Patient Dies After Treatment With Rocket Pharmaceuticals’ Danon Disease Gene Therapy RP-A501 in Phase 2 Trial

A patient has passed away after treatment with Rocket Pharmaceuticals’ RP-A501, an investigational adeno-associated virus serotype 9 (AAV9) vector-based gene therapy intended to treat Danon disease, in the context of a pivotal phase 2 clinical trial (NCT06092034).¹

The patient’s death occurred after an acute systemic infection and was associated with an unexpected serious adverse event (SAE) of clinical complications related to a capillary leak syndrome. A comprehensive root cause analysis is currently being carried out by the company, which is in active communication with the FDA and other important stakeholders. A current focus of this analysis is a novel immune suppression agent specific to the AAV9-Danon program that was recently added to the gene therapy’s pretreatment regimen with the intention of reducing complement activation, a phenomena that had been seen in some participants.

Rocket stated that dosing in the trial was paused when it became aware of the SAE and that the FDA put a clinical hold on the trial on May 23, 2025, to enable continued evaluation of the event. The company noted that it is currently working with the FDA, the study’s independent data safety monitoring committee, clinical investigators, and scientific experts with regard to the SAE, and that it intends to continue the trial as soon as it can safely do so. Although, an estimated completion date for the study can not be provided until the clinical hold is resolved.

“We are heartbroken by this loss and are fully committed to our mission to develop gene therapies that address the underlying cause of devastating diseases like Danon,” Gaurav Shah, MD, the chief executive officer of Rocket Pharmaceuticals, said in a statement.¹ “We are immensely grateful for the patients and families who participate in this important research.”

Rocket originally announced that the phase 2 trial had maxed out its recruitment in September of last year, with 12 male patients having been enrolled across sites in the United States and Europe.² All patients received a dose of 6.7x10¹³ GC/kg of the gene therapy and the first 2 patients were enrolled as part of a pediatric safety run-in, which utilized sequential enrollment and required at least 3 months of follow-up before further recruitment. RP-A501 was previously evaluated in a phase 1 clinical trial (NCT03882437) for patients with Danon disease.

Notably, long-term data from the phase 1 study were presented at the American Heart Association (AHA) Scientific Sessions 2024 by Joseph Rossano, MD, MS, FAAP, FACC, the Jennifer Terker Endowed Chair in Pediatric Cardiology, codirector of the Cardiac Center, and chief of the Division of Cardiology at the Children's Hospital of Philadelphia, and published in the New England Journal of Medicine.^3,4 Treatment with the gene therapy product showed evidence of LAMP2 expression in 6 patients’ immunohistochemical analysis, and in 5 of 6 evaluable patients in the 24- to 36-month window. A reduction of left ventricular mass index by at least 10% after 12 months, sustained up to 54 months post infusion, was also reported. The therapy was deemed generally well-tolerated, with all patients alive and in stable condition after more than 4 years of follow-up.

“In our phase 1, open-label study, we observed improvements in New York Heart Association class and KCCQ-12 [Kansas City Cardiomyopathy Questionnaire] scores (ranging from 0 to 100, with higher scores indicating better health status) of at least 5 points in all 6 evaluable patients,” Rossano et al wrote.³ “Improvements in KCCQ-12 of 5 points or more are considered to be clinically meaningful in adults. Most of the patients—many of whom in the absence of this therapy would have probably had end-stage heart failure or died—reported full participation in school, work, and leisure-related activities after RP-A501 treatment.”

REFERENCES
1. Rocket Pharmaceuticals provides update on phase 2 clinical trial of RP-A501 for Danon disease. News release. Rocket Pharmaceuticals, Inc. May 27, 2025. Accessed May 27, 2025. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-provides-update-phase-2-clinical-trial-rp
2. Rocket Pharmaceuticals announces completion of enrollment in phase 2 pivotal trial of RP-A501 for the treatment of Danon disease. News release. September 17, 2024. Accessed September 19, 2024. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-completion-enrollment-phase-2
3. Greenberg B, Taylor M, Adler E, et al. Phase 1 Study of AAV9.LAMP2B Gene Therapy in Danon Disease. N Engl J Med. Published online November 18, 2024.doi:10.1056/NEJMoa2412392
4. Rossano J. Danon Disease Phase 1 RP-A501 Results: The First Single-Dose Intravenous Gene Therapy with Recombinant Adeno-Associated Virus (AAV9:LAMP2B) for a Monogenic Cardiomyopathy. Presented at: AHA Scientific Sessions November 16-18, 2024; Presentation 4168378