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any side effects related to the gene therapy. “As far as I can see, we have a very safe product,” Mendell said. The study is expected to produce data in mid-2018.
“Whatever is going on with Solid that has required the chairman of their scientific advisory board to resign in protest and has required the FDA to place them on clinical hold is, to the best of our knowledge, something unique to whatever is going on at Solid,” said Sarepta CEO Doug Ingram. “It probably would benefit all of us, and the patient community, if Solid would provide more information about exactly what is going on with their program that is causing problems.”
A Pfizer spokesperson said that the company hasn’t identified preclinical data that would preclude it from bringing its Duchenne gene therapy into human testing.
Pat Furlong, the founding president and CEO of the nonprofit patient advocacy group Parent Project Muscular Dystrophy, which has helped fund the Nationwide trial and collaborated with Solid, added: “We have the utmost respect for Dr. Wilson and value his opinion, but we also believe in the work of Solid, as well as Pfizer and have confidence in the scientific progress leading up to these studies.”
These therapies are being closely watched because gene therapy offers the potential for a one-time, long lasting treatment. Two Duchenne treatments are on the market—eteplirsen (Exondys 51), from Sarepta, and deflazacort (Emflaza), now owned by PTC Therapeutics (NASDAQ: PTCT). Neither are cures. Sarepta’s drug is supposed to slow the progression of the disease in a subset of patients, roughly 13 percent with a specific genetic malfunction. Deflazacort is a muscle-boosting steroid already widely available in other countries, also meant to help slow Duchenne.
Companies and academic institutions have been increasingly investing in gene therapy, however, for a longer lasting solution that can reach a wider swath of patients. Methods being advanced by Solid, Sarepta, and Pfizer would supply genetic instructions for a patient’s body to produce an engineered form of the muscle-protecting protein dystrophin, which Duchenne patients lack.
Solid, Sarepta, and Pfizer are doing this by engineering a smaller version of the dystrophin gene that is easier to deliver into patients’ cells. The hope is this will slow or halt the disease’s progress. Mendell says the major question with this approach is whether the so-called microdystrophin “will compromise function.”
“We hope that it doesn’t, but we won’t know until we start seeing,” he said.
In Solid’s Jan. 16 regulatory filing, Jim Wilson’s concern that prompted his resignation is “high systemic dosing of AAV.”
AAV-related side effects have not been a problem with gene therapies such as Spark Therapeutics’s (NASDAQ: ONCE) voretigene neparvovec (Luxturna)—the first approved in the U.S.—that are delivered to a specific tissue—the eye, for Luxturna, for instance. For Duchenne, however, the gene therapy is infused into the bloodstream and travels in less controlled fashion to various parts of the body, like skeletal and cardiac muscle.
Mendell respects why Wilson might be “risk-averse” about Duchenne gene therapy, but he’s encouraged by what he’s seen so far given his own experience.
In addition to Duchenne gene therapy, Mendell was also the lead investigator in an early stage study of the experimental AVXS-101 from AveXis (NASDAQ: AVXS), for spinal muscular atrophy, another rare genetic disease that affects motor function. Patients in that study were given high doses of AAV. The most significant issue was a spike in liver enzymes in four patients that was suppressed with steroids and didn’t lead to any notable side effects, Mendell says. Meanwhile, children who typically die before the age of two didn’t, and two were walking who wouldn’t have been otherwise expected to.
Mendell said experienced scientists had warned that the doses in the trial would probably be unsafe. But if he and his team hadn’t tested high doses, “we wouldn’t have saved lives and wouldn’t have had patients walking.”
The study results were published in the New England Journal of Medicine in 2017.