RP-A501 (AAV9.LAMP2B)

As of October 2026, clinical evidence for RP-A501 comes from two uncontrolled trials in male participants with Danon disease. RP-A501-0219 was a non-randomized, open-label phase 1 trial of a single intravenous infusion, with sequential cohorts by age and dose. It treated 7 participants between June 2019 and March 2022: 5 aged 15 years or older and 2 aged 11 to 14 years. Five participants (3 adults or older adolescents and 2 children) received 6.7 × 10¹³ GC/kg, and 2 adults or older adolescents received 1.1 × 10¹⁴ GC/kg. All received transient immunomodulation, which differed by cohort: a steroid alone in 1 participant, a steroid with tacrolimus in 2, rituximab with a steroid and tacrolimus in 2, and rituximab with a steroid and sirolimus in 2. The trial is published, with data over 24 to 54 months. The phase 1 results cited in this report come from the published abstract and from company presentations, announcements, and securities filings. The company has continued to report long-term follow-up of the same participants, most recently from a data extraction of July 31, 2026, at a median follow-up of 5.7 years (range 4.3 to 7.1 years). RP-A501-0123 is a single-arm, open-label phase 2 trial that the company describes as pivotal. It had dosed 9 participants as of October 2026. Its results are preliminary and are reported by the company alone, from a data extraction of August 7, 2026, with cohort 4 safety data as of September 4, 2026. No peer-reviewed report of phase 2 results was found.

Phase 1 efficacy results cover 6 of the 7 participants. The seventh, who received the higher dose and had a left ventricular ejection fraction below 40% at enrollment (reported as 35% in documents of 2021 and 2023 and as 32% in the 2026 Form 10-K), had progressive heart failure and underwent heart transplantation 5 months after infusion. The company attributes the transplantation to progression of Danon disease and describes the participant as “not evaluable for efficacy”. In the 6 participants with normal ejection fraction at baseline, the published abstract reports cardiac LAMP2 protein expression, a reduction from baseline in or stabilization of left ventricular mass index, preservation of ejection fraction, and a reduction in or stabilization of cardiac troponin I and NT-proBNP. In the July 31, 2026 data extraction, the company reports that at about 12 months (month 18 in 2 participants) all 6 had LAMP2 protein expression of Grade 1 or higher and a decrease in left ventricular mass index of 10% or more, with individual decreases of 11% to 32%. At the most recent visit (month 36 to month 84), the participant-level table gives changes in left ventricular mass index of -32%, -31%, -12%, -7%, -47%, and +3%: a decrease of 10% or more in 4 of 6 participants and a value below baseline in 5 of 6. The participant with the 3% increase at month 36 had a 15% decrease at month 12, and left ventricular posterior wall thickness in that participant had increased by 66% at month 36. The same presentation states that LAMP2 protein expression was durable in all participants and records Grade 0 staining in 1 participant at the 30-month and 36-month assessments, with vector RNA and DNA persisting through 60 months. From baseline to the most recent visit, cardiac troponin I decreased by 31% to 99% and NT-proBNP by 31% to 90% in all 6 participants, NYHA class changed from II to I in 5 participants and remained II in 1, and the KCCQ-12 score increased by 7 to 56 points. At the earlier data cut of April 19, 2024, the median reductions were 24% for left ventricular mass index, 84% for cardiac troponin I, and 57% for natriuretic peptide (attributed to NT-proBNP in the 2024 Form 8-K and to BNP in the 2026 Form 10-K), and the median KCCQ improvement was 27 points. Overall survival was 100% at the July 31, 2026 extraction. One further participant underwent heart transplantation 4.8 years after infusion, after that extraction.

RP-A501-0123 enrolls males aged 8 years or older with a pathogenic or likely pathogenic LAMP2 variant, left ventricular hypertrophy, a left ventricular ejection fraction of 50% or more, NYHA class II to III symptoms, and elevated high-sensitivity troponin I. The design aligned with the FDA in September 2023 was 12 participants at 6.7 × 10¹³ GC/kg. Six participants were dosed at that level before the trial was paused in May 2025: 1 aged 15 years or older (cohort 1) and 3 aged 8 to 14 years (cohort 2), who received two doses of rituximab with sirolimus and corticosteroids, and 2 (cohort 3) whose regimen also contained the C3 inhibitor pegcetacoplan. The pivotal population is now the 12 participants of cohort 4, who receive commercial-grade product at 3.8 × 10¹³ GC/kg with three doses of rituximab, sirolimus, and corticosteroids, without pegcetacoplan. The company states that the dose was recalibrated to account for the higher full-to-empty capsid ratio of the current product. Three of the 12 had been dosed as of October 2026, and 9 remained to be enrolled and treated. The registry lists one primary outcome at 12 months that requires both myocardial LAMP2 protein expression of Grade 1 or higher by immunohistochemistry and a decrease of 10% or more in left ventricular mass index. The company describes these as co-primary endpoints intended to support accelerated approval and defines success as at least 7 of 12 participants meeting both criteria. The company expects to complete dosing by mid-2027, to report topline results in mid-2028, and to file a biologics license application in late 2028; the registry gives an estimated primary completion of June 2028. Preliminary efficacy data are limited to the 4 participants of cohorts 1 and 2, at most recent visits of 18 to 36 months. Left ventricular mass index changed by -36%, -35%, +9%, and -30% (a decrease of 10% or more in 3 of 4 participants), NT-proBNP by -19%, -7%, -19%, and -30%, and cardiac troponin I by -49%, -14%, +122%, and -14%. NYHA class improved to class I in 3 participants and remained class II in 1, and the KCCQ-12 overall score changed by 0, +2, +16, and +35 points. Data from the 2 participants of cohort 3 were excluded. No myocardial LAMP2 protein expression result, 12-month responder status, event-free survival result, or cohort 4 efficacy result was found for the phase 2 trial, and the company states that “results from earlier cohorts may not predict outcomes at the recalibrated dose under the modified protocol”.

In phase 1, 1 of the 2 participants given 1.1 × 10¹⁴ GC/kg had grade 4 complement-mediated thrombotic microangiopathy with thrombocytopenia and acute kidney injury. The event was treated with eculizumab and transient hemodialysis, and kidney function returned to baseline within three weeks. This was the participant who underwent transplantation at 5 months, which the company states was not associated with the event. Three participants (2 at the lower dose and 1 at the higher dose) had a grade 3 glucocorticoid-related exacerbation of skeletal myopathy that resolved with steroid taper, and a 2022 presentation also lists grade 3 transaminase increase in 3 participants and grade 3 Salmonella sepsis in 1. The FDA placed the program on clinical hold in May 2021 and lifted the hold on August 16, 2021, after the protocol was modified. The higher dose was discontinued and an ejection fraction below 40% became an exclusion criterion. The 2 pediatric participants, treated afterward with rituximab, sirolimus, and a lower corticosteroid dose, had no serious adverse event related to RP-A501. The published abstract reports complete resolution of side effects at 24 to 54 months. In phase 2, the company's table of Grade 3 or higher serious adverse events related to RP-A501 (data extraction of August 7, 2026) lists at least 1 such event in 3 of 4 participants (75.0%) in cohorts 1 and 2, in 2 of 2 (100%) in cohort 3, and in 1 of 3 (33.3%) in cohort 4. Thrombotic microangiopathy is listed in 3 participants dosed at 6.7 × 10¹³ GC/kg: 2 of 4 (50.0%) in cohorts 1 and 2 and 1 of 2 (50.0%) in cohort 3. A 2025 news report of the company's conference call states that the C3 inhibitor was added after at least two cases of thrombotic microangiopathy and that one case was linked to a genetic mutation that confers complement sensitivity. In cohorts 1 and 2, acute kidney injury, renal failure, hepatic enzyme increase, cardiac arrest, posterior reversible encephalopathy syndrome, and rhabdomyolysis are each listed in 1 participant. In May 2025, the 2 participants of cohort 3 had serious adverse events involving capillary leak syndrome with multi-organ damage, and 1 died on May 25, 2025, after an acute systemic infection, which the European Union trial record describes as bacteremia and sepsis. The company's announcement of May 27, 2025 described one affected participant, and its 2026 filings describe two. Dosing was halted on May 7, 2025, and the FDA placed the trial on clinical hold on May 23, 2025, and lifted the hold in August 2025. The 2026 Form 10-Q states that an investigation concluded the events were likely the result of the combination of the C3 inhibitor and RP-A501; the 2026 Form 10-K also describes the investigation as tracing the events to the protocol amendment that added the C3 inhibitor. The modified protocol lowered the dose to 3.8 × 10¹³ GC/kg, discontinued prophylactic use of the C3 inhibitor, set a lower threshold for giving the C5 inhibitor eculizumab, and required the first 3 participants to be treated sequentially at least four weeks apart. The company describes the modified protocol as including enhanced eligibility criteria, and a 2026 commentary states that the eligibility criteria remained unchanged. In the first 3 participants dosed under the modified protocol, the company reports no thrombotic microangiopathy, capillary leak, or significant complement-mediated adverse event through 3 months, 1 Grade 3 increase in gamma-glutamyltransferase related to RP-A501 that resolved, and a decrease in platelet count at week 8 to 9 that was not deemed clinically significant and resolved after medication changes. In an announcement of September 15, 2026, the company reported that the FDA had confirmed continued enrollment and dosing under the modified protocol. The incidence of all adverse events, including non-serious events and events below Grade 3, was not found for the phase 2 trial.

The phase 2 trial has no concurrent control arm. The company states that a global natural history study, running concurrently, will serve as the external comparator. RP-NI-A501-0223 is a company-sponsored observational study with prospective and retrospective data collection in males aged 8 years or older and females aged 8 to 50 years, at 15 locations in 6 countries. Its registry record estimates enrollment of 60 participants and a primary completion date of December 2029 and states that a subset of participants will be used as an external control arm; the company reported more than 50 participants enrolled in its second quarter 2026 results announcement. RP-NI-A501-0122 is a completed retrospective chart review of 59 participants (21 males and 38 females) at 15 locations in 5 European countries, which a September 2023 company presentation lists among the natural history data sets for the external comparator. No results were found for either study. The September 2023 presentation refers to “Appropriate matching to ensure robust comparisons”. No document found states the number of participants in the external control subset, the matching variables, the selection rules, the statistical hypothesis, the sample size justification, or the statistical method of comparison with the pivotal trial. The natural history comparison shown in the October 2026 company presentation uses unpublished data from the International Danon Disease Registry, from 22 untreated males for left ventricular mass and 20 for BNP.

The following evidence was not found as of October 2026. No randomized or concurrently controlled comparison has been reported, and no direct or indirect comparison of RP-A501 with heart transplantation was found. No clinical data were found for females or for children younger than 8 years. Experience with reduced ejection fraction is the 1 phase 1 participant who underwent transplantation at 5 months, and the phase 2 trial requires an ejection fraction of 50% or more. Experience at 3.8 × 10¹³ GC/kg is about 3 months of safety follow-up in 3 participants, and no phase 1 participant received that dose. The registered outcome measures of the phase 2 trial are myocardial LAMP2 protein expression, left ventricular mass index, cardiac biomarkers, KCCQ-12 score, NYHA class, event-free survival, and safety, and a 2023 journal article states that extracardiac symptoms, including skeletal myopathy, retinal impairment, and intellectual disability, will be largely unaffected by gene therapy. Follow-up extends to a maximum of 7.1 years in phase 1 and 36 months in phase 2, and a 2026 commentary states that longer-term follow-up is required to assess durability of gene expression, late toxicity, and clinical outcomes, including survival free from heart transplantation. Both trials give a single infusion, and the same commentary describes the inability to re-dose after neutralizing antibody formation as a limitation of current AAV platforms.