[Updated 7:25 p.m. See below.] Safety concerns stymied Sarepta Therapeutics’ attempt to win FDA approval last August for golodirsen (Vyondys 53), its second Duchenne muscular dystrophy drug. But an appeal of the decision led to a surprise reversal by the regulator last month, with little explanation why.
Details are now surfacing about the safety risks that led the FDA to initially reject the therapy. And the regulator contends that much more would be known about the extent of those risks if Sarepta (NASDAQ: [[ticker:SRPT]]) had conducted a study it was ordered to start in 2016 as a condition of the approval of Sarepta’s first Duchenne drug.
Those details were described in the letter the FDA sent to Cambridge, MA-based Sarepta notifying the company about the rejection. FDA rejection letters are typically kept private, but on Wednesday, the FDA posted the August correspondence on its website. It was signed by Ellis Unger, director of the agency’s Office of Drug Evaluation in the Center for Drug Evaluation and Research.
Sarepta spokeswoman Tracy Sorrentino wrote in an email that Sarepta has been working with the agency since approval of its first Duchenne drug, eteplirsen (Exondys 51), and the post-marketing study for that drug is underway and expected to be complete in 2024. [Paragraph added with Sarepta comment, and story updated throughout.]
Golodirsen is an RNA-based drug developed to boost production of dystrophin, a muscle protein that Duchenne patients, who are mostly boys, lack. Eteplirsen (Exondys 51), Sarepta’s first Duchenne drug, was developed to do the same thing. The drugs, which are given as weekly infusions, cover different subsets of Duchenne patients based on their genetic profiles.
The similarities between the two Sarepta drugs point the way to the concerns that led the FDA to reject golodirsen in August. The FDA letter noted that patients who receive golodirsen face the risk of infection due to the administration of the drug through an intravenous infusion port. The letter also flagged the risk of kidney damage. Both of these risks are potentially life threatening, and the kidney damage is “difficult or impossible to monitor,” the letter said.
When the FDA approved eteplirsen in 2016, it was the first drug to win the regulatory nod to treat Duchenne, a rare inherited disease that leads to progressive muscle weakness, and ultimately, death. At the time of the FDA decision, the concern about infection was raised but was not found in the 12-patient clinical trial that was the basis for evaluating the drug.
Since eteplirsen reached the market, there are more patients to evaluate. Of the 469 patients who received the drug through March 18, 2019, 11 of them, or 2.3 percent, developed infections, according to adverse event reports submitted in connection with eteplirsen. The FDA letter quashes any characterization of those infections as being solely related to the apparatus used to administer the drug. “If these devices are necessary to deliver the drug, then these infections must be construed to be drug-related,” the letter states.
Infection risks are higher in Duchenne patients because they are typically taking corticosteroids, which increases susceptibility to infections. The FDA says the infection risks reported for eteplirsen directly apply to patients who might receive golodirsen. “Ignoring the applicability of these infections to boys who would receive golodirsen is irresponsible, as this puts boys at even greater risk of complications and death,” the letter says.
Toxicity to the kidneys is a known risk of antisense oligonucleotides, the class of drugs to which eteplirsen and golodirsen belong. In animal studies, chronic exposure to golodirsen led to severe decline in kidney function, with some animals showing kidney failure leading to death. The FDA says that golodirsen is excreted in the urine mostly unchanged. Therefore, as kidney function declines, a patient’s exposure to the drug increases.
One way to monitor kidney function is to measure levels of creatinine, a muscle waste product that is removed by the kidneys. But the FDA notes that because the muscles of Duchenne patients already have diminished creatinine production, it can’t be
