Gene Therapy Yields Improvements in Danon Disease


Rocket Pharma presented updated data from adult and pediatric patients at the 2022 HFSA meeting.

The gene therapy RP-A501 (Rocket Pharmaceuticals) was well-tolerated and yielded functional improvements in adult and pediatric patients with Danon disease, according to data from a phase 1 trial (NCT03882437) presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2022.

“Today’s Danon Disease trial results, the most comprehensive investigational gene therapy dataset for any cardiac condition, demonstrate positive early findings in pediatric patients and continued robust activity in adults that represent potential freedom from the devastating effects of this disease, including those that lead to heart transplantation or death,” Gaurav Shah, MD, chief executive officer, Rocket Pharma, said in a statement. “Results showed RP-A501 was generally well tolerated with evidence of durable treatment effect and improvement of Danon Disease, including for both pediatric patients with up to nine months of follow-up and four adult patients with up to 36 months of follow-up. Further, efficacy data from the pediatric patients are following similar or more favorable positive trends as in the adults at a similar timeframe. Pediatric patients showed vacuole clearance and marked reductions in brain natriuretic peptide (BNP) and troponin. We also observed improvement in New York Heart Association (NYHA) class and early improvements in the Kansas City Cardiomyopathy Questionnaire (KCCQ) for both patients.”

RP-A501 consists of a recombinant adeno-associated serotype 9 (AAV9) capsid that delivers a functional version of the human LAMP2B transgene (AAV9.LAMP2B). The new data from the phase 1 trial evaluating RP-A501 presented at the meeting has a data cutoff of September 27, 2022, and includes early efficacy data with updated safety data from the low-dose (6.7 x 1013 GC/kg; n = 2) pediatric cohort, as well as updated efficacy and safety data from young adult and adolescent patients in the low-dose (n = 3) and high-dose (1.1 x 1014 GC/kg; n = 2) cohorts.

RP-A501 was well-tolerated in the low-dose cohorts. In the 2 pediatric patients with 6 and 11 months of follow-up, there were no complement-related adverse events (AEs) and minimal complementactivation. These patients had normal-range platelets and no significant toxicities, skeletal myopathy, or late transaminase elevations. They had also received a modified immunomodulatory regimen to mitigate AEs. RP-A501 has continued to be well-tolerated in adult cohorts as well.

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“Data collected in adults from biomarker, clinical and functional parameters trend towards improvement in the initial months following gene therapy and appear durable for two to three years after treatment. I am particularly excited that 5 out of 5 currently enrolled pediatric and adult patients with a closely monitored immunomodulatory regimen showed improvement in NYHA class (from 2 to 1) with a follow-up of six to 36 months,” Shah added. “Simply put, these data indicate that these patients are no longer afflicted with cardiac disease symptoms during regular activity or cardiac-related limitations in physical activity. In this devastating disease with markedly shortened life span, stabilization alone may be considered meaningful, so the sustained improvements we’ve seen exceed our expectations and could be transformative for patients receiving gene therapy.”

Investigators found that LAMP2B gene expression was 21.1% in the first pediatric patient and 34.7% in the second via immunohistochemistry. Both pediatric and adult patients had evidence of durable and meaningful cardiac LAMP2B expression at 3 months through 24 months. These findings are consistent with earlier efficacy data observed.

Other positive efficacy findings included a decrease in vacuolar area, a decrease in BNP, decreases in troponin, improvements in NYHA class, improvements in KCCQ, and reductions in left ventricular wall thickness in pediatric and adult patients.

“Taken together, we believe the totality of data from the six patients currently enrolled in the Phase 1 trial will support advancement toward a Phase 2 pivotal study,” Shah added. “We recently convened an advisory board of international experts who endorsed our planned Phase 2 study design and endpoints, and we look forward to further discussions with the FDA later this year.”

Rocket Pharmaceuticals announces positive updates from phase 1 clinical trial for RP-A501 in Danon disease at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2022. News release. Rocket Pharmaceuticals. September 30, 2022.
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