Rocket Pharmaceuticals has announced promising long-term safety and efficacy results from its Phase 1 RP-A501 study, evaluating the investigational gene therapy for Danon disease. The data, presented at the American Heart Association (AHA) Scientific Sessions 2024 and published in the New England Journal of Medicine, indicate that RP-A501 was generally well-tolerated and led to sustained LAMP2 protein expression in patients with Danon disease for up to 5 years.
The Phase 1 trial (NCT03882437) included seven patients aged 11 to 21 years with evidence of left ventricular (LV) hypertrophy and New York Heart Association (NYHA) class II symptoms. Patients were divided into three cohorts receiving varying doses of RP-A501, a recombinant adeno-associated virus serotype 9 (AAV9) vector containing the LAMP2B transgene. The primary endpoint was safety, with secondary endpoints including LAMP2 protein expression and changes in cardiac function.
Sustained Efficacy and Improved Cardiac Function
Results showed evidence of LAMP2 expression in all six evaluable patients via immunohistochemical analysis, sustained in five patients within the 24- to 36-month window. There was also a reduction of LV mass index by at least 10% after 12 months, sustained up to 54 months post-infusion. Median myocardial vector copy number per diploid nucleus was measured at 0.251 (range, 0.042 to 1.36), and median LAMP2B transcript copies per μg RNA was 3.72 × 105 (range, 7.53 × 104 to 1.28 × 107), indicating successful transduction.
According to Rossano et al., improvements in NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ-12) scores of at least 5 points were observed in all six evaluable patients. A 5-point improvement in KCCQ-12 is considered clinically meaningful in adults. Many patients reported full participation in school, work, and leisure activities post-treatment, suggesting a significant enhancement in their quality of life.
Safety Profile and Adverse Events
The therapy was generally well-tolerated, with all patients remaining alive and in stable condition after over 4 years of follow-up. Most adverse events (AEs) were grade 1 or 2, with the most common being vomiting (n = 19), headache (n = 18), myopathy (n = 13), and increased alanine aminotransferase levels (n = 12). Nineteen AEs of grade 3 or higher occurred in six patients, all of which resolved.
Most AEs occurred within the first 5 months post-infusion, with only three non-serious AEs reported after 12 months. Treatment-related serious AEs, including grade 3 increases in alanine aminotransferase levels and complement-mediated grade 4 thrombotic microangiopathy, were observed predominantly in cohorts 1 and 2 and resolved without sequelae. One patient underwent heart transplantation 5 months post-RP-A501 treatment due to progressive heart failure.
Expert Commentary and Future Directions
Barry H. Greenberg, MD, FHFSA, noted the encouraging long-term safety and efficacy results, highlighting the improvements and/or normalization across multiple quantifiable parameters used in clinical practice. He emphasized the lack of alternative therapies that demonstrate improvement in Danon disease-related cardiomyopathy, positioning RP-A501 as a promising treatment option.
Eric Adler, MD, of the University of California San Diego, highlighted the ongoing revolution in precision cardiovascular disease treatment, noting the numerous gene therapies in the pipeline. He emphasized the importance of identifying appropriate patients and developing consensus around surrogate endpoints for future trials.
A pivotal phase II study is currently underway in 12 males ages 8 and older with Danon disease to further evaluate the efficacy and safety of RP-A501.
