Danon Disease Phase 1 RP-A501 Results: The First Single-Dose Intravenous Gene Therapy with Recombinant Adeno-Associated Virus (AAV9:LAMP2B) for a Monogenic Cardiomyopathy
Abstract Body (Do not enter title and authors here): Hypothesis & Purpose: Danon disease (DD) is an X-linked cardiomyopathy (CMP) caused by LAMP2 mutations resulting in LAMP2 deficiency. Male DD patients (pts) develop rapidly progressive severe hypertrophic CMP causing mortality at median age 19-20y. We tested whether RP-A501, an adeno-associated virus serotype 9 encoding a normal human LAMP2 isoform B (AAV9.LAMP2B) can be administered safely and reverse DD phenotype.
Study Design & Methods: Phase 1 trial (NCT03882437) of male DD pts with LAMP2 mutations and CMP in cohorts: ≥15y (n=5; adult/adolescent) and 8-14y (n=2; pediatric). Pts were followed for 24-36m post-RP-A501.
Sample Size: 7
Population Studied: Male DD pts with no LAMP2 expression, NYHA Class II symptoms, and LV hypertrophy
Intervention: Single IV infusion of RP-A501 at 6.7x1013 GC/kg (low dose) or 1.1x1014 GC/kg (high dose). Immunomodulation (IM): 2-3m prednisone, tacrolimus/sirolimus, and rituximab.
Power Calculations: N/A
Primary Endpoints: Safety, LAMP2 expression
Secondary Endpoints: Sustained LAMP2 expression, disease stabilization and clinical improvement
Outcomes: Seven males with DD age 12-21y (median 18.3y) received RP-A501 (N=5 low dose and N=2 high dose).
Most adverse events (AEs) were non-serious. All RP-A501- or IM-related AEs were manageable and reversible. One pt had an RP-A501-related grade 4 AE (SAE) of thrombotic microangiopathy and renal failure (with full recovery). Grade 3 steroid-related myopathy with full recovery occurred in 3 adult pts. No RP-A501- or steroid-related SAEs were seen in pediatric pts receiving enhanced IM (sirolimus, reduced-dose steroid).
All pts are alive and stable up to 4.5y follow-up. One pt with baseline LV systolic dysfunction had progressive heart failure attributed to DD and required heart transplant 5m post-RP-A501. All evaluable (6/6) pts had cardiac LAMP2 expression at 12m (sustained up to 36m). In 6/6 pts, BNP improved/stabilized and troponin improved at most recent evaluation (54m adult/adolescent; 24m ped). LV mass index was reduced by ≥10% at 12-24m post RP-A501 in 6/6 pts. Improvements in NYHA Class and KCCQ score in 6/6 pts persisted up to 4.5y follow-up.
RP-A501 was associated with acceptable safety and conferred sustained myocardial LAMP2 expression, with stabilized and largely improved serologic, echocardiographic, and clinical CMP parameters. In contrast to demonstrated rapid decline and early mortality in DD, all pts are alive and 6/6 evaluable pts are NYHA Class I at 24-54m follow-up.
Greenberg, Barry
( University of California, San Diego Medical Center
, La Jolla
, California
, United States
)
Coggins, Matthew
( Rocket Pharmaceuticals, Inc.
, Cranbury
, New Jersey
, United States
)
Schwartz, Jonathan
( Rocket Pharmaceuticals, Inc.
, Cranbury
, New Jersey
, United States
)
Rossano, Joseph
( Children’s Hospital of Philadelphia
, Philadelphia
, Pennsylvania
, United States
)
Taylor, Matthew
( University of Colorado Anschutz Medical Campus
, Aurora
, Colorado
, United States
)
Colan, Steven
( Boston Children's Hospital
, Boston
, Massachusetts
, United States
)
Adler, Eric
( University of California, San Diego Medical Center
, La Jolla
, California
, United States
)
Ricks, David
( Rocket Pharmaceuticals, Inc.
, Cranbury
, New Jersey
, United States
)
Yarabe, Paul
( Rocket Pharmaceuticals, Inc.
, Cranbury
, New Jersey
, United States
)
Battiprolu, Pavan
( Rocket Pharmaceuticals, Inc.
, Cranbury
, New Jersey
, United States
)
Shah, Guarav
( Rocket Pharmaceuticals, Inc.
, Cranbury
, New Jersey
, United States
)
Patel, Kinnari
( Rocket Pharmaceuticals, Inc.
, Cranbury
, New Jersey
, United States
)
Author Disclosures:
Barry Greenberg:DO NOT have relevant financial relationships
| Matthew Coggins:No Answer
| Jonathan Schwartz:DO have relevant financial relationships
;
Employee:Rocket Pharma:Active (exists now)
; Individual Stocks/Stock Options:Rocket Pharma:Active (exists now)
| Joseph Rossano:DO have relevant financial relationships
;
Consultant:Bayer:Active (exists now)
; Consultant:Biomarin:Active (exists now)
; Consultant:Merck:Active (exists now)
; Consultant:AskBio:Active (exists now)
; Consultant:CRI Biotech :Active (exists now)
; Consultant:Bristol Myers Squibb:Active (exists now)
| Matthew Taylor:DO NOT have relevant financial relationships
| Steven Colan:DO NOT have relevant financial relationships
| Eric Adler:DO have relevant financial relationships
;
Employee:Lexeo Therapeutics:Active (exists now)
; Consultant:Kiniska Pharmaceuticals:Past (completed)
; Consultant:Abbott:Past (completed)
; Consultant:Abiomed:Past (completed)
; Ownership Interest:Papillion Therapeutics:Active (exists now)
; Other (please indicate in the box next to the company name):Solid Biosciences:Past (completed)
; Research Funding (PI or named investigator):Rocket Pharmaceuticals:Past (completed)
; Royalties/Patent Beneficiary:Rocket Pharmaceuticals:Active (exists now)
; Individual Stocks/Stock Options:Lexeo Therapeutics:Active (exists now)
; Royalties/Patent Beneficiary:Lexeo Therapeutics:Active (exists now)
| David Ricks:No Answer
| Paul Yarabe:No Answer
| Pavan Battiprolu:No Answer
| Guarav Shah:No Answer
| Kinnari Patel:No Answer