An experimental gene therapy from Sarepta Therapeutics increased levels of the gene missing in an ultra-rare form of muscular dystrophy, according to data the company presented Friday.
The company has said it plans to file for approval in the disease, known as limb girdle muscular dystrophy (LGMD) 2E. That would make it the first approved treatment in LGMD, a broad collection of highly rare diseases that can deprive patients of the ability to walk and in some case shorten life. But it is likely to face a significant uphill battle.
The LGMD 2E therapy relies on the same gene-ferrying virus that Sarepta uses in its other treatments, including its approved gene therapy for Duchenne muscular dystrophy, Elevidys, and experimental gene therapies for several other LGMD subtypes.
Since March, three different patients have died of liver failure after receiving one of these therapies, including two teenagers with Duchenne and a 51-year-old man with a different LGMD subtype.
The FDA has halted all of Sarepta’s LGMD trials and, before politicians and patient advocates intervened, demanded Sarepta halt all Elevidys shipments. (It is still not available for older and sicker patients, who can no longer walk.)
Sarepta has since abandoned its other experimental LGMD gene therapies, dealing a deep blow to a patient community that had waited years for Sarepta to start clinical trials. But it said it would continue pushing for approval in LGMD 2E, as the company had already dosed all the patients in a pivotal trial.
Data from the trial,presented for the first time Friday at the World Muscle Society in Vienna, were positive.
LGMD 2E, a particularly severe subtype, is caused by the absence or deficient levels of β-sarcoglycan, a protein that protects muscle cells. Sarepta treated 11 patients who could still walk. Before treatment, only around 15% of these patients’ muscle fibers contained the key protein. After treatment, 59% of their fibers contained the gene
It increased the total amount of protein patients produced, relative to healthy individuals, by around 30 percentage points. .
“Those data support a good amount of protein expression and hopefully functional benefit in the future,” said Nicholas Johnson, division chief of neuromuscular, at Virginia Commonwealth University in an email.
The question is how regulators will interpret those results, in light of the risks. Sarepta’s plan for LGMD had always relied on a great degree of regulatory flexibility. Because most LGMD subtypes are slow-moving and ultra-rare, it would have been difficult to run a traditional randomized trial.
The FDA previously agreed to allow Sarepta to apply for accelerated approval, a form of conditional authorization, by just showing the treatment increased protein levels. Then it could convert to full approval by following those patients for years and comparing their decline to natural history.
Since then, the Trump Administration has turned over virtually the entire agency’s leadership, while the deaths linked to Sarepta’s gene therapy virus have substantially changed the risk-benefit calculus.
There were no deaths in LGMD 2E trial. But 11 of the 17 patients had an adverse event consistent with acute liver injury, including one patient who is still dealing with a “non-serious” adverse event.
Given that all three deaths were in patients who could no longer walk, it’s possible usage could be confined to youngest and healthiest patients. The therapy also seemed more effective in these patients. The six non-ambulatory patients in the study saw smaller increases in protein-positive muscle fibers — 24% – than the ambulatory patients.
“You will want to select patients judiciously,” said Johnson, who has also started a company to develop LGMD gene therapies with newer and potentially safer viruses. “I don’t know if the FDA will provide a black box, but a lot of clinicians I have spoken with here are thinking about ambulatory patients only.”
