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RP-A501 for Danon Disease: Gene Therapy Maintains Clinical Stability

Principal investigator Barry Greenberg, MD, FHFSA, shares extended results from the phase 1 trial and also preliminary pediatric safety results in a presentation at ASGCT 2022.

Investigators first shared positive early data1 on RP-A501 (Rocket Pharmaceuticals) in November 2021, but now extended results from the phase 1 study (NCT03882437) are further supporting the gene therapy’s ability to induce a sustained clinical benefit in patients with Danon disease (DD).

RP-A501 was generally well-tolerated and successfully conferred cardiac LAMP2B gene expression, according to an oral presentation at the American Society of Gene & Cell Therapy 25th Annual Meeting, held in Washington, DC, and virtually May 16-19, 2022.2 Principal investigator Barry H. Greenberg, MD, FHFSA, director of the Advanced Heart Failure Treatment Program and professor of medicine at UC San Diego Health, also shared preliminary pediatric safety data and updates on clinical stability of the therapy in a video interview with CGTL.

The non-randomized, open-label phase 1 study is evaluating the safety and efficacy of a single intravenous infusion of RP-A501 (AAV9.LAMP2B) at 2 doses: 6.7 x 1013 GC/kg (low dose) and 1.1 x 1014 GC/kg (high dose). Participants included male patients with a diagnosis of DD with LAMP2 mutation and cardiac involvement who were then split into an adult and adolescent cohort (> 15 years) and a pediatric cohort (8–14 years).

The primary end points were safety at each dose level, target tissue transduction and LAMP2B expression, effect on cardiomyocyte morphology, and clinical stabilization and improvement. Three adult/adolescent patients received a low dose of RP-A501, 2 patients received the high dose, and 2 pediatric patients received the low dose.

Investigators tracked a number of clinical biomarkers, including New York Heart Association (NYHA) class; B-type natriuretic peptide (BNP) levels, which are a key marker of heart failure; left ventricular (LV) wall thickness and ejection fraction; cardiac output and dystolic dysfunction; 6-minute walk test (6MWT) results; and cardiac LAMP2B gene expression.

“All adolescent and adult patients who were treated (≥ 15 years; n = 3 patients at 6.7 x 1013 GC/kg, n = 2 patients at 1.1 x 1014 GC/kg) with observed immunosuppressive regimen compliance (n = 4) had evidence of cardiac LAMP2B expression which ranged from 67-100% vs. normal control by immunohistochemistry,” the research team reported.

Two patients in the adult/adolescent cohort whose BNP levels measured 942 and 176, respectively, at baseline, measured 200 and 44 at 18- and 15-months of follow-up, respectively. Both of their NYHA classification dropped from II to I. The second patient in the high dose adult cohort underwent a heart transplant at 5 months for progressive DD.

“The added results are the clinical stability of the patients. These are young boys, between the ages of 15 and 21 when they were initially treated. That said, [it’s] the time when most patients, particularly the male patients with Danon, begin to deteriorate and what we’ve seen is clinical stability in these patients,” he told CGTL. “Although we don’t have a control population, I think the evidence of clinical stability is quite encouraging. We’ve also seen some improvement in their natriuretic peptides, which are a measure of wall stress and congestion in the myocardium…Finally, at least in 1 of our patients, we saw some evidence of regression in left ventricular wall thickness.”

The treatment was generally well-tolerated in the adult cohort, with 1 patient in the high-dose cohort experiencing some grade 4 serious adverse events (AEs), including thrombotic microangiopathy associated with thrombocytopenia and acute kidney injury and renal failure. The patient resolved fully with eculizumab and temporary hemodialysis.

Three patients in the adult cohort experienced grade 3 transaminase increase, which was transient and resolved with immunosuppression.

For the pediatric population (n = 2), investigators implemented additional risk mitigation strategies, including an enhanced prophylactic immunosuppressive regimen.

“In response to what we learned in the adult cohort, we really changed the means of surveillance and the immunosuppression that’s being administered to these patients and what I’ll report is really that these patients did well,” Greenberg said. “They tolerated this without much difficulty which, I think, is important for this kind of therapy.”

RP-A501 was generally well-tolerated in both pediatric patients, with T- and B-cell directed immunosuppression associated with markedly reduced complement activation relative to the adult cohort. Platelets remained in the normal range in both patients after receipt of therapy, and there were no complement-related clinical or laboratory AEs reported.

Investigators previously announced1 that, based on observational safety and efficacy data, they would no longer administer the high dose and focus instead on the low-dose cohort. According to Greenberg, that decision was made because of a lack of added efficacy at a higher dose and because of a potentially increased likelihood of adverse events.

Next steps for RP-A501 include more patients dosed and longer follow-up.

“I think this has been a terrific opportunity for us to look at trying to treat cardiac disease that’s due to a single-gene abnormality,” Greenberg said. “This seems to me to be very amenable to gene therapy, and what we have in the study with the patients with Danon disease is what I believe could be a prototype for approaching monogenic disorders in the future.”

The findings support phase 2 evaluation of RP-A501 in Danon disease, Greenberg concluded.

  1. Johnson V. Danon disease gene therapy yields sustained clinical benefit. CGTL website. Published November 18, 2021. Accessed May 9, 2022. https://www.cgtlive.com/view/danon-disease-gene-therapy-yields-sustained-clinical-benefit
  2. Greenberg B, Rossano J, Epstein S, et al. Extended results from first-in-human clinical trial of rp-a501 (aav9:lamp2b) gene therapy treatment for Danon disease. Presented at: American Society of Gene & Cell Therapy 25th Annual Meeting; May 16-19, 2022; Washington, DC. Accessed May 9, 2022. https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=3743