Abstract 10727: Results from First-in-Human Clinical Trial of RP-A501 (AAV9:LAMP2B) Gene Therapy Treatment for Danon Disease

Abstract

Background: Danon disease (DD) is an X-linked disorder caused by mutations in the LAMP2 gene that is essential for autophagy. DD is characterized by severe cardiomyopathy for which treatment options are limited. Median survival for male patients (pts) is approximately 19 years (y). DD natural history is notable for modest cardiac abnormalities in early phases detectable by measurement of left ventricular global longitudinal strain (GLS) or natriuretic peptides (NPs) followed by rapid progression, particularly in males during the second and third decade. Methods: This open-label Phase 1 study evaluates the safety of a single IV infusion of RP-A501 (AAV9. LAMP2B ) at dose levels of 6.7 x 10 13 GC/kg (low dose) and 1.1 x 10 14 GC/kg (high dose) in male DD pts in two age groups: ≥15 y and 8-14 y. Eligibility criteria include a DD diagnosis with LAMP2 mutation and cardiac involvement. Results: In Cohort 1 (N=3 pts, ≥15 y, 6.7 x 10 13 GC/kg), RP-A501 increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC) in myocardial tissue. The two pts in Cohort 1 with observed immunosuppressive regimen compliance had high cardiac LAMP2B expression: 67.8% and 92.4% vs. normal control by IHC; up to 61% by WB. In both pts, NYHA Class improved from II to I. NPs were reduced by 59% and 42% at 9 and 12 months, respectively. All 3 pts had similar or mildly improved 6MWT, improved myocardial EM morphology with decreased autophagic vacuoles, improved/stabilized GLS and reported increases in physical activity. Adverse events were mostly manageable with transient immunosuppression. Reversible platelet decreases and transaminase elevations that returned to baseline within 2 months were seen. One patient treated with 1.1 x 10 14 GC/kg had complement-mediated thrombocytopenia and acute kidney injury requiring transient hemodialysis that fully recovered. An exacerbation of skeletal myopathy in 3 of the 5 patients resolved with steroid taper. Conclusions: This ongoing first-in-human trial demonstrates that the low dose of RP-A501 gene therapy for DD was generally well-tolerated, confers cardiac LAMP2B gene expression, and is associated with preliminary evidence of cardiac and clinical benefits.