- Sarepta Therapeutics' microdystrophin gene therapy program has hit a road block, as the Phase 1/2a trial has been put on hold by the Food and Drug Administration after the discovery of an out-of-specification lot.
- An analysis showed trace levels of DNA fragments in research-grade plasmids supplied by an undisclosed third party. The Research Institute at Nationwide Children's Hospital notified Sarepta, and the two organizations developed an action plan, which includes the use of GMP-s plasmid.
- Provided the plan is accepted by the FDA, Sarepta expects to begin dosing patients by the end of 2018 as intended, with an interim analysis in the second half of 2019. The company's share price has declined since the news was announced Wednesday, closing about 4% lower on Thursday.
Preliminary animal tests of the lot under scrutiny have shown no safety issues triggered by the DNA fragment traces. The FDA notes patient safety is the top priority, however, and Sarepta has been quick to take action.
"We intend to rapidly respond to the FDA's clinical hold letter, including a commitment to the Agency to only use GMP-s plasmid," said Doug Ingram, Sarepta's president and CEO, in a statement.
Joseph Schwartz, an equity analyst at Leerink, sees the contamination issue as "minor and solvable in short order," particularly as the batch was not used in the ongoing Phase 1/2 study, and examinations of biopsies from four treated patients showed no signs of any unexpected DNA fragments.
"According to [management], Sarepta has also received clear guidance on how to address the issue at hand and thus believes the FDA's questions can be addressed quickly," Schwartz wrote in a note to investors. "We anticipate clarity on the clinical hold in the near future."
The study's full enrollment of six patients may not happen either, as Sarepta opts to follow just the four patients already dosed.
"In our follow-up discussion, Sarepta noted that it decided to monitor the same [four patients] … due to the robustness of the data and the positive draft guidance on gene therapy in rare diseases. Having achieved strong proof of concept, conserving drug material to be utilized in a (potentially) pivotal trial strikes us as more strategic than completing a [Phase] 1/2 study as originally intended," wrote Schwartz.
It's possible that this situation could have triggered the company into starting dosing patients in the cohort C part of the study, which has the potential to serve as a registrational trial, by the end of 2018. Cohort C is a randomized study involving 24 patients, and the company suggested at a recent event that this could expedite the microdystrophin program.
"Resolution of the clinical hold takes priority, but upon its removal, [management] will refocus efforts on getting this study under way," Schwartz wrote.
Sarepta's isn't the first clinical hold for an investigational DMD drug. Solid Biosciences' SGT-001 microdystrophin gene transfer program recently had its clinical hold lifted. The hold followed the hospitalization of a trial participant in the IGNITE DMD Phase 1/2 study, but enrollment has now restarted with a readout of the interim analysis planned for the second half of 2019.