For the third time this year, a patient treated with a Sarepta Therapeutics gene therapy has died, a revelation that comes as the company tries to earn back patient and investor trust amid a series of safety setbacks.
The first two fatalities were teenage boys treated with the commercialized Duchenne muscular dystrophy gene therapy Elevidys. The latest fatality was a 51-year-old man who received SRP-9004, an experimental gene therapy for limb-girdle muscular dystrophy 2D/R3. All three patients died after developing acute liver failure.
BioCentury first reported the latest fatality late Thursday. Sarepta confirmed the development, then held a conference call on Friday, during which financial analysts peppered executives with questions about why they didn’t disclose the fatality Wednesday, when the company announced a cash-saving corporate restructuring that will cut 36% of its staff and stop further development of two limb girdle programs, including SRP-9004.
Sarepta CEO Doug Ingram defended the company’s level of disclosure, telling analysts that the fatality was not a material event nor was it central to the topics discussed Wednesday. He added that the company’s decision not to proceed with the two limb-girdle programs was financial, and was made independent of the fatality. Ingram explained that there was no further dosing in the limb-girdle study, so the proper way to discuss the fatality would be in the presentation of the full study results, which Sarepta plans to do at a future medical meeting.
“As relates to materiality, certainly if there was a material change in the safety signal of one of our marketed therapies, we would disclose that publicly,” Ingram said. “I think we have, I believe, a very laudable history of being extraordinarily transparent, not only with the physician and patient community, but with our investor base as well.”
Louise Rodino-Klapac, the company’s head of R&D and chief scientific officer, said the deceased limb-girdle patient was a 51-year-old, non-ambulatory man. The death happened a month ago, about 11 weeks after dosing. Rodino-Klapac said Sarepta notified the FDA first about the life-threatening liver complication, then about the death.
“The FDA was properly informed along the way of this case,” she said.
Another analyst asked whether Sarepta is aware of any other fatalities associated with its gene therapies. Rodino-Klapac replied no.
Despite Ingram’s explanation, analysts and investors see the developments with SRP-9004 as material and relevant to the company and to Elevidys. Sarepta’s gene therapies are delivered to their destinations in the body aboard adeno-associated viruses (AAV). Adverse reactions are a known risk of genetic medicines that use these engineered viruses. In a research note, Leerink Partners analyst Joseph Schwartz noted that the AAV vector used for SRP-9004 is the same one used in Elevidys. It’s also used in SRP-9003, a Sarepta gene therapy candidate for another form of limb-girdle muscular dystrophy. Sarepta plans to file an application later this year seeking FDA approval of SRP-9003.
William Blair analyst Sami Corwin said in a research note that given the deceased limb-girdle patient’s age, the high dose of the AAV-based gene therapy was the likely cause of the liver failure. She said this fatality could lead to greater scrutiny of SRP-9003. It could also amplify hesitancy of Duchenne patients to use Elevidys and increase investor distrust due to the failure to disclose the death, she said.
In another research note, Corwin said William Blair believes the lack of transparency from Sarepta management is contributing to the company’s stock price decline. Shares closed Friday at $14.07, down nearly 36% from Thursday’s close. Corwin added that the lack of transparency is harmful to the AAV gene therapy field more broadly.
Elevidys initially appeared to be a bright spot in Sarepta’s corporate shakeup announcement. The company said Wednesday that the FDA asked for a label update to include a black box warning, which analysts interpreted as positive because it suggests the product won’t be pulled from the market. But Elevidys might not be available to Duchenne patients much longer. The FDA will ask Sarepta to stop all shipments of the gene therapy, Reuters reported Friday afternoon, citing an unnamed source familiar with the matter. The FDA has been investigating the fatalities associated with Elevidys, an inquiry it announced in late June following the report of the second death.
In a note sent to investors after Friday’s market close, Leerink’s Schwartz said his firm is not confident that Sarepta understands the liver safety signal enough to identify a patient population where the safety risk is acceptable. He added the FDA may want to make an example of Elevidys and removal of the product from the market is becoming a legitimate risk. Leerink can no longer recommend Sarepta’s stock “under any circumstances.”
“We strongly disagree with management regarding their opinion on the materiality of the third death for their gene therapy platform, and again we think this significantly undermines their credibility,” Schwartz said. “We also disagree with management’s opinion that this death does not have readthrough to Elevidys and see mounting commercial risk for that program following another gene therapy death.”
On Friday afternoon, the FDA placed clinical holds on Sarepta’s limb-girdle studies and asked the company to voluntarily stop all shipments of Elevidys. The regulator also revoked the platform technology designation for the technology that Sarepta used to develop its gene therapies. The FDA said given the new information, the preliminary evidence is insufficient to show that this technology can be used safely in another therapy.
Sarepta is not stopping shipments of Elevidys. In a statement issued Friday evening, Sarepta said its interpretation of the scientific data shows no new or changed safety signals in ambulatory Duchenne patients and the company will continue to supply the gene therapy for treatment of this patient group.
[Story updated throughout with additional analyst comments, FDA action, and Sarepta response.]
Photo: Michael Nagle/Bloomberg, via Getty Images
