FDA Lifts Clinical Hold on Rocket’s Trial for Danon Disease Gene Therapy RP-A501

The FDA has lifted its clinical hold on Rocket Pharmaceuticals’ pivotal phase 2 clinical trial (NCT06092034) evaluating RP-A501, an investigational adeno-associated virus serotype 9 (AAV9) vector-based gene therapy intended to treat Danon disease.¹

The hold was originally placed on the trial by the FDA on May 23, 2025, following the death of a patient treated in the study.² 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. At the time the hold was announced, a comprehensive root cause analysis was underway, with a focus on a novel immune suppression agent specific to the AAV9-Danon program that had recently been 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.

With regard to the lifting of the hold, Rocket noted that the FDA had indicated the company has addressed the issues leading to the clinical hold to its satisfaction. As per the FDA’s authorization for the study’s continuation, a recalibrated dose for the gene therapy, 3.8 x 10¹³ GC/kg, will be used for the next 3 patients to be treated in the study and the patients will be treated in a sequential manner with intervals of 4 weeks or greater between each treatment. Notably, 6 patients have been treated in the phase 2 study so far, and RP-A501 has previously been evaluated for Danon disease in a phase 1 clinical trial (NCT03882437).

“This adjusted dose aligns with the lower range of administered doses that were associated with efficacy across multiple biomarkers, echocardiographic and clinical end points in the phase 1 study, and has been determined as most likely to confer the safety and efficacy identified in the low-dose phase 1 cohorts,” Rocket said in a statement.¹ “In addition, Rocket will collaborate with investigators to implement an immunomodulatory regimen more closely reflecting that administered in the phase 1 pediatric cohort. The revised regimen discontinues prophylactic use of a C3 complement inhibitor, while maintaining sirolimus, rituximab, and steroids. Additionally, the protocol will specify a lower threshold for administering a C5 inhibitor (eculizumab) in response to impending complement activation.”

Data from the phase 1 trial have previously been published in the New England Journal of Medicine (NEJM) and presented at the American Heart Association Scientific Sessions 2024.^3,4 Notably, evidence of LAMP2 expression was observed in the immunohistochemical analysis for 6 patients, with 5 of 6 evaluable patients showing this within 24 to 36 months posttreatment. Furthermore, at 12 months posttreatment, a decrease of at least 10% in left ventricular mass index was seen, which was maintained for up to 54 months after treatment. With regard to safety, all patients remained alive and in stable condition more than 4 years after treatment, and the therapy was characterized as generally well-tolerated.

“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,” the authors of the NEJM paper 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 announces FDA has lifted the clinical hold on the pivotal phase 2 trial of RP-A501 for the treatment of Danon disease. News release. Rocket Pharmaceuticals, Inc. August 20, 2025. Accessed August 21, 2025. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-fda-has-lifted-clinical-hold
2. Rocket Pharmaceuticals provides update on phase 2 clinical trial of RP-A501 for Danon disease. News release. Rocket Pharmaceuticals, Inc. May 27, 2025. Accessed August 21, 2025. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-provides-update-phase-2-clinical-trial-rp
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