Rocket Pharmaceuticals Announces FDA Lifts Clinical Hold on Pivotal Phase 2 Trial of RP-A501 in Danon Disease
Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT), a fully integrated, late-stage biotechnology company advancing a diverse pipeline of genetic therapies for rare and devastating disorders, has announced a critical milestone in its clinical development efforts. The U.S. Food and Drug Administration (FDA) has officially lifted the clinical hold on Rocket’s pivotal Phase 2 trial of RP-A501, its investigational gene therapy for Danon disease, a rare and life-threatening genetic disorder that currently has no approved treatment.
The clinical hold was resolved in under three months, a turnaround that highlights both the FDA’s efficiency in reviewing and addressing safety considerations and Rocket’s responsiveness in making protocol adjustments to ensure patient well-being while preserving the integrity of the pivotal trial. For Rocket, the decision not only enables a resumption of the Phase 2 program but also represents a reaffirmation of its scientific and regulatory strategy for advancing a potentially transformative therapy for patients with Danon disease.
FDA Resolution and Adjustments to Study Design
In correspondence with Rocket, the FDA confirmed that the company had satisfactorily addressed the agency’s concerns that initially triggered the clinical hold. As part of the resolution, the Phase 2 protocol has been amended to incorporate new dosing parameters and an adjusted immunomodulatory regimen designed to further strengthen patient safety.
The revised trial will initially resume with three patients, each sequentially dosed at an adjusted level of 3.8 x 10¹³ genome copies per kilogram (GC/kg) of RP-A501. Each patient will be treated with a minimum four-week interval between administrations to closely monitor outcomes before advancing to additional participants.
This recalibrated dose represents a shift from the earlier Phase 2 dose of 6.7 x 10¹³ GC/kg and has been aligned with the lower range of doses that Rocket previously demonstrated meaningful efficacy in Rocket’s Phase 1 study. Notably, in those earlier low-dose cohorts, improvements were observed across multiple domains, including biomarker readouts, echocardiographic measures, and clinical endpoints. The new dose level has therefore been deemed most likely to balance efficacy with enhanced safety margins.
The immunomodulatory regimen has also been refined. While Rocket previously included prophylactic administration of a C3 complement inhibitor, this component will now be discontinued. Instead, the regimen will retain the use of sirolimus, rituximab, and steroids, which were successfully deployed in the Phase 1 pediatric cohort. In addition, the revised protocol sets a lower threshold for the introduction of a C5 inhibitor (eculizumab) in the event of impending complement activation, ensuring patients are protected against inflammatory risks without unnecessary pre-treatment.
Current Progress in the Phase 2 Study
To date, six patients with Danon disease have already been treated in the Phase 2 study at the higher 6.7 x 10¹³ GC/kg dose level. With the clinical hold lifted, Rocket will move forward with treating the next three patients at the revised 3.8 x 10¹³ GC/kg level. These patients will serve as a critical dataset for evaluating both the safety and efficacy of the new dose before expanding enrollment to complete the 12-patient pivotal study.
The Rocket company has indicated that further updates on the trial are expected once data from these next three patients have been collected and reviewed, providing the scientific and patient community with greater clarity on the impact of the modified protocol.
Overview of the RP-A501 Pivotal Phase 2 Trial
The ongoing global, single-arm, multi-center pivotal Phase 2 trial is designed to evaluate the efficacy and safety of RP-A501 in patients with Danon disease. The study aims to enroll 12 patients in total, beginning with a pediatric safety run-in (n=2). Six patients were already treated at the higher 6.7 x 10¹³ GC/kg dose, and three additional patients will now be treated at the adjusted 3.8 x 10¹³ GC/kg level before the study expands to its full cohort.
The trial is carefully structured to generate data that could support accelerated approval. Its co-primary endpoints focus on:
- LAMP2 protein expression – measuring restoration of the deficient lysosome-associated membrane protein 2, the underlying cause of Danon disease.
- Reduction in left ventricular mass – a critical cardiac marker given that Danon disease leads to severe hypertrophic cardiomyopathy.
In addition to these co-primary endpoints, the study is tracking troponin as a key secondary endpoint, given its role as a sensitive biomarker of cardiac injury.
Other secondary endpoints include:
- Natriuretic peptides, another class of cardiac biomarkers.
- Patient-reported outcomes, such as the Kansas City Cardiomyopathy Questionnaire (KCCQ).
- Functional assessments, such as New York Heart Association (NYHA) classification.
- Event-free survival at 24 months.
- Treatment-emergent safety events.
Longer-term follow-up of these endpoints is expected to support a potential full approval should RP-A501 demonstrate sustained efficacy and safety.
Concurrent Natural History Study
To strengthen the clinical development program, Rocket is also conducting a global natural history study in parallel with the pivotal trial. This study provides valuable context by tracking the natural progression of Danon disease in untreated patients, thereby establishing a robust comparator dataset.
Importantly, all patients in the pivotal Phase 2 trial are required to complete a three-month observational pre-treatment run-in period. This run-in allows for the careful assessment of biomarker trajectories—particularly troponin levels—prior to gene therapy administration, ensuring that post-treatment improvements can be measured against each patient’s own baseline progression.
The Unmet Need in Danon Disease
Danon disease is a rare X-linked lysosomal storage disorder caused by mutations in the LAMP2 gene, leading to deficient or absent LAMP2 protein. The disease is characterized by profound cardiac manifestations, including severe hypertrophic cardiomyopathy, skeletal muscle weakness, and in many cases, cognitive impairment.
The condition is life-threatening, particularly for male patients who typically present with rapidly progressive cardiac disease in adolescence or early adulthood. Without effective interventions, many affected males succumb to heart failure or require cardiac transplantation in their teens or twenties. Females generally have a milder but still significant disease course.
Currently, no approved therapies exist for Danon disease, and management is limited to supportive care and heart transplantation in advanced cases. As such, RP-A501—a gene therapy designed to restore LAMP2 protein expression—has the potential to be the first disease-modifying therapy for this devastating condition.
With the clinical hold lifted and the Phase 2 pivotal trial back on track, Rocket Pharmaceuticals is once again positioned to advance RP-A501 toward regulatory approval. The company has reiterated its commitment to working closely with investigators, regulators, and the patient community to ensure the trial progresses responsibly and efficiently.
Future updates, particularly those expected following the treatment of the next three patients at the recalibrated dose, will provide important insights into RP-A501’s therapeutic potential and its safety profile under the adjusted regimen.
For now, the FDA’s decision marks a significant step forward in the development of a therapy that could transform the outlook for patients living with Danon disease.
