NDA Submitted for Ozanimod for Relapsing Multiple Sclerosis

Jay Backstrom, MD, the chief medical officer for Celgene

Jay Backstrom, MD

The FDA has received a new drug application (NDA) for ozanimod for the treatment of relapsing multiple sclerosis (MS) in adults, according to manufacturer Celgene.¹

Celgene’s NDA for the treatment was supported by a pair of phase 3 trials, SUNBEAM (NCT02294058) and RADIANCE (NCT01628393). Ozanimod was additionally submitted to the European Medicines Agency earlier this month.

“New oral treatment options with differentiated profiles like ozanimod are needed to help address an unmet need for people with relapsing forms of MS,” said Jay Backstrom, MD, the chief medical officer for Celgene, in a statement. “With concurrent applications in the U.S. and EU, we look forward to advancing this promising medicine through the regulatory review process to provide a new option for the treatment of RMS in 2020.”

Previously known as RPC1063, the oral sphingosine 1-phosphate (S1P) receptor modulator binds with high affinity to selective S1P subtypes 1 (S1P1) and 5 (S1P₅). Its mechanism of therapeutic action is unknown. In clinical trials, the immune-inflammatory agent has also been tested for ulcerative colitis and Crohn disease.

In the RADIANCE trial, ozanimod was evaluated in 258 participants randomly assigned to either placebo (n = 88), 0.5-mg ozanimod (n = 87), or 1-mg ozanimod (n = 83). Ultimately, the mean cumulative number of gadolinium-enhancing (Gd+) lesions at weeks 12 to 24 was 11.1 (standard deviation [SD], 29.9) in the placebo group in comparison to only 1.5 (3.7) in the 0.5-mg dose group (odds ratio [OR], 0.16; 95% CI, 0.08 to 0.30; P <.0001) and 1.5 (SD, 3.4) in the 1-mg dose group (OR, 0.11; 95% CI, 0.06 to 0.21; P <.0001).²

All told, 3 serious adverse events (AEs), which were deemed unrelated to treatment, were reported in the 0.5 mg group. They included a case of optic neuritis, a case of somatoform autonomic dysfunction, and a case of HPV-related cervical squamous metaplasia. No serious infectious or cardiac AEs were reported, nor were any cases of macular edema. Most common AEs in the ozanimod groups compared with placebo were nasopharyngitis (0.5 mg, 11; 1 mg, 5; placebo, 12), headache (0.5 mg, 5; 1 mg, 3; placebo, 8), and urinary tract infections (0.5 mg, 6; 1 mg, 2; placebo, 2).²

In the extension trial, led by Jeffrey A. Cohen, MD, from the Mellen Center for MS Treatment and Research at Cleveland Clinic, patients that had been randomized to once daily ozanimod hydrochloride in doses of either 0.5 mg (n = 41) or 1 mg (n = 85) remained on their assigned dose, while those who had been administered placebo were re-randomized 1:1 to those same dosing options (0.5 mg, n = 42; 1 mg, n = 81) for a 2-year period.³

In total, 223 of the 249 total participants completed the blinded extension period. At the 2-year mark, the percentage of those free of Gd+ lesions ranged from 86.5% to 94.6%. Among those who were initially assigned to placebo, 69.0% and 58.5% of those reassigned to the 1-mg and 0.5-mg doses, respectively, were Gd+ lesion-free at entry into the extension, compared with 84.7% and 87.7% of those originally on the 0.5-mg and 1-mg doses, respectively. At the end of year 1, the percentage of those who were Gd+ lesion-free had increased to a range of 91.1% to 92.9%.

The unadjusted annualized relapse rate (ARR) during the blinded extension period was 0.32 for the 0.5-mg arm, 0.18 for the 1-mg arm, 0.30 for the placebo-to-0.5 mg arm, and 0.18 for the placebo-to-1 mg arm. The mean (standard deviation) change from baseline in Expanded Disability Status Scale (EDSS) at the 2-year mark was 0.2 (0.85) for the 0.5 mg treatment group, 0.1 (0.64) for the 1 mg group, 0.3 (0.76) for the placebo-to-0.5 mg arm, and 0.2 (0.67) for the placebo-to-1 mg arm.

In February 2017, Celgene announced positive topline data from the SUNBEAM trial, which also assessed 1-mg and 0.5-mg doses of ozanimod in 1346 patients with MS, in comparison with weekly interferon ß-1a (Avonex, Biogen). That top-line data revealed that both the ozanimod treatment arms demonstrated statistically significant and clinically meaningful improvements compared with interferon ß-1a in annualized relapse rate and a number of secondary end points, including the number of gadolinium-enhancing magnetic resonance imaging (MRI) lesions and the number of new or enlarging T2 MRI lesions at month 12.⁴

"The safety and efficacy results from SUNBEAM are consistent with the long-term results from the phase II trial (RADIANCE). These data add to the growing body of evidence supporting the use of ozanimod as a disease-modifying therapy for relapsing forms of multiple sclerosis," Bruce Cree, MD, PhD, an associate professor of neurology at the University of California San Francisco’s Multiple Sclerosis Center, said at the time the data were announced.

REFERENCES

1. Celgene Submits Application to FDA for Ozanimod for the Treatment of Relapsing Forms of Multiple Sclerosis [press release]. Summit, NJ: Celgene; Published March 25, 2019. businesswire.com/news/home/20190325005794/en. Accessed March 26, 2019.

2. Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-81.

doi

: 10.1016/S1474-4422(16)00018-1.

3. Cohen JA, Comi G, Arnold DL, et al. Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study. Mult Scler J. epub July 25, 2018.

doi

: 10.1177/1352458518789884.

4. Celgene Announces Positive Results from Phase III SUNBEAM Trial of Oral Ozanimod in Patients with Relapsing Multiple Sclerosis [press release]. Summit, NJ: Celgene; Published February 17, 2017. ir.celgene.com/press-releases/press-release-details/2017/Celgene-Announces-Positive-Results-from-Phase-III-SUNBEAM-Trial-of-Oral-Ozanimod-in-Patients-with-Relapsing-Multiple-Sclerosis/default.aspx. Accessed March 26, 2019.