A journey through the FDA’s newly released complete response letters gave glimpses into the journeys to market for Eli Lilly’s Alzheimer’s antibody Kisunla, Sarepta’s DMD gene therapy Vyondys 53 and Gilead’s HIV drug Sunlenca.
We love a sunshine moment here at BioSpace, but the FDA’s release of 200 complete response letters as an act of “radical transparency” was a doozy.
These letters are sent to companies to reject a drug application, and the FDA has never—except in extremely rare circumstances—made public its reasons for rejecting a therapy. Instead, the company receiving the letter can announce, or not, that its drug has been rejected and why. Most do so as they are beholden to shareholders, but they are under no obligation to reveal the full nature of the complete response letter (CRL). Many simply say in a short and sweet press release that there were no safety concerns and move on.
Sometimes CRLs are included in a drug approval package, but the FDA’s release yesterday for the first time gives us a batch of rejection letters from the past decade in one place. All for drugs that eventually made it to market. There were biosimilars, injection devices and flu shots. The most common themes were inspection issues at drug manufacturing facilities, quality issues and safety concerns.
Much of the issues cited are things that have come to light over time, but when the FDA gives you a stack of documents, you dive in.
Lilly’s Alzheimer’s Med Gets Kicked Down the Road
Eli Lilly’s Kisunla was arguably one of the most closely watched drugs ever. It was set to follow Biogen and Eisai’s rival medicine Leqembi, the first ever disease-modifying therapy for Alzheimer’s disease that ultimately received accelerated approval in January 2023 after a swift review. Lilly had hoped that Kisunla would receive the same treatment, but instead the application hit a series of roadblocks along the way. Kisunla was finally approved in July 2024, but this week we got a glimpse at all the FDA had to say on the application, which was submitted in May 2022.
The undated CRL—signed by Billy Dunn, then director of the office of neuroscience—rejected Lilly’s application for accelerated approval. Lilly had been hoping to get early market access based on studies showing a reduction of amyloid plaques in the brain.
Dunn’s team determined that the application for Kisunla was insufficient to determine the long-term safety of the drug for Alzheimer’s. The FDA had wanted at least 100 patients exposed to it for at least 12 months, but Lilly only submitted data on 49.
Lilly tested Kisunla with a treatment protocol that allowed patients to stop taking the drug once their plaques had declined to a prespecified threshold as seen on a PET scan. Some patients didn’t take the study drug for a full 12 months, while others needed a longer dosing period.
The FDA reasoned that in the real world, enough patients would need a year or more of treatment that Lilly should have provided more long-term data. The FDA also took issue with the fact that much of the six-month safety data had come from open-label studies.
The FDA asked for more safety data that highlighted any new study results, particularly for adverse events. Since entering the market, both Kisunla and Leqembi have been shadowed by safety concerns, with several deaths resulting from treatment with drugs in the monoclonal antibody class for Alzheimer’s. Lilly recently received a dosing label update for Kisunla in an effort to ease safety concerns.
Sarepta’s DMD Setback Linked to Ominous Safety Issues
Sarepta’s Vyondys 53 was approved by the FDA in December 2019 as the first targeted treatment option for patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. But four months prior, the drug was shot down by the regulator in a CRL signed by Ellis Unger, then director of the Office of Drug Evaluation at the Center for Drug Evaluation and Research.
In its rationale for the rejection, the agency noted the likelihood that the clinical benefit from Vyondys 53 would be “commensurately small,” given the “small increase in truncated dystrophin” elicited by the therapy. Unger went on to detail that in boys tested after receiving Vyondys 53, “essentially all” showed progressive loss of physical function, and that there was “no correlation” between physical performance and the amount of dystrophin that Vyondys 53 produced in them.
As if that wasn’t bruising enough, Unger listed out a litany of safety issues experienced by patients taking Exonydys 51. These included “serious infections related to delivery of the drug” and “renal toxicity.” Both, he writes, “are potentially life-threatening,” with the latter being “difficult or impossible to monitor.”
This second warning is particularly ominous in light of the two recent deaths from acute liver failure attributed to Sarepta’s gene therapy Elevidys. While Vyondys 53 is an antisense oligonucleotide (ASO), rather than an adeno-associated virus (AAV)-based gene therapy like Elevidys, both mechanisms have been associated with hepatic injury, as Unger stated of ASOs in the letter.
Sarepta subsequently filed an appeal and met with the FDA to address the issues raised by the regulator in the CRL. That ultimately led to Vyondys 53’s approval by Peter Stein, then director of the FDA’s Office of New Drugs who departed the agency in April.
Gilead’s Glass Vial Blunder Delays HIV Drug’s Market Entry
Gilead is probably still celebrating last month’s approval of twice-yearly lenacapavir, known in that indication as Yeztugo, for prevention of HIV. But in March 2022, it was a different story when the company was seeking approval for the drug to treat HIV-1 infection in heavily treatment-experienced adults with multi-drug-resistant HIV-1 infection.
The FDA rejected the long-acting HIV-1 capsid inhibitor due to issues with the glass vials that would house the medicine. Gilead was upfront about this when announcing the regulatory delay. In the CRL, then deputy director of the Office of Infectious Diseases at the Center for Drug Evaluation and Research Adam Sherwat explained that Gilead’s own data pointed to the problem.
The letter stated that highly alkaline solutions are incompatible with borosilicate glass vials, which are commonly used for pharmaceutical packaging. Gilead reportedly found glass particles in clinical batches of lenacapavir, suggesting this incompatibility. Gilead had proposed using aluminosilicate glass instead, but Sherwat called the data to support this “incomplete and ambiguous.”
Gilead was asked to provide more evidence to support the use of the alternative glass, ultimately delaying the approval of lenacapavir to August 2022. The drug is now available for the drug-resistant HIV indication as Sunlenca.
Editor’s Note: Dan Samorodnitsky contributed to this piece.
