FDA Sends Refusal to File Letter for Ozanimod

The promising relapsing MS therapy had previously shown benefits in relpase rates and T2 lesion limitation.

The trajectory of a promising multiple sclerosis (MS) therapy has temporarily stopped.

The new drug application (NDA) for Celgene’s ozanimod, a novel investigative therapy for the treatment of patients with relapsing MS, was rejected by the US Food and Drug Administration (FDA) this week. The FDA submitted a Refusal to File (RTF) letter to the company, citing insufficient nonclinical and clinical pharmacology sections in its application, according to Celgene.

Ozanimod is an oral selective modulator of the sphingosine 1-phosphate 1 (S1PR1) and 5 (S1PR5) receptors. By binding with the S1PR1, researchers believe the therapy could inhibit certain subsets of activated lymphocytes from migrating to sites of patient inflammation. This could lead to anti-inflammatory activity through a reduction of circulating T and B lymphocytes.

Aside from relapsing MS, it is currently under clinical review for the treatment of ulcerative colitis and Crohn’s disease.

The therapy had shown continued success in clinical trials leading up to the FDA’s RTF letter this week. In October 2017, 2-year data from the phase 3, 1313-patient RADIANCE study presented at the 2017 MS Paris Meeting in Paris, France reported that ozanimod had significantly reduced annualized relapse rates (ARR) and new/enlarging T2 lesions in patients with relapsing MS.

The trial compared 0.5 mg and 1.0 mg dose ozanimod to interferon beta-1a (IFN) in split patient populations. The mean ARR was 0.218 for patients taking 0.5 mg ozanimod, and 0.172 for those taking 1.0 mg. When compared to the mean ARR of IFN dose groups, the novel therapy represented a 21% (P = .0167) and 38% (P < .0001) ARR reduction in patient groups, respectively.

Patients undergoing ozanimod therapy reported a mean 2.092 new/enlarging T2 lessions — a 34% (P = .0001) and 42% (P <.0001) reduction to that of the 3.183 lesions reported by the IFN group, respectively.

Jeffrey A. Cohen, MD, Mellen Center for MS Treatment and Research, Cleveland Clinic, told MD Magazine at the time that brain volume, cortical gray matter volume, and thalamic volume loss were also slowed compared with IFN.

In response to the FDA decision, Celgene announced intentions to seek “immediate guidance” from the FDA in the form of a Type A meeting request to understand what information is required for an NDA resubmission.

"We remain confident in ozanimod's clinical profile demonstrated in the pivotal program in relapsing forms of multiple sclerosis," Jay Backstrom, MD, Chief Medical Officer and Head of Global Regulatory Affairs for Celgene said. "We will work with the FDA to expeditiously

address all outstanding items and bring this important medicine to patients."

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