3/1.9 1.4/2.3 0.9/0.7
Unadjusted annualized relapse rate 0.57/0.35 0.41/0.12 0.43/0.38 0.24/0.17

Safety Profile: No Cardiac Issues

Treatment-emergent adverse events (TEAEs) associated with ozanimod over the 2-plus years of the blinded extension phase were consistent with those seen in the core treatment period, with no apparent differences between doses.

At least one TEAE was seen in 79% (0.5 mg) and 76% (1.0 mg) of patients, but none of the serious TEAEs were considered related to the drug. The most common TEAE was increased alanine aminotransferase (ALT) levels, which occurred in 37% to 51%. ALT levels at least three times the upper limit of normal (ULN) occurred in about 5% of patients in the extension period.

"Five patients discontinued the study according to protocol requirements for ALT more than five times the ULN, but all improved or recovered after drug discontinuation," Dr Skolnick said. Other common TEAEs were nasopharyngitis, upper respiratory tract infection, urinary tract infection, and headache. No cases of macular edema were observed, and there were no serious opportunistic infections, malignancies, or clinically significant pulmonary TEAEs.  

Because cardiac safety is a concern with fingolimod, it was important to show the lack of cardiac issues with ozanimod, he said. During the extension phase, patients exhibited no first-dose bradycardia and no second-degree or greater atrioventricular block. Mild blunting of the normal diurnal heart rate was observed. The largest mean decrease in heart rate relative to predose was 3.5 beats/min at hour 6 on day 1, with no associated symptoms.

"The safety and tolerability results suggest a favorable benefit-to-risk profile for ozanimod that awaits confirmation in the ongoing phase 3 trials, RADIANCE Part B and SUNBEAM," he said.

Safety May Be Selling Point

David E. Jones, MD, assistant professor of neurology at the James Q. Miller MS Clinic of the University of Virginia Health System, Charlottesville, said he welcomes the data on ozanimod, especially on safety.

"It's a more selective agent than fingolimod in that it only recognizes S1P subtypes 1 and 5. The assumption is that this will be associated with fewer cardiac side effects, and the data we heard today from RADIANCE suggests this is true," he said. "I think this is important."

For one reason, starting new patients on fingolimod can be somewhat "burdensome to providers and to patients," he said, because 6-hour monitoring is recommended to monitor for "first dose phenomenon." For patients taking β-blockers, calcium-channel blockers, or other drugs that affect heart rate, 24-hour monitoring is recommended. "We admit these patients overnight, so for them, it's even more of a burden," he said.

"I would expect ozanimod is equally effective as fingolimod, if not more so, and I think the safety profile will be better," he said. He also believes the lack of occurrence of macular edema in the study is important because this adverse event occurred in 0.4% of patients in the fingolimod trial.

"Right now, it's recommended that patients have an ophthalmic evaluation at baseline and 3 to 4 months after starting fingolimod, so this would be another aspect of convenience with this drug," he offered.

The study was supported by Celgene. Dr Comi disclosed consulting for Almirall, Forward Pharma, Genzyme, Merck, and Novartis and  speaking for Biogen, Celgene Corp, EXCEMED, Receptos, Roche, Sanofi, and Teva. Dr Skolnick is employed by Receptos, a subsidiary of Celgene Corp. Dr Jones has consulted for Biogen and Genzyme.

Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting. Abstract DX05. Presented May 26, 2017.

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