Celgene IBD Pipeline In Question As Mongersen Crohn’s Disease Trial Ends
Executive Summary
Celgene will stop late-stage testing of its investigative therapy mongersen for Crohn’s disease after a data monitoring committee said it would be futile to continue.
Celgene Corp.'s hope of becoming an inflammation and immunology leader is being threatened as it pulls the plug on two studies evaluating mongersen for the treatment Crohn's disease at the recommendation of the trial's independent data monitoring committee.
Celgene's I&I Programs
Mongersen is an oligonucleotide that decreases a protein called Smad7 that is abnormally high in Crohn's disease. High levels of Smad7 interfere with an anti-inflammatory pathway in the gut called TGF-β1, which leads to increased inflammation.
Ozanimod is a novel, selective, sphingosine 1-phosphate 1 (S1PR1) and 5 (S1PR5) receptor modulator in development for immune-inflammatory indications including relapsing multiple sclerosis, ulcerative colitis and Crohn's disease. Selective binding with S1PR1 is believed to inhibit a specific subset of activated lymphocytes from migrating to sites of inflammation. The result is a reduction of circulating T and B lymphocytes that leads to anti-inflammatory activity, according to Celgene.
Otezla is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels which is thought to indirectly modulate the production of inflammatory mediators.
Widely known for its oncology therapies Revlimid (lenalidomide) and Pomalyst (pomalidomide), Celgene's foray in the inflammation and immunology segment had been drawing attention as it explored three oral drugs: Otezla (apremilast), ozanimod, and mongersen (formerly GED-0301), each with different mechanism of action in inflammatory bowel disease (see box). Celgene has been hoping to use these research efforts to establish a position in the underserved areas of Crohn's disease and ulcerative colitis. (Also see "Celgene Sets Sights On Becoming Inflammation and Immunology Power Player" - Pink Sheet, 20 Jul, 2015.)
But that aspiration was knocked on the head Oct. 19 when Celgene said that after consulting the data safety and monitoring committee that was overseeing the main mongersen study, called REVOLVE, it had decided to stop developing the drug.
It cited a futility analysis, implying the medicine was not effective, but said there were no safety problems.
Celgene said it will now assess whether to continue its clinical program for mongersen. But in a brief statement Celgene gave no details on how mongersen fared in the Phase III REVOLVE or Phase III SUSTAIN extension trials. Celgene has also been developing mongersen in combination with ozanimod.
"While the loss of one of the company's most advanced and high-profile pipeline programs is, in and of itself, disappointing, we believe the announcement will have a broader impact of calling into question the value of the rest of the pipeline." - Baird
Celgene is abandoning its Phase III DEFINE trial, which like REVOLVE had been intended to assess mongersen in Crohn’s disease, and that the biotech will now study the full dataset from a Phase II study evaluating mongersen in ulcerative colitis to determine what to do next.
Striking a hopeful note, Scott Smith, president and chief operating officer, stated that Celgene remains "committed to advancing our portfolio of novel medicines for patients suffering from this disease and other inflammatory bowel disorders."
Failure Seen Having Wide Impact
But some analysts warned the failure of mongersen in Crohn's disease has wide ramifications.
Analysts at Baird Equity Research said that "while the loss of one of the company's most advanced and high-profile pipeline programs is, in and of itself, disappointing, we believe the announcement will have a broader impact of calling into question the value of the rest of the pipeline."
Mongersen has been one of Celgene's most emphasized pipeline assets, and was a cornerstone of its move into inflammation and immunology. The medicine was bought in April 2014 for $710m from with Nogra Pharma Ltd., a private Irish company based in Dublin, and had been widely viewed as a potential blockbuster. Celgene at the time said that if the drug moved through development and was approved, Nogra would get another $815m, plus tiered sales milestones that could pass $1bn. (Also see "Deal Watch: Much Activity Beyond GSK/Novartis/Lilly Pacts And Valeant/Allergan Bid" - Pink Sheet, 28 Apr, 2014.)
Though Celgene is awaiting data on mongersen's impact on ulcerative colitis, some analysts believe the drug's target SMAD has more mechanistic rationale in Crohn's disease, leaving little hope for mongersen's commercial prospects.
"With the opportunity now gone – and Otezla arguably unable to pick up slack due to recent measures taken to boost demand – we believe ozanimod will have to outperform already-high commercial expectations," the Baird analysts said in a reaction note.
Analysts at Bernstein concurred, saying in a note that "with no clarity if the failure is due to something specific to Crohn's disease, or the drug, it is inherently a very high-risk program."
"With the ozanimod program advancing, we expect that unless results in ulcerative colitis are fantastic, the [mongersen] program would be discontinued," they concluded.