Two Phase 3 Trials Show Ozanimod Effective in Relapsing MS

Deborah Brauser

November 06, 2017

PARIS — Full findings from the phase 3 SUNBEAM and RADIANCE trials expand on previously released topline results showing that the investigational oral agent ozanimod (RPC1063, Celgene) reduces disease progression in patients with relapsing multiple sclerosis (RMS).

Full data from both multicenter, randomized controlled trials were presented for the first time here at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting.

In SUNBEAM, which included more than 1300 patients, those who received once-daily ozanimod 0.5 mg or 1 mg for 1 year had significantly greater reductions in annualized relapse rate (ARR, the primary endpoint) than patients who received weekly 30-µg intramuscular injections of interferon β-1a (IFN; Avonex, Biogen).

MRI findings showed that the ozanimod group also had greater reductions in gadolinium-enhancing (GdE) lesions and new or enlarging T2 lesions.

"A dose response was consistently demonstrated across efficacy endpoints," Giancarlo Comi, MD, San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, Italy, told attendees.

In RADIANCE part B, which also included more than 1300 patients with RMS, the groups receiving 0.5 or 1 mg daily of ozanimod had greater ARR reductions at 2 years than the group receiving IFN.

In addition, the number of new or enlarging T2 lesions was reduced by 34% and 42% for the two doses, respectively, compared with IFN, and the number of GdE lesions was reduced by 47% and 53%.

In both trials, there were few serious adverse events (SAEs), which did not differ significantly between treatment groups, and no serious cardiac-related AEs, serious opportunistic infections, or treatment-related deaths occurred.

Jeffrey A. Cohen, MD, Mellen Center for MS Treatment and Research, Cleveland Clinic, Ohio, presented these findings in the meeting's Late Breaking News session.

"The results of the two trials were largely similar. Both showed benefit on relapse, which was the primary endpoint, and supported secondary endpoints. Importantly, they also showed excellent safety and tolerability," Dr Cohen told Medscape Medical News.

Celgene notes in a press release that, on the basis of these data, it will be filing a regulatory submission for ozanimod in the United States by the end of this year and in the European Union in the first half of 2018.

SUNBEAM: Primary, Secondary Outcomes

Ozanimod is an immunomodulator that selectively targets sphingosine 1-phosphate 1 (S1P) and 5 receptors. Preliminary topline results from SUNBEAM were reported by the pharmaceutical company in February 2017, and topline results from RADIANCE were reported in May 2017.

At the ECTRIMS-ACTRIMS meeting, detailed results were released for both trials.

In SUNBEAM, 1346 adult patients with RMS aged 18 to 55 years (mean age, 36 years; 66% women; baseline Expanded Disability Status Scale [EDSS] score, 2.6) were enrolled at 152 sites in 20 countries. All were randomly assigned to receive ozanimod, 0.5 mg (n = 451) or 1.0 mg (n = 447), or IFN (n = 448) over 12 months.

The ARR was 0.24 for the 0.5-mg group, which represented a 31% reduction compared with the IFN group (ARR, 0.35; P = .001). The ARR was 0.18 for the 1.0-mg group, representing a 48% reduction (P < .0001).

There were also significantly greater reductions associated with both doses of ozanimod vs IFN in the secondary outcomes of adjusted number of new or enlarging T2 lesions per scan over 1 year (P = .003 and P < .0001, respectively) and adjusted number of GdE lesions (P = .02 and P < .0001, respectively).

Table 1. MRI Outcomes in Active-Treatment vs IFN Groups

Outcome Ozanimod 0.05 mg (Reduction vs IFN) Ozanimod 1.0 mg (Reduction vs IFN)
No. of new/enlarging T2 lesions 2.14 (25) 1.47 (48)
No. of GdE lesions 0.29 (34) 0.16 (63)

 

The results were mixed for percentage change from baseline in brain volume loss at 1 year. The change in whole brain volume loss was –0.39 for the 1.0-mg group vs –0.57 for the IFN group, which Dr Comi called "nominally significant" (P < .0001), while the change of –0.50 for the ozanimod 0.5-mg group was not (P = .06).

Changes in cortical grey volume loss were significantly different for both investigational treatment groups (–0.38 and –0.16, respectively) vs the IFN group (–0.99), as were changes in thalamic volume loss (–1.03 and –0.97 vs –1.56; P < .0001 for all comparisons).

Reports of any AE were shown for 57.2% and 59.8% of the ozanimod 0.5- and 1.0-mg groups, respectively, vs 75.5% for the IFN group. Serious AEs were reported by 3.5%, 2.9%, and 2.5%, respectively.

"No distinct serious adverse event pattern was reported in the study," said Dr Comi.

The most common AEs in patients receiving ozanimod were nasopharyngitis, headache, and upper respiratory tract infection. While about 4% of each dosing group reported influenza-like illness, 51% of the IFN group reported this AE. Second-degree or higher atrioventricular blocks were not reported.

"These efficacy and safety results demonstrate a favorable benefit-risk profile for ozanimod in relapsing MS," said Dr Comi.

Bright Findings in RADIANCE

In RADIANCE part B, 1320 patients with RMS (67% women; mean age, 36 years; baseline EDSS score, 2.5) were enrolled at 147 sites in 21 countries. They also were randomly assigned to 0.5 mg of ozanimod (n = 443), 1.0 mg of ozanimod (n = 434), or IFN (n = 443) treatment groups, but over 24 months.

The ARR over 2 years was 0.22 for the 0.5-mg group, which represented a 21% reduction over the IFN group (ARR, 0.28; P = .02). The ARR was 0.17 for the 1.0=mg group, representing a 38% reduction (P < .0001).

As in SUNBEAM, the RADIANCE patients receiving either ozanimod dose had greater reductions in new or enlarging T2 lesions (P = .0001 and P < .0001, respectively) and GdE lesions (P = .003 and P = .0006) vs IFN.

Table 2. SUNBEAM 2-Year Outcomes in Active-Treatment vs IFN Groups

Outcome Ozanimod 0.05 mg (Reduction vs IFN) Ozanimod 1.0 mg (Reduction vs IFN)
No. of new/enlarging T2 lesions 2.09 (34) 1.84 (42)
No. of GdE lesions 0.197 (47) 0.176 (53)

 

The median percentage changes in normalized brain volume loss were –0.71 and –0.69 for the two active treatment groups, respectively, vs –0.94 for the IFN group (P < .0001 for both comparisons).

Changes in cortical gray volume loss were –0.55 and –0.53 vs –1.27 (P < .0001 for both comparisons); changes in thalamic volume loss were –1.33 and –1.28 vs –1.88 (P = .001 and P < .0001, respectively).

Any AEs for the 3 treatment groups were reported by 74.3%, 74.7%, and 83.0%, respectively, while serious AEs were reported by 7.1%, 6.5%, and 6.4%.

There was one death in the ozanimod 0.5-mg group, "but it was a death by drowning on day 637 and considered to be unrelated to the study drug," noted Dr Cohen.

As with SUNBEAM, nasopharyngitis, headache, and upper respiratory tract infection were the most commonly reported AEs in the ozanimod groups, and influenza-like illness was the most commonly reported in the IFN group (48.9%).

No Significant CDP Difference

Prespecified pooled analysis of both phase 3 trials showed that the active treatment was not significantly superior to IFN in time to 3-month confirmed disability progression (CDP).

However, "a very low rate of disability progression was observed across all treatment groups," noted the drug manufacturer in a press release.

Altogether, 58 patients in the ozanimod 0.5-mg group (6.5%) and 67 patients in the 1-mg group (7.6%) had 3-month CDP by month 24 vs 69 in the IFN group (7.8%).

In SUNBEAM only, 17 (3.8%), 13 (2.9%), and 19 patients in the three treatment groups, respectively, had 3-month CDP at 15 months. In other words, "a 31% risk reduction for ozanimod 1 mg vs IFN was observed," said Dr Comi.

In RADIANCE only, 41 (9.3%), 54 (12.5%), and 50 (11.3%) patients reached that outcome.

Overall, Dr Cohen said it's an optimistic time for the field. "We have a wide range and an increasing range of options for relapsing MS, and we're starting to make some progress on progressive MS, which is great."

Cautious Optimism?

"I think this drug is interesting because it's targeting two selective receptors and its results are very good," chair of the ECTRIMS-ACTRIMS conference, Catherine Lubetzki, MD, PhD, professor of neurology at Pierre and Marie Curie University, Paris, France, told Medscape Medical News when asked for comment.

She added that ozanimod "is a little bit different" from siponimod (Novartis), which is an S1P receptor modulator, "and it's a new advance. I don't know what will happen with approval, but I think these are two very strong studies."

During the Clinical Highlights session that ended the meeting, Robert J. Fox, MD, staff neurologist at the Cleveland Clinic, noted the study showed reduced ARR, while also showing how to measure "segmented atrophy" in cortical gray matter and the thalamic region, "helping us to know better how our therapies are working."

On the basis of the study data, "this adds another S1P modulator to our list of potential therapies," said Dr Fox.

However, Bernhard Hemmer, MD, head of the Department of Neurology at the Technical University in Munich, Germany, was not so impressed.

"The primary outcome was positive but the comparison to Avonex with respect to progression was negative," said Dr Hemmer. "To be honest, I don't really see any major difference to fingolimod" (Gilenya, Novartis), another S1P modulator already approved, he added.

"It's always hard to see without a head-to-head comparison, but the data I've seen showed a nice effect on relapse rate but no effect on progression" compared with IFN.

He added that the field of MS now has so many treatment options that it's no longer about whether a drug has some effect but how strong it is compared with others.

"I just don't think this is a step forward like we have seen with ocrelizumab" (Ocrevus, La Roche), concluded Dr Hemmer.

SUNBEAM and RADIANCE were funded by Celgene. Dr Comi reports compensations for consultancy and/or speaking activities from Celgene/Receptos, Almirall, Biogen, EXCEMED, Forward Pharm, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. Dr Cohen reports personal compensation for consulting for Celgene and Adamas and as co-editor of Multiple Sclerosis Journal – Experimental, Translational and Clinical.

7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017. Parallel Session 13, oral presentation 232, presented October 27, 2017. Late Breaking News session, oral presentation 280, presented October 28, 2017.

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