The FDA notified Sarepta Therapeutics that its Phase I/IIa Micro-Dystrophin Gene Therapy Trial for Duchenne muscular dystrophy (DMD) has been placed on a clinical hold because of contamination of its therapeutic.
The U.S. Food and Drug Administration (FDA) notified Cambridge, Massachusetts-based Sarepta Therapeutics that its Phase I/IIa Micro-Dystrophin Gene Therapy Trial for Duchenne muscular dystrophy (DMD) has been placed on a clinical hold because of contamination of its therapeutic. The announcement came through the Research Institute at Nationwide Children’s Hospital, where the clinical trial is being conducted.
At issue was the discovery of a trace amount of DNA fragment in what they’re calling a “research-grade third-party supplied plasmid.” A plasmid is typically a small, circular DNA strand in the cytoplasm of a bacteria that is used in gene manipulation. It is physically separated from chromosomal DNA and can replicate independently. In this context, they carry the genetic material the company is using in its gene therapy.
According to STAT, the lot tested hadn’t been used in patients, but four patients had received a dose from a different lot from the same supplier. The DNA fragment in question hadn’t been found in biopsies taken from any of the patients, and no side effects were reported.
Doug Ingram, Sarepta’s president and chief executive officer, told STAT, “There’s nothing particular in the sequence that was troubling.” The issue was essentially that the fragment was there, and shouldn’t have been. He went on to say, “It has been standard practice for academic institutions to use research-grade plasmids for early-stage clinical programs.”
Now the company expects to address the problem by using plasmids manufactured to different standards. It’s possible it will use the same supplier.
“We have good ideas for where we’re going to go for our third-party supplier,” Ingram told STAT. “We know the source of the problem, we have been given clear guidance on how to address the issue, and we have a plan for our clinical development program to remain on track.”
The Research Institute and Sarepta have made a plan to respond to the problem and expect to submit it to the FDA for review immediately. Once the FDA accepts the action plan, the company expects no particular delay in dosing patients as originally planned by the end of 2018.
“Patient safety is our top priority at Sarepta as we know it is for Nationwide Children’s Research Institute,” Ingram 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 micro-dystrophin program with the goal of commencing a pivotal trial by year-end 2018.”
DMD is a muscle wasting disease caused by mutations in the dystrophin gene, which results in insufficient levels of the dystrophin protein. It is a progressive disease that usually causes death in early adulthood, with serious complications that include heart or respiratory-related problems. It mostly affects boys, about 1 in every 3,500 or 5,000 male children.
Its controversial drug for DMD, Exondys 51, only targets DMD patients amenable to skipping exon 51. The company is working on gene therapies that affect different patient populations. The particular gene therapy discussed here, Micro-Dystrophin Gene Therapy, was developed by Nationwide and licensed by Sarepta.
