Danon Disease Gene Therapy Yields Sustained Clinical Benefit


Following updated safety data, Rocket Pharmaceuticals has decided to discontinue the high-dose cohort.

Rocket Pharmaceuticals has announced updated data from the phase 1 trial (NCT03882437) of RP-A501 that demonstrate that the gene therapy continues to be well-tolerated with sustained clinical benefit in Danon disease.

“We are excited to announce positive data from our RP-A501 trial for Danon disease showing clinical, functional and biomarker improvements at one year or beyond and potential early separation from the natural course of disease in adult and adolescent patients,” said Gaurav Shah, MD, chief executive officer, Rocket Pharmaceuticals, in a statement. “Male patients living with Danon Disease suffer a heavy disease burden and face rapidly progressive heart failure in their teenage years. In this setting, even stabilization is highly beneficial, and clinical improvements as seen in our trial could be transformative and represent a step forward for the treatment of monogenic heart failure and gene therapy for cardiac diseases. We have initiated treatment in the pediatric cohort at the low-dose and anticipate moving as rapidly as possible toward Phase 2.”

The update includes interim safety and efficacy data from both adult and adolescent patients in the low-dose (6.7e13 vg/kg; n=3) and high-dose (1.1e14 vg/kg; n=2) cohorts. The lower dose was well-tolerated, with transient adverse events (AEs) with no lasting sequelae. Early elevations in transaminase and creatinine kinase returned to baseline or decreased.

At the higher dose level, an r-adeno-associated virus (AAV) dose-dependent toxicity was observed in 1 of 2 patients. The patient developed thrombotic microangiopathy (TMA) which fully resolved with transient hemodialysis and other supportive treatment. The most common serious AE was steroid-induced myopathy in 3 patients, 2 in the low-dose and 1 in the high-dose, which resolved after discontinuing corticosteroid. As previously disclosed, 1 patient in the high-dose cohort underwent a heart transplant at month 5.

READ MORE: Gene Therapy for LAD-1 Demonstrates Efficacy

Following the latest safety data, Rocket Pharmaceuticals will discontinue the high-dose cohort and focus on the low-dose cohort. The company has also developed an updated study protocol with the FDA to mitigate future developments of TMA and treatment-related adverse events.

“I am very encouraged by the ability to safely administer RP-A501 and show robust gene expression in the hearts of these young male patients with this devasting monogenic disorder. The clinical data to date also demonstrate encouraging results including clinical stabilization of this rapidly progressive disease,” principal investigator Barry Greenberg, MD, FHFSA, director, Advanced Heart Failure Treatment Program, UC San Diego Health, and professor, medicine, UC San Diego School of Medicine, added to the statement.

Investigators observed an improvement in New York Heart Association (NYHA) class from 2 to 1 in 2 low-dose patients and 1 high-dose patient that had closely monitored immunosuppression with follow-up of at least 1 year. Additionally, 1 low-dose patient stabilized in NYHA class without a closely monitored immunosuppressive regimen.

B-type natriuretic peptide (BNP) substantially improved in all 3 low-dose patients and 1 high-dose patient compared with baseline. Left ventricular wall thickness (mean, –23%) and ejection fraction (mean, +20%) also improved or stabilized in 2 low-dose and 1 high-dose patient at 12 to 18 months compared with baseline, and all 3 low-dose patients and 1 high-dose patient improved on 6-minute walk test distances compared with baseline.

Investigators also evaluated LAMP2B gene expression by immunohistochemistry, Western blot, and electron microscopy and found sustained expression in both dose-levels in the 3 patients with a closely monitored immunosuppressive regimen.

“Danon disease is another special program for Rocket... because it represents the first potential curative genetic therapy for a heart syndrome of any kind. Heart disease is the biggest killer in the US, and I think getting an anchor on a genetic approach to heart disease is a big step forward for the industry and for people,” Shah told GeneTherapyLive in a previous interview.

Rocket Pharmaceuticals announces positive updates from phase 1 clinical trial of RP-A501 in Danon disease. News release. Rocket Pharmaceuticals. November 15, 2021. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-positive-updates-phase-1
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