Topline Findings
- FDA lifts clinical hold on RP-A501 trial: Rocket Pharmaceuticals’ pivotal Phase II study for Danon disease resumes less than three months after the hold.
- Revised dosing and safety strategy: The trial will continue with a lower 3.8 x 10¹³ GC/kg dose and an updated immunomodulatory regimen to enhance patient safety.
- Gene therapy advances for rare cardiac disorder: RP-A501 remains the first investigational gene therapy for a cardiovascular condition with FDA designations that include RMAT, Fast Track, Rare Pediatric, and Orphan Drug.
The FDA has lifted the clinical hold on Rocket Pharmaceuticals’ pivotal Phase II trial (NCT06092034) of RP-A501 for the treatment of Danon disease, less than three months after the hold was issued. According to the company, the FDA confirmed that issues outlined in the hold were satisfactorily addressed, allowing the trial to resume with a recalibrated dose of 3.8 x 10¹³ GC/kg in three patients, administered sequentially with a minimum four-week interval.1
How Will the Revised Dosing and Regimen Shape the Trial?
Rocket provided additional context on the dosing and immunomodulatory plan. In a press release, the company noted that the adjusted dose is aligned with the lower range of doses that were already administered and showed safety and efficacy in multiple biomarkers, echocardiographic and clinical endpoints from the Phase I portion of the trial.
The manufacturer added that it will collaborate with trial investigators to administer an immunomodulatory regimen that is more closely aligned with what patients received in the Phase I pediatric cohort.
Thus far, the adjusted dose has been administered six patients with Danon disease. Additional updates regarding the trial are expected to be released after data from the next three patients become available.
Trial Design and Endpoints
- The global, single-arm, multi-center pivotal trial is currently evaluating the efficacy and safety of RP-A501 in 12 patients with Danon disease.
- The trial started with pediatric safety run-in of two patients and has since enrolled a total of six individuals who received treatment at a dose of 6.7 x 10¹³ GC/kg.
- As indicated under the updated protocol that Rocket agreed upon with the FDA after the clinical hold was lifted, the next three patients will receive a lower dose of 3.8 x 10¹³ GC/kg, each treated at least four weeks apart, before enrolling the remaining participants to complete the trial.
- The primary endpoint of the trial is to evaluate the efficacy of RP-A501 via co-primary endpoint comprised of lysosome-associated membrane protein 2 isoform B (LAMP2B) myocardial tissue expression and left ventricular mass index.
- The key secondary endpoint is change in troponin.
- Additional secondary endpoints include natriuretic peptides, Kansas City Cardiomyopathy Questionnaire, New York Heart Association class, event free survival to two years, and treatment emergent adverse events (AEs).1,2
Patient Safety and Clinical Hold Background
The clinical hold was first announced in May after a patient experienced a serious AE that involved clinical complications related to a capillary leak syndrome. This eventually led to the patient’s death.3
“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,” said Gaurav Shah, MD, CEO, Rocket Pharmaceuticals, in a May press release. “We are immensely grateful for the patients and families who participate in this important research.”
Investigational Gene Therapy and Regulatory Designations
According to Rocket, RP-A501 is the first gene therapy for a cardiovascular condition to demonstrate safety and efficacy in clinical trials. The treatment uses an adeno-associated virus serotype 9 vector to deliver a functional copy of the human LAMP2B gene through a single intravenous infusion.
In clinical trials, the therapy has been observed to reach heart muscle cells and transfer the LAMP2B gene to cardiac tissue, which was associated with improvements in heart structure and function. The program has been granted several regulatory designations from the FDA, including RMAT, Fast Track, Rare Pediatric, and Orphan Drug status.1
Prevalence of Danon Disease
According to Medscape, the incidence of Danon disease is currently unknown. This is most likely due to incidence rates being too low to allow investigators to estimate its frequency in a given population.4
References
- Rocket Pharmaceuticals Announces FDA Has Lifted the Clinical Hold on the Pivotal Phase 2 Trial of RP-A501 for the Treatment of Danon Disease. BusinessWire. August 20, 2025. Accessed August 20, 2025. https://www.businesswire.com/news/home/20250820073531/en/Rocket-Pharmaceuticals-Announces-FDA-Has-Lifted-the-Clinical-Hold-on-the-Pivotal-Phase-2-Trial-of-RP-A501-for-the-Treatment-of-Danon-Disease
- A Gene Therapy Study of RP-A501 in Male Patients With Danon Disease. Clinicaltrials.gov. Accessed August 20, 2025. https://www.clinicaltrials.gov/study/NCT06092034?term=NCT06092034&rank=1
- Rocket Pharmaceuticals Provides Update on Phase 2 Clinical Trial of RP-A501 for Danon Disease. Rocket Pharma. May 27, 2025. Accessed August 20, 2025. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-provides-update-phase-2-clinical-trial-rp/?utm_source=chatgpt.com
- Danon Disease. Medscape. November 24, 2021. Accessed August 20, 2025. https://emedicine.medscape.com/article/952782-overview#a6
