Celgene said it will weigh whether to continue its clinical program for GED-0301 (mongersen)—for which it committed up to $2.6 billion in 2014—following the Crohn’s disease candidate’s failure in a Phase III trial and a Phase III extension study.

The biotech giant said yesterday it was ending the Phase III REVOLVE trial (CD-002; NCT 02596893) and the Phase III SUSTAIN extension trial (CD-004; NCT02641392). Celegene said its decisions came at the recommendation of the study’s data monitoring committee, which carried out an interim futility analysis assessing overall risk and benefit.

In an announcement and a regulatory filing, Celgene shed no light on how GED-0301 failed REVOLVE or SUSTAIN.

REVOLVE’s primary endpoint was the proportion of patients achieving clinical remission as defined by stool frequency and abdominal pain (in the U.S.), and by the Crohn's Disease Activity Index (CDAI) elsewhere in the world. During the trial, launched in December 2015, an estimated 1064 patients were to be randomized to either GED-0301 or placebo. REVOLVE’s estimated primary completion date was September 28, 2018, Celgene said on the trial’s ClinicalTrials.gov page, last updated September 29.

SUSTAIN was intended to assess long-term safety data of GED-0301 for up to four years in adult patients who participated in REVOLVE and were to take part in a since-scrapped Phase III study, DEFINE (CD-003), as well as adolescents ages 12 to 17 who were to participate in DEFINE. SUSTAIN’s primary endpoint was the type, frequency, and severity of adverse events, and its relationship to investigational product, discontinuation due to adverse events, and clinically significant changes in electrocardiograms, vital signs, and/or laboratory findings.

Celgene said it will abort DEFINE—which like REVOLVE had been intended to assess GED-0301 in Crohn’s—and study the full dataset from a Phase II study evaluating GED-0301 in ulcerative colitis (UC; NCT02601300) before determining next steps.

Assessing Financial Impacts

“We are continuing to assess the financial impacts of discontinuing the Trials,” Celgene stated in a regulatory filing.

In that filing, Celgene disclosed that it will incur a charge against fourth-quarter 2017 earnings related to significant impairment of GED-0301, an in-process R&D asset whose value the company stated was approximately $1.6 billion, as well as wind-down costs associated with ending the trials and related development activity, to be partially offset by a “significant” reduction in its approximately $1.4 billion of GED-0301–contingent consideration liabilities.

“The exact amount of the net pre-tax charge to earnings has not yet been determined, but is estimated to be in the range of $300 million to $500 million, or $0.27 to $0.45 per diluted share after tax,” Celgene stated. “Approximately 50[%] of the net charge will require cash payments.”

GED-0301 is a first-in-class oral antisense DNA oligonucleotide targeting Smad7 mRNA. Celgene acquired rights to develop and commercialize GED-0301 from Nogra Pharma in 2014 for $710 million upfront, up to $815 million in payments tied to regulatory and development milestones, and up to $1.05 billion in aggregate tiered sales milestone payments if annual net sales reach $4 billion.

In its announcement yesterday, Celgene cited the progress of two pipeline candidates with gastrointestinal indications. One is Otezla® (apremilast), for which a Phase II trial (UC-001) in UC is ongoing with data expected by year-end 2017.

Should results prove positive, Celgene said, a broad Phase III program in UC could begin in 2018.

Looking to Ozanimod

The other pipeline candidate is ozanimod, an oral, once-daily, selective sphingosine 1-phosphate 1 and 5 receptor modulator being developed for Crohn’s and UC, as well as relapsing multiple sclerosis (MS). Celgene inherited ozanimod when it acquired Receptos in 2015 for about $7.2 billion.

Celgene says it still expects to launch a Phase III trial “in the next few months” assessing ozanimod in Crohn’s. Earlier this month, it presented two-year data from the Phase II TOUCHSTONE trial in UC and Phase II data from the STEPSTONE trial in Crohn’s at the World Congress of Gastroenterology meeting. Ozanimod is also under study for UC in the Phase III TRUENORTH trial.

“Despite the likely termination of the GED-0301 program, we still believe that ozanimod will be a meaningful contributor to long-term revenues due to differentiation on cardiac safety versus Gilenya® [fingolimod],” Canaccord Genuity analyst John Newman, Ph.D., said in a note to investors.

Celgene said yesterday that it plans to present data showing that ozanimod does not impact cytotoxic T-lymphocyte function in vitro, thus showing differentiation from Novartis-owned Gilenya’s activity on SET-PP2A. Ozanimod has been projected by EvaluatePharma to reach $2.1 billion in revenues by 2022.

“We continue to expect positive data from the Phase [III] RADIANCE study in MS for ozanimod at ECTRIMS, the European Committee for Treatement and Research in Multiple Sclerosis, which should bolster ozanimod’s approval prospect,” Dr. Newman said. He added that Celgene is expected to submit by year’s end a New Drug Application to the FDA for ozanimod for relapsing MS.

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