Evicenter
P&T meetings

RP-A501 (AAV9.LAMP2B)

Danon disease

Regulatory submission
BLA planned for late 2028
Last updated
300 sources

Product information and disease descriptionPlace of product in therapyApproaches to treatment

Expected outcomes of therapy

17 evidence topics · 14 sources

Pivotal trial success criterion, October 2026

“Trial success requires at least seven patients to meet both response criteria at 12 months: myocardial LAMP2 protein expression of at least Grade 1 and a reduction in left ventricular mass index of at least 10% from baseline.” (opens the source at this quote in a new tab)

“At least 7 of 12 responders at 12 months” (opens the source at this quote in a new tab)

“Each responder must meet both criteria” (opens the source at this quote in a new tab)

“Meeting the pivotal study’s efficacy success criterion would not, by itself, establish that RP-A501 will receive regulatory approval.” (opens the source at this quote in a new tab)

Registered endpoint thresholds at 12 months and event-free survival to 60 months

“Myocardial tissue expression of LAMP2 protein improved from baseline to ≥ Grade 1 (by IHC), AND, ≥ 10% decrease in LVMI from baseline.” (opens the source at this quote in a new tab)

“≥ 20% decrease in NT-proBNP from baseline” (opens the source at this quote in a new tab)

“Event free survival with events defined as death, heart transplant, mechanical circulatory support (MCS) or heart failure hospitalization” (opens the source at this quote in a new tab)

“From infusion to 60 months post infusion” (opens the source at this quote in a new tab)

Phase 1 publication: outcomes over 24 to 54 months in 7 participants

“At 24 to 54 months, all the patients were alive, with complete resolution of side effects.” (opens the source at this quote in a new tab)

“A single infusion of RP-A501 appeared to be safe and was associated with cardiac LAMP2 expression and evidence of clinical improvement over a period of 24 to 54 months.” (opens the source at this quote in a new tab)

Phase 1 follow-up to 7 years, data extracted July 31, 2026: survival and transplant-free survival

“100% overall survival; median transplant-free survival not reached at median follow-up: 5.7 years (range: 4.3–7.1 years)” (opens the source at this quote in a new tab)

Phase 1 follow-up: left ventricular mass index at approximately 12 months and at 3 to 7 years

“At approximately 12 months, all six patients in the principal Phase 1 analysis demonstrated myocardial LAMP2 protein expression and at least a 10% reduction in left ventricular mass index.” (opens the source at this quote in a new tab)

“At follow-up of approximately three to seven years, left ventricular mass index was below baseline in five of six patients, with reductions of at least 10% in four patients.” (opens the source at this quote in a new tab)

Phase 1 follow-up: loss of detectable LAMP2 protein staining in one participant with persisting vector RNA and DNA

“Grade 0 LAMP2 protein IHC staining at the 30- and 36-month assessments, however, LAMP2B vector RNA and DNA (VCN) levels have persisted through 60 months of follow-up” (opens the source at this quote in a new tab)

Size of change the company describes as meaningful on the Kansas City Cardiomyopathy Questionnaire

“Changes in KCCQ score of +/- 5 points are considered meaningful and have been shown to correlate with HF outcomes.” (opens the source at this quote in a new tab)

Surrogate endpoints and the accelerated approval pathway

“These endpoints are intended to support a potential accelerated approval pathway.” (opens the source at this quote in a new tab)

“To support accelerated approval, the study will assess the efficacy of RP-A501 as measured by the biomarker-based co-primary endpoint consisting of improvements in LAMP2 protein expression (≥ Grade 1, as measured by immunohistochemistry), and reductions in LVMI.” (opens the source at this quote in a new tab)

“These endpoints could support full approval with longer-term follow-up.” (opens the source at this quote in a new tab)

“As a condition of accelerated approval, the FDA may impose specific obligations with defined timelines, including to perform confirmatory clinical trials with due diligence.” (opens the source at this quote in a new tab)

FDA guidance: confirmation of clinical benefit after accelerated approval of a regenerative medicine therapy

“Sponsors of drugs that have been granted accelerated approval have been required to conduct post-approval confirmatory studies to verify and describe the anticipated effects of their products on irreversible morbidity and mortality or other clinical benefit (Ref. 2).” (opens the source at this quote in a new tab)

“sponsors of products that have been granted RMAT designation and which receive accelerated approval may be able to fulfill the post-approval requirements from clinical evidence obtained from sources other than the traditional confirmatory clinical trials.” (opens the source at this quote in a new tab)

Candidate surrogate endpoints from natural history data

“The results from this study suggest that potential surrogate end points for therapeutic trials could include LVEF, LV mass, LVEDD, and LV wall thickness in male patients, and LVEF, LVEDD, and LV wall thickness in female patients.” (opens the source at this quote in a new tab)

Unknowns: durability, late toxicity, and clinical outcomes

“Longer-term follow-up is required to assess durability of gene expression, late toxicity, and clinical outcomes, including survival and survival free from heart transplantation.” (opens the source at this quote in a new tab)

“Clinical observations presented here are based on small, uncontrolled studies with varying follow-up.” (opens the source at this quote in a new tab)

Unknowns: retreatment after antibody formation

“Finally, the inability to re-dose due to neutralizing antibody formation remains a major limitation of current AAV platforms, emphasizing the importance of first-dose optimization and long-term durability assessment.” (opens the source at this quote in a new tab)

“the generation of antibodies specifically to the delivered rAAV capsid severely limits re-dosing strategies to boost efficacy, which is one of the major hurdles to AAV-mediated gene therapy” (opens the source at this quote in a new tab)

Unknowns: extracardiac disease

“Whereas gene therapy may ameliorate cardiac symptoms, extracardiac symptoms including skeletal myopathy, retinal impairment, and intellectual disability will be largely unaffected by this therapy.” (opens the source at this quote in a new tab)

Natural history benchmark: yearly change in untreated males, unpublished registry data cited by the company

“BNP increases by 42.17 ± 18.46 pg/mL per year in untreated Danon males” (opens the source at this quote in a new tab)

“LV Mass increases by 39.86 ± 4.01 g per year in untreated Danon males” (opens the source at this quote in a new tab)

“Unpublished data from International Danon Disease Registry” (opens the source at this quote in a new tab)

Natural history benchmark: death, transplantation, or assist device in the International Danon Disease Registry

“The incidence of the HF outcome was higher in male (40%, n=21) compared with female patients (22%, n=14)” (opens the source at this quote in a new tab)

“Additionally, the actuarial median age of HF outcome was younger in male compared with female patients with median time to HF outcome from birth being 25 years old in male and 63 years old in female patients” (opens the source at this quote in a new tab)

Natural history benchmark: composite outcome in a systematic review of 146 published cases

“The composite outcome of death, heart transplant or ventricular assist devices occurred equally in both sexes (32% of females and 37% of males, p = 0.60) but later in females (median age 38 years) than in males (median age 21 years, p < 0.001).” (opens the source at this quote in a new tab)

External comparator for the pivotal trial

“A subset of patients will be used as an External Control Arm for comparison to RP-A501 Trial participants.” (opens the source at this quote in a new tab)