Roche’s RG6206 becomes second myostatin inhibitor to fail in DMD in past year

The failure of Roche’s RG6206 marks another blow to the hypothesis that blocking myostatin can improve muscle growth and function in ambulatory boys with Duchenne muscular dystrophy.

Roche (SIX:ROG; OTCQX:RHHBY) sent a letter Wednesday to the DMD community, including non-profit Parent Project Muscular Dystrophy (PPMD), disclosing that the company was discontinuing development of the anti-MSTN adnectin IgG1-Fc fusion protein after a preplanned interim futility analysis showed RG6206 was unlikely to meet the primary endpoint of an improvement in the North Star Ambulatory Assessment in the Phase II/III SPITFIRE trial.

The SPITFIRE failure is the second clinical anti-MSTN to be discontinued since mid-2018. In August 2018, Pfizer Inc. (NYSE:PFE) terminated two Phase II trials of anti-MSTN mAb domagrozumab (PF-06252616) to treat DMD after one trial missed the primary endpoint (see “Pfizer Ends Phase II Trials of DMD Candidate”).

MSTN emerged as a promising target for muscle wasting or atrophying diseases after previous research had shown that mutations in the MSTN gene led to muscle hypertrophy in animals and humans.

The results appear to validate findings published in 2017 by University College London researchers that showed low MSTN expression levels in muscle biopsies from patients with muscle wasting or atrophying diseases including DMD, indicating that targeting MSTN may not be a successful therapeutic strategy (see “Low Levels of Myostatin May Impair Muscular Atrophy and Dystrophy Treatments”).

MSTN inhibitors in the clinic include ACE-083 from Acceleron Pharma Inc. (NASDAQ:XLRN) and SRK-015 from Scholar Rock Holding Corp. (NASDAQ:SRRK). ACE-083 is a ligand trap inhibiting MSTN and activins that is in a Phase II trial to treat muscle atrophy disease Charcot-Marie-Tooth, with data expected in 1H20. SRK-015 is an inhibitor of the latent form of MSTN that is in the Phase II TOPAZ trial to treat spinal muscular atrophy (SMA), with data expected in 2021.

Roche gained rights to RG6206 through a 2017 deal from Bristol-Myers Squibb Co. (NYSE:BMY), under which BMS received $170 million up front and was eligible for $205 million in milestones, plus royalties.

In other DMD news, during the 3Q19 investor call for Sarepta Therapeutics Inc. (NASDAQ:SRPT) Thursday, President and CEO Douglas Ingram declined to provide any update on the regulatory status of Vyondys 53 golodirsen. In August the therapy received a complete response letter to treat DMD patients amenable to skipping exon 53 based on preclinical findings of an injection site infection risk and renal toxicity (see “Sarepta Sinks After FDA Rejects DMD Therapy”).

Ingram said Sarepta “will await clarity on the Vyondys matter before we submit for casimersen in the United States.” Sarepta had been planning to submit an NDA for casimersen, a phosphorodiamidate morpholino oligomer (PMO) targeting exon 45, by mid-year.

Targets - MSTN (GDF8) - Myostatin

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