Celgene has acknowledged that the FDA sent the company a “Refuse to File” letter in response to its New Drug Application (NDA) for the relapsing multiple sclerosis (MS) candidate ozanimod—the biotech’s second setback to one of its later-stage drug candidates in recent months.

Ozanimod is a novel, oral, selective sphingosine 1-phosphate 1 (S1PR1) and 5 (S1PR5) receptor modulator being developed for relapsing MS as well as ulcerative colitis and Crohn's disease. Celgene has reasoned that selective binding with S1PR1 would inhibit a specific subset of activated lymphocytes from migrating to sites of inflammation, resulting in a reduction of circulating T and B lymphocytes leading to anti-inflammatory activity.

“Upon its preliminary review, the FDA determined that the nonclinical and clinical pharmacology sections in the NDA were insufficient to permit a complete review,” Celgene said in a statement issued yesterday after the close of the markets, without offering details.

The company added that it intends to seek immediate guidance, including requesting a Type A meeting with the FDA, to learn what additional information will be required to resubmit the NDA.

“We will work with the FDA to expeditiously address all outstanding items and bring this important medicine to patients,” declared Jay Backstrom, M.D., Celgene CMO and head of global regulatory affairs, in the statement. “We remain confident in ozanimod’s clinical profile demonstrated in the pivotal program in relapsing forms of multiple sclerosis.”

On October 28, Celgene announced positive results for ozanimod in two Phase III trials. In the SUNBEAM study, the company said ozanimod showed a significant reduction in both annualized relapse rate (ARR) and new or enlarging T2 lesions over one year at the 1-mg and 0.5-mg doses compared with Biogen’s marketed MS treatment Avonex® (interferon beta-1a). In the RADIANCE study, Ozanimod demonstrated significant reductions in ARR over two years of treatment, new or enlarging T2 lesions, and gadolinium-enhanced MRI lesions for both doses compared with Avonex.

However, ozanimod did not reach statistical significance compared with Avonex in the time to 3-month confirmed disability progression in a prespecified pooled analysis of the SUNBEAM and RADIANCE™ Part B studies.

“Preparing for World-Class Launch”

Still, Terrie Curran, Celgene’s president of inflammation & immunology, trumpeted the outcomes of SUNBEAM and RADIANCE last month during the company’s conference call with analysts that followed the release of fourth-quarter 2017 results.

 “We are highly encouraged by the results we’ve seen,” Curran said January 25, according to a transcript published by Seeking Alpha. “We remain focused on preparing for world-class launch in the RMS [relapsing MS] market. We’ve been aggressively expanding our commercial structure across numerous functions and adding important capability in critical areas of market access and patient support services.

Celgene inherited ozanimod when it acquired Receptos in 2015 for about $7.2 billion. At the time, Celgene projected ozanimod to generate peak annual sales ranging from $4 billion to $6 billion—forecasts based on the drug gaining approvals for both MS and ulcerative colitis. Thomson Reuters, however, had predicted annual sales growing from about $263 million in 2019 to $3.46 billion by 2024.

Investors responded to Celgene’s ozanimod setback with a selloff that lowered the company’s share price 6% from yesterday’s close of $95.78, to $89.99 in premarket trading as of 9:13 a.m., near the 52-week low of $88.32.

Also, SunTrust Robinson Humphrey downgraded Celgene shares from “Buy” to “Hold” and cut its price target from $139 to $106 a share.

Ozanimod is Celgene’s second later-stage pipeline candidate to see a development setback. In October, Celgene acknowledged that its Crohn’s disease candidate GED-0301 (mongersen) failed a Phase III trial and a Phase III extension study in October 2017, despite the company committing up to $2.6 billion since 2014 toward developing the first-in-class oral antisense DNA oligonucleotide targeting Smad7 mRNA.

In reporting fourth-quarter 2017 results, Celgene said charges related to the halt of the trials primarily explain why its R&D expenses ballooned last year to $5.915 billion from $4.470 billion in 2016. Those charges included impairment of an in-process R&D asset and other one-time charges related to wind down costs associated with the trials in Crohn's disease and certain development activities.

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