FDA Places DMD Gene Therapy Trial on Hold


A third-party manufacturing issue has delayed a phase I/IIa study for Sarepta Therapeutics.

Dr Doug Ingram

Doug Ingram, Sarepta's president and chief executive officer

Doug Ingram

A phase I/IIa clinical trial exploring a microdystrophin gene therapy for patients with Duchenne muscular dystrophy (DMD) has been placed on hold by the FDA due to a third-party manufacturing concern, according to Sarepta Therapeutics, the company developing the therapy. The notification of the stop was delivered to the Research Institute at Nationwide Children’s Hospital, where the trial is being conducted.

During a routine inspection of therapy quality, an unexpected DNA fragment was found in research-grade plasmid that was being sourced from a third-party for the study. Doses containing the DNA fragment were not administered to patients, and analysis found that it was not associated with safety concerns nor protein expression, according to Sarepta.

For future doses in the trial, the company plans to switch from research-grade plasmid to good manufacturing practice (GMP)-certified plasmid, which can take from 6 weeks to more than 20 weeks to manufacture, depending on the source. The FDA is currently reviewing the change. The company hopes to commence the clinical trial by the end of 2018.

“Patient safety is our top priority at Sarepta as we know it is for Nationwide Children’s Research Institute,” Doug Ingram, Sarepta’s president and chief executive officer, said in a statement. “We intend to rapidly respond to the FDA’s clinical hold letter, including a commitment to the Agency to only use GMP-s plasmid. Independently, we will also request a meeting with the Agency to discuss the microdystrophin program with the goal of commencing a pivotal trial by year-end 2018.”

The microdystrophin therapy, known as AAVrh74.MHCK7.micro-Dystrophin, consists of a rhesus monkey-derived AAV vector, which shows lower immunogenicity rates in existing early-stage clinical studies. The MHCK7 cassette allows for AAVrh74 to effectively enter skeletal, diaphragm, and cardiac muscle preferentially via the blood, making it an ideal candidate for neuromuscular diseases.

Results from earlier batches of the gene therapy used in the phase I/IIa study were announced in June 2018. Three patients treated with the gene therapy exhibited a robust expression of transduced microdystrophin, which was properly localized to the muscle sarcolemma. Additionally, all 3 patients showed significant decreases of serum creatine kinase levels, with a mean 87% reduction by day 60.

The mean microdystrophin, which was measured by Western blot, was 38.2% compared with normal. Utilizing Sarepta’s method, which adjusts for fat and fibrotic tissue, the rate was 53.7% compared with normal. A mean of 1.6 vector copies per cell nucleus was found and was consistent with the microdystrophin expression levels observed.

No serious adverse events were noted in the study, and 2 patients who experienced elevated gamma-glutamyl transferase corrected within a week and returned to baseline levels through increased steroid intake. Furthermore, during the first week of treatment, patients experienced transient nausea which correlated with increased steroid dosing.

The low toxicity is notable, as other AAV-based therapies have met safety challenges for patients with DMD. One such therapy, SGT-001, was placed on clinical hold by the FDA for safety concerns related to a reduction in red blood cell count and complement activation. Notably, SGT-001 utilizes a different promoter cassette known as CK8, which is different from the MHCK7 promoter used for AAVrh74.MHCK7.micro-Dystrophin.

Pfizer is also developing a third gene therapy utilizing AAV-mediated microdystrophin gene transfer for DMD. This agent, PF-06939926, was first administered to a patient in March 2018. Early data from this preliminary trial are anticipated in 2019.

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