Sarepta Again Works Appeals Magic to Win Approval
[Report by David McFarland] How is it that Sarepta is able to again win FDA approval for a Duchenne muscular dystrophy (DMD) drug despite significant resistance from agency superiors? Just-posted approval documents from last month’s green light for Sarepta’s DMD drug Vyondys 53 (golodirsen) shed some light into how the surprise accelerated approval was achieved under FDA’s appeals process four months after the agency rejected the NDA and issued a complete response letter (see story).
The circumstances of the Vyondys 53 approval are eerily reminiscent of the controversial approval the company won three years earlier for DMD drug Exondys 51 (eteplirsen). In both of those reviews, Office of Drug Evaluation 1 director Ellis Unger held up approval over doubts about whether the drugs’ ability to slightly increase dystrophin levels in DMD patients was significant. In Vyondys 53’s review, Unger was also concerned with two safety issues — infections related to vascular access; and renal toxicity — that were discussed in the approval documents, which include a rare posting of the complete response letter (CRL).
After receiving the CRL, the company appealed the rejection to Office of New Drugs director Peter Stein, who concluded that clinically meaningful benefits “are reasonably likely to be seen with golodirsen, consistent with evidence on the effects of low levels of dystrophin (vs. complete absence),” the documents said. On the safety issues, “Stein concluded that monitoring of renal function in DMD patients was feasible with serial monitoring of measures of renal function,” according to the documents. “He noted that all patients should have a baseline direct [glomerular filtration rate] measured prior to initiation of therapy with golodirsen. Regarding the use of ports for vascular access, Dr. Stein felt that this must be considered related to the use of the drug and should be considered in the risk-benefit balance for golodirsen.”
Three years earlier, then-Office of New Drugs director John Jenkins sided with Unger and challenged (see story) CDER director Janet Woodcock’s decision to overrule their objections and to approve Exondys 51. Her decision was eventually appealed by Unger to then-FDA commissioner Robert Califf, who deferred to Woodcock’s “judgment and authority.”
Both Exondys and Vyondys 53’s continued marketing are contingent upon confirmatory studies demonstrating clinical benefit, which seemed to be a bone of contention for Unger when he issued the Vyondys 53 CRL and reminded the company that no such study had been initiated in the three years after gaining approval for Exondys. “Given that you have established a standard paradigm and design for these types of studies, given that you have relationships with a number of DMD referral centers, and given that some 469 patients have received commercial eteplirsen, it is necessary to ask why you have not initiated your required confirmatory study with due diligence,” Unger wrote in the letter.
“We possess no more knowledge,” Unger continued, “than we did three years ago in terms of the likelihood that small amounts of truncated dystrophin will lead to clinical benefit. Such information, if available now, could have informed our decision-making for golodirsen. And for eteplirsen, patients are being subjected to the risk of serious and life-threatening infections. One could even argue that eteplirsen’s benefit-risk profile has changed in light of new information regarding the risk of serious infections and the uncertainty of its benefit. Please understand that your failure to initiate eteplirsen’s confirmatory study with due diligence is very concerning to FDA and is of concern to the public.”
Additionally, several FDA observers are questioning the company’s characterization of the CRL for Vyondys 53 when it disclosed the rejection last August. Sarepta then said the CRL generally raised two concerns: the risk of infections related to intravenous infusion ports, and renal toxicity seen in pre-clinical models of golodirsen and observed following administration of other antisense oligonucleotides. It also expressed surprise at receiving the CRL, stating that “over the entire course of its review, the agency did not raise any issues suggesting the non-approvability of golodirsen, including the issues that formed the basis of the complete response letter.”
The company made no mention of the fact that FDA was first concerned that the drug showed a small increase in dystrophin levels in DMD patients that should translate into a small clinical benefit. “I have reached the conclusion that this small benefit, which has not yet been verified, does not outweigh its risks,” Unger wrote.