Gene Therapy RP-A501 Shows Promising Phase 1 Results in Danon Disease
The Rocket Pharmaceuticals AAV9 treatment was assessed in a 3-cohort trial of 7 patients, showing good safety and encouraging efficacy signals.
Joseph Rossano, MD, MS, FAAP, FACC
Rocket Pharmaceuticals has announced the long-term safety and efficacy results from the phase 1 RP-A501 study (NCT03882437) of its investigational gene therapy RP-A501, noting that the treatment was well tolerated on the whole, and that all the patients with Danon disease demonstrated sustained LAMP2 protein expression after 1 year and up to 60 months, among other positive indicators.1,2
The data 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 Philadelphia2; and simultaneously published in the New England Journal of Medicine.1 Gaurav Shah, MD, the CEO of Rocket Pharma, said in a statement that the data represented a “critical milestone” for the program “and cardiac gene therapy in general, demonstrating for the first time that AAV conferred long-term efficacy in a cardiac indication. This program represents the most comprehensive investigational gene therapy dataset for any cardiac condition.”3
Shah continued, “As is true for many other recent internal and peer company programs, when gene therapy works, it is life changing. RP-A501 is being developed as a potential one-time gene therapy and the results of the long-term Phase 1 study show the promise of gene therapy across cardiac diseases, including PKP2-ACM, BAG3-DCM and others.”
Efficacy Findings
Overall, the trial included 7 patients between the ages of 11 and 21 years, all of whom had evidence of left ventricular (LV) hypertrophy (median mass, 438 g; range, 232-989) and New York Heart Association class II symptoms. All but 1 patient had LV ejection fraction of at least 40%. Patients were divided in to 3 cohorts: Cohort 1, which included 3 patients who received a dose of 6.7 × 1013 genome copies per kg (low-dose RP-A501); Cohort 2, which included 2 patients who received a dose of 1.1 × 1014 genome copies per kg (high-dose RP-A501); Cohort 3, which included 2 patients who received a dose of 6.7 × 1013 genome copies per kg.
The delivery of the recombinant adeno-associated virus serotype 9 (AAV9) containing the transgene LAMP2B showed evidence of LAMP2 expression in all 6 patients’ immunohistochemical analysis and in 5 of 6 evaluable patients in 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. Transduction was shown by measure of median myocardial vector copy number per diploid nucleus (0.251; range, 0.042 to 1.36) and median LAMP2B transcript copies per μg RNA (3.72 × 105; range, 7.53 × 104 to 1.28 × 107).
“In our phase 1, open-label study, we observed improvements in NYHA 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.1 “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.”
READ MORE: First Patient Dosed in RIDGE-1 Trial for Tenaya’s ARV Cardiomyopathy Gene Therapy TN-401
Safety Profile
The therapy was deemed generally well-tolerated, with all patients alive and in stable condition after more than 4 years of follow-up. Most adverse events (AEs) were categorized as grad 1 or 2, with the highest incidence overall including vomiting (n = 19), headache (n = 18), myopathy (n = 13), and increase in alanine aminotransferase level (n = 12). There were 19 AEs of grade 3 or higher that occurred in 6 patients (grade 3, n = 11; grade 4, n = 8), but all of these resolved.
Rossano and colleagues wrote that most AEs occurred within the first 5 months post infusion, substantially decreasing thereafter, with only 3 nonserious AEs reported after 12 months. All treatment-related serious AEs were reported in the 2 to 4 months post infusion, observed predominantly in cohorts 1 and 2, and all resolved without sequelae. The treatment-related serious AEs included the following:
- Patients 1, 2, and 3 reported grade 3 increases in alanine aminotransferase levels; grade 2 nausea, vomiting, and increased aspartate aminotransferase levels; and grade 1 pyrexia.
- Patient 5 experienced complement-mediated grade 4 thrombotic microangiopathy, grade 4 thrombocytopenia, and acute kidney injury that resulted in renal replacement therapy. A complete recovery of platelet count and renal function was observed within 4 weeks after initiation of renal replacement therapy, and a heart transplantation was undergone 5 months after RP-A501 treatment. This explanted heart showed severe hypertrophy and extensive fibrosis, without evidence of microvascular or other thrombosis and without evidence of lymphocytic cellular infiltration.
“The long-term safety and efficacy results in the phase 1 study are very encouraging for patients with Danon disease. In this study we found consistent, robust improvements and/or normalization across multiple quantifiable parameters that cardiologists use in clinical practice for assessing risk and making management decisions,” first author Barry H. Greenberg, MD, FHFSA, a distinguished professor of medicine at University of California, San Diego School of Medicine, and director of the Advanced Heart Failure Treatment Program at UC San Diego Health, said in a statement.3 “Currently, there are no other therapies that have been shown to demonstrate improvement of Danon disease-related cardiomyopathy, and while heart transplantation can prolong life, it is not curative and is associated with significant one-year mortality and complications. Data from this study shows promise for the Danon disease community.”
REFERENCES
1. 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
2. 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 SessionsNovember 16-18, 2024; Presentation 4168378
3. Rocket Pharmaceuticals Announces New England Journal of Medicine Publication of Phase 1 RP-A501 Long-Term Data and Presents at Late-Breaking Scientific Sessions at 2024 American Heart Association Conference. Rocket Pharmaceuticals. News release. November 18, 2024. Accessed November 27, 2024. https://www.businesswire.com/news/home/20241118710322/en/Rocket-Pharmaceuticals-Announces-New-England-Journal-of-Medicine-Publication-of-Phase-1-RP-A501-Long-Term-Data-and-Presents-at-Late-Breaking-Scientific-Sessions-at-2024-American-Heart-Association-Conference
First Patient Dosed in RIDGE-1 Trial for Tenaya’s ARV Cardiomyopathy Gene Therapy TN-401
November 26th 2024The patient’s dosing took place at the University of California, San Francisco, although the multicenter study is expected to eventually dose patients at other locations in the United States, United Kingdom, and Europe.
