SHERIDAN, WYOMING – July 12, 2025 – A landmark release of 200 complete response letters (CRLs) by the U.S. Food and Drug Administration (FDA) has unveiled a decade of regulatory decisions behind once-rejected therapies, now approved and on the market. Among the most revealing cases are Eli Lilly’s Alzheimer’s treatment Kisunla, Sarepta’s Duchenne muscular dystrophy drug Vyondys 53, and Gilead’s long-acting HIV therapy Sunlenca.
This unprecedented act of “radical transparency” by the FDA marks a rare window into the regulatory reasoning typically hidden from public view. Each letter provides detailed insight into the challenges biopharmaceutical companies face—from inadequate safety data to packaging compatibility issues—offering strategic guidance for future drug development and market approval.
Kisunla CRL Highlights FDA’s Long-Term Safety Expectations
Eli Lilly’s Kisunla, approved in July 2024 for Alzheimer’s disease, was initially rejected due to insufficient safety data. The CRL, signed by Billy Dunn, then director of the FDA’s office of neuroscience, rejected the 2022 application for accelerated approval. Lilly aimed to gain early access based on reductions in amyloid plaques seen in imaging studies.
“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’s trial design allowed patients to stop treatment once plaque levels fell below a certain threshold. However, the FDA found this approach problematic for real-world use, noting variability in treatment duration and reliance on open-label safety data. The agency requested more robust, long-term evidence, especially regarding adverse events. Since approval, Lilly has updated the Kisunla dosing label in response to ongoing safety concerns.
Vyondys 53 Faced Scrutiny over Clinical Benefit and Safety Risks
Sarepta’s Vyondys 53, approved in December 2019, was initially rejected four months earlier. The CRL, signed by Ellis Unger, then director of the Office of Drug Evaluation, questioned both efficacy and safety.
“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.”
Unger also highlighted safety issues seen with a related therapy, 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.’”
The warning proved prescient, following recent fatalities linked to Sarepta’s gene therapy Elevidys. Though mechanistically distinct, both products share risk profiles the agency flagged in the CRL. After meetings with the FDA, Sarepta secured final approval from Peter Stein, then director of the Office of New Drugs.
Sunlenca Delay Rooted in Glass Vial Compatibility
Gilead’s Sunlenca faced a regulatory hurdle in March 2022 when the FDA rejected its HIV-1 therapy application due to concerns with pharmaceutical packaging materials. In the CRL, Adam Sherwat, then deputy director of the Office of Infectious Diseases, pointed to data integrity issues related to drug-container interaction.
“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.’”
The agency required additional validation for the new vial type, delaying approval until August 2022. Sunlenca is now available for HIV-1 patients with multidrug resistance and has since expanded its indication to include prevention.
Strategic Implications for Regulatory Pathways
The released CRLs offer valuable lessons for developers navigating the complex regulatory environment:
- Long-term safety data must align with real-world treatment expectations.
- Clinical outcomes must be clearly correlated with mechanistic targets.
- Manufacturing and packaging decisions must be supported by complete and validated data.
By opening access to these documents, the FDA is signaling a new era of regulatory clarity. Companies that integrate these insights early in development stand to reduce approval risks and accelerate time to market.
Learn more at www.fda.gov