- The Food and Drug Administration's surprise decision to approve Sarepta Therapeutics' new drug Vyondys 53 came over the objections of a senior reviewer who highlighted the risk of serious injury or death from infections and kidney complications.
- The agency's review, posted online Wednesday, revealed 11 known cases of hospitalizations and two deaths from infections linked to infusion ports used with Sarepta's marketed Duchenne muscular dystrophy drug, Exondys 51. Those reports likely understate the number of infections seen in clinical practice, according to the reviewer, who decided in August to reject Sarepta's initial application for Vyondys.
- Kidney complications, which were also flagged in the August rejection, were observed only in rats treated with the drug. But therapies with a similar mechanism of action have caused problems in humans' kidneys and the FDA's report noted how normal biomarkers of kidney function can't be relied upon in DMD patients.
The FDA's rejection of Vyondys 53 (golodirsen) was almost as much of a surprise as its approval four months later after an appeal. Documents disclosed Wednesday reveal the review was nearly as contentious as Sarepta's first marketed drug, Exondys 51 (eteplirsen).
A central figure in both reviews has been Ellis Unger, director of the FDA's Office of Drug Evaluation I, who signed the Complete Response Letter notifying Sarepta of the agency's initial decision to reject Vyondys. He coined the phrase "elegant placebo" to describe Exondys, and his opinion of Vyondys was little better.
The objection to both on efficacy grounds is that the production of dystrophin — a key muscle building drug deficient in Duchenne patients — stimulated by both drugs is very modest and hasn't yet been shown to make a difference in patients' ability to walk and move.
A further point raised by Unger is the risk of infection, including life-threatening sepsis, resulting from central venous access ports used to infuse patients with Exondys. Eleven cases have been reported to the FDA, with two deaths.
Although the drug isn't directly implicated, Unger wrote, "if these devices are necessary to deliver the drug, then these infections must be construed to be drug-related." The risk is further heightened by the use of immune-suppressive corticosteroids, which makes it harder for the patients to fight the infection.
Half of the 60 patients in the Vyondys clinical development program used infusion ports.
The final approval letter, signed by the acting director of the Office of Neuroscience, Billy Dunn, was accompanied with a risk mitigation document in which Sarepta said it will provide patient and provider education about the appropriate use of infusion ports. Unger's earlier Complete Response Letter tersely noted, "No matter the level of expertise of healthcare providers involved in inserting and managing central access ports, infections will occur."
The kidney risk, meanwhile, is well-known from use of other drugs using the platform underpinning Exondys and Vyondys, which are both antisense oligonucleotides. Problems were only seen in rats, with several animal deaths occurring with Vyondys and none with Exondys, according to Unger's clinical review.
There were two concerns raised by the Complete Response Letter. First, Vyondys is excreted mostly unchanged in the urine. So in DMD patients with reduced kidney function, an inability to excrete Vyondys would lead to ever-increasing exposures to the drug and progressing toxicity.
The second concern centers on the ability to monitor kidney function. One measure of kidney function, levels of a chemical called creatinine, is not reliable in DMD patients because they have naturally elevated levels thanks to the muscle breakdown resulting from their condition.
The label eventually approved for Vyondys calls on doctors to perform a baseline kidney function test and, after initiating therapy, routinely monitor kidney function through frequent urine collection to look for signs of dysfunction.
A final concern Unger raised in the Complete Response Letter is Sarepta's failure to initiate a trial to confirm that small increases in dystrophin can help slow or reverse the decline of DMD patients. Without that data, he writes, it is difficult for the FDA to judge whether Vyondys is worth the risk of infection and kidney problems.
The final approval letter reminded Sarepta of the need to carry out a long-standing proposal to study Vyondys and a similar experimental drug, casimersen, to test whether patients taking it perform better on a walking test than patients taking placebo.
RBC analyst Brian Abrahams said Unger's comments suggest there was an element of "payback" in the Complete Response Letter, but that the documents released today bode well for approval of casimersen.