Danon Disease Gene Therapy Improves Disease Biomarkers


All evaluable patients had improvements in natriuretic peptides, left ventricular volume, and NYHA class.

Data from a phase 1 trial (NCT03882437) suggest that Rocket Pharmaceuticals’ RP-A501 gene therapy improves biomarkers associated with prognosis in hypertrophic cardiomyopathy (HCM) in male patients with Danon disease and with pathogenic LAMP2 mutations.

The updated data were presented at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California, by Joseph Rossano, MD, MS, FAAP, FACC, Jennifer Terker Endowed Chair of pediatric cardiology, and codirector, Cardiac Center, and chief, division of cardiology, Children’s Hospital of Philadelphia

"Male patients tend to develop a severe rapidly progressive heart failure that occurs during adolescence. The median age at death occurs at 20 years of age and the median age of needing heart transplant is similar. It's important to note that while heart transplant can be a life prolonging therapy, our standard medications and treatment regimens for heart failuredo not alter disease progression or improve prognosis,” Rossano said during his presentation. “We believe that the time to intervene in this disease is earlier, before the development of end stage cardiomyopathy,when a treatment will likely be most effective.”

RP-A501, an adeno-associated virus serotype 9 encoding a normal copy of the human LAMP2B isoform (AAV9.LAMP2B), being evaluated in a single-dose, open-label trial that enrolled 5 male patients over the age of 15 years and 2 male patients between 8 and 14 years to receive either a 6.7 x 1013 GC/kg (low dose) or 1.1 x 1014 GC/kg (high dose; only in older patients and discontinued) intravenous infusion of RP-A501 as well as transient immunomodulation including prednisone and rituximab, as well as sirolimus for the most recently treated pediatric patients. The participants had a median age of 18.3 years (range, 11.7-21.1) and were NYHA class 2 at baseline. Six of 7 patients were compliant to the immunomodulation regimen. As of May 2023, all patients were alive and stable.

READ MORE: Gene Therapy Improves Quality of Life in Patients With Glycogen Storage Disease Type 1a

Investigators found that RP-A501 was well-tolerated and there were no serious adverse events (AEs) of steroid myopathy (SM) or thrombotic microangiopathy (TMA) after optimizing immunomodulation. Prior to that, there were 2 cases of grade 3 SM in the low-dose adult group and 1 case of grade 4 TMA and 1 case of grade 3 steroid myopathy in the high-dose older group. All serious AEs resolved with supportive care.One patient with left ventricular (VL) systolic dysfunction had progressive heart failure believed to be related to disease progression and required a heart transplant 5 months after infusion.

Preliminary efficacy data demonstrated LAMP2 expression in all evaluable patients which was mostly sustained with reduced LV mass (14-48% decrease from baseline). Brain natriuretic peptide, troponin, LV wall thickness, and NYHA class improved in all evaluable patients by 12 to 18 months and were sustained for up to 26 months. These findings compare favorable against a natural history prospective study (NCT03766386) in patients with Danon disease, none of which improved in NYHA class or BNP.

“Our phase 1 study demonstrated a favorable risk-benefit profile for RPA501 in pediatric adolescent males with Danon disease... we are hopeful to advance to a pivotal global phase 2 study later on this year,” Rossano concluded.

Greenberg B, Rossano J, Taylor M, et al. Danon disease: RP-A501 phase 1 results. The first single-dose intravenous (IV) gene thearpy with recombinant adeno-associated virus (AAV:LAMP2B) for a monogenic cardiomyopathy. Presented at: ASGCT 2023 Meeting, May 16-20, in Los Angeles, California. Abstract #9
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