FDA Lifts Hold on Sarepta’s Phase 1/2 Trial on Gene Therapy for DMD

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |


The U.S. Food and Drug Administration has lifted the clinical hold on a Phase 1/2 trial evaluating Sarepta Therapeutics‘ micro-dystrophin gene therapy candidate for Duchenne muscular dystrophy (DMD), the company announced in a press release.

On July 25, the FDA placed the trial on hold after finding trace amounts of plasmid DNA that is used in the raw material to make the therapy. The trial is being conducted at Nationwide Children’s Hospital in Columbus, Ohio.

Preliminary testing showed that these trace fragments were quickly cleared by the body and showed no safety concerns.

Researchers at Nationwide Children’s Hospital in collaboration with Sarepta submitted a response addressing the FDA’s concerns. In their response, they included an audit of the plasmid supplier and have committed to using GMP-Source plasmids, or Good Manufacturing Practice plasmids, that ensure the material is of high quality, allowing a controlled composition of the DNA used in the therapy.

“Thanks to the diligent and rapid work of my Sarepta colleagues and Nationwide Children’s Hospital in compiling and submitting a complete response and the expeditious evaluation by the FDA in reviewing the response and removing this clinical hold, we have been able to address the clinical hold in record time and without delay to this profoundly important clinical program,” Doug Ingram, Sarepta’s president and CEO, said in the release

“Our focus now is on meeting with the Division to take guidance and gain alignment around what we hope to be our registration trial for our micro-dystrophin program and achieving our goal of commencing that trial by year-end 2018,” he said.

Sarepta’s gene therapy delivers a functional version of the dystrophin gene (DMD), missing in DMD patients.

The investigational therapy, called rAAVrh74.MHCK7.micro-dystrophin, uses a viral carrier — the adeno-associated virus, or AAV — to deliver a shorter version of the DMD gene, called microdystrophin. Although shorter, the microdystrophin gene contains enough information to produce and restore the function of dystrophin.

After positive results in an animal model, the Phase 1/2 clinical trial (NCT03375164) was launched at Nationwide Children’s Hospital, supported by Sarepta.

The trial includes 12 boys with DMD divided equally into two groups — one group from 3 months to 3 years of age, and a second group between 4 and 7 years old. Each participant receives a single dose of the gene therapy administered into the blood. Additionally, they’re given corticosteroids to prevent their immune system from targeting and destroying the gene therapy.

A muscle biopsy is performed before the patients receive the gene therapy, at the start of the study, and again 90 days after treatment to determine the therapy’s success in replacing the missing dystrophin protein.

Participants will be followed over three years, during which they will be monitored for side effects and changes in muscular capacity through physical examinations.

Sarepta had previously announced promising interim results for the first three treated boys in the older age group. The therapy increased the production of a functional dystrophin protein and reduced their muscle damage.

Three months after treatment, all three patients showed a 76.2% expression of dystrophin protein, confirming the therapy’s successful delivery to the muscles.

Additionally, the therapy significantly reduced their muscle damage, as shown by a decrease of more than 87% in the levels of creatine kinase, an enzyme used as a biomarker for muscle damage.

While two patients began to show signs of liver damage, these were resolved within a week after appropriate treatment.