Abstract 11117: Phase 1 Danon Disease Results: The First Single Dose Intravenous (IV) Gene Therapy (RP-A501) With Recombinant Adeno-Associated Virus (AAV9:LAMP2B) for a Monogenic Cardiomyopathy

Background: Danon disease (DD) is a rare X-linked monogenic cardiomyopathy and multisystemic disorder caused by mutations in the LAMP2 gene. Male DD patients (pts) develop severe progressive hypertrophic cardiomyopathy (HCM), left ventricular (LV) dysfunction and arrhythmias resulting in a median mortality below age 20 years (y). Methods: This open-label, single-dose, phase 1 trial enrolled male DD pts with a LAMP2 mutation and cardiomyopathy in two age groups: ≥15 y and 8-14 y. Pts received IV infusion of RP-A501, an adeno-associated virus with a normal copy of the human LAMP2B gene (AAV9:LAMP2B), at doses of 6.7 x 1013 GC/kg (low dose) and 1.1 x 1014 GC/kg (high dose). Immunomodulation (IM) included prednisone and rituximab, with additional sirolimus for the most recently treated pediatric pts. Results: Between June 2019 and March 2022, 7 males with DD age 11.7 - 21.1y (median 18.3y; N=5 adult and N=2 pediatric) received RP-A501 (N=5 low dose and N=2 high dose). 83% of pts were NYHA Class II; one was NYHA Class III. IM compliance was confirmed in 6/7 pts. All pts are alive and stable at 3-30 months (m) follow-up. One adult pt with baseline LV systolic dysfunction required heart transplant at 5m post RP-A501, most likely related to DD progression. All adverse events (AEs) related to RP-A501 or IM were manageable and reversible. No RP-A501-related SAEs were observed in the pediatric pts. On baseline endomyocardial biopsy, no pts had significant LAMP2B expression; 100% (N=6/6) of evaluable pts had cardiac LAMP2B expression within 6m of therapy with improved myocardial structure in 5/6. Pts evaluable beyond 6m had stabilized or improved BNP (N=5/5), troponin (N=5/5), and LV ejection fraction (N=5/5) by 6-12m, and stabilized/improved LV wall thickness (N=4/4) and NYHA Class (N=4/4) by 12-18m. These findings persist up to 30m post RP-A501. Conclusions: Results from this phase 1 trial in DD demonstrate that B- and T-lymphocyte directed immunomodulation enables safe IV RP-A501 gene therapy administration, resulting in cardiomyocyte transduction, LAMP2B expression, improved autophagy, and improved/stabilized serologic, echocardiographic and clinical parameters associated with survival in HCM. Updated results will be presented.