16 November 2021 - - US-based genetic therapies developer Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) has posted updated data from the Phase 1 clinical trial evaluating a single intravenous infusion of RP-A501, the company's investigational gene therapy, for the treatment of Danon Disease, the company said.

This update, which includes interim safety and efficacy data from patients in the low-dose (6.7e13 vg/kg; n=3) and high-dose (1.1e14 vg/kg; n=2) adult and adolescent cohorts, demonstrates RP-A501 was generally well tolerated at the low-dose and conferred sustained clinical benefit.

Dr. Barry Greenberg, director of the Advanced Heart Failure Treatment Program at UC San Diego Health, Professor of Medicine at UC San Diego School of Medicine, and the principal investigator of the RP-A501 clinical study, is presenting a subset of the data at the American Heart Association Scientific Sessions 2021.

RP-A501 was generally well tolerated at the 6.7e13 vg/kg dose level. All observed adverse effects were reversible with no lasting sequelae. Early transaminase and creatinine kinase elevations returned to baseline or decreased.

As previously disclosed, RP-A501 r-AAV dose-dependent toxicity was seen in one of the two patients treated at the 1.1e14 vg/kg dose level.

The affected patient, who received the largest total dose, developed thrombotic microangiopathy that fully resolved with supportive treatment including transient hemodialysis.

Across both dose levels, the most common serious adverse event observed was steroid-induced myopathy in three patients (two low-dose and one high-dose) which resolved subsequent to corticosteroid discontinuation.

Based on the observed safety and efficacy to-date, the company will focus on the low-dose cohort moving forward and will no longer administer the high-dose to study patients.

An updated protocol developed in collaboration with the FDA has been implemented to mitigate development of TMA and other treatment-related adverse events.
Clinical and Biomarker Results for Patients With at Least 12 Months Follow-Up

NYHA class: An improvement in NYHA class (from II to I) was observed in three patients (two low-dose and one high-dose) who had closely monitored immunosuppression with follow-up greater than one year and stabilization was observed in one low-dose patient without a closely monitored immunosuppressive regimen.

BNP: A substantial improvement in B-type natriuretic peptide, a key marker of heart failure, was observed in all three low-dose patients and one high-dose patient.

Among the three low-dose patients, BNP decreased from a pretreatment baseline by 57% at 24 months, 79% at 18 months, and 75% at 15 months, respectively. In the high-dose patient, BNP decreased from a pretreatment baseline by 67% at 12 months.

LV wall thickness and ejection fraction: In patients with closely monitored immunosuppression (two low-dose and one high-dose) left ventricular posterior wall thickness improved (average 23% decrease compared to pretreatment baseline) and ejection fraction improved or stabilized (average 20% increase compared to pretreatment baseline) at 12 to 18 months on echocardiography.

Severe and progressive wall thickening is a hallmark of the hypertrophic cardiomyopathy of Danon Disease and is a major contributor to early mortality in male patients.

Cardiac output and diastolic dysfunction: Cardiac output remained normal for all patients with improved or stable left heart filling pressures as measured by cardiac catheterization.

6MWT: Three low-dose patients and one high-dose patient demonstrated improvements in the 6-minute walk test. One low-dose patient improved from a pretreatment baseline of 443 meters (m) to 467 m at 24 months.

The second low-dose patient improved from a pretreatment baseline of 405 m to 410 m at 18 months. The third low-dose patient improved from a pretreatment baseline of 427 m to 435 m at 15 months. The high-dose patient improved from a pretreatment baseline of 436 m to 492 m at 12 months.

Gene expression: Evidence of sustained cardiac LAMP2B gene expression by immunohistochemistry and Western blot with qualitative improvement of vacuoles and cardiac tissue architecture on electron microscopy was observed at both dose levels.

Sustained cardiac LAMP2B gene expression by immunohistochemistry was observed in all three patients with a closely monitored immunosuppressive regimen.

Specifically, LAMP2B gene expression by immunohistochemistry in the low-dose (6.7e13 vg/kg) was 68% in one patient at Month 12 and 92% in another patient at Month 9. In one patient who received the high-dose (1.1e14 vg/kg), LAMP2B gene expression by immunohistochemistry was 100% at Month 12.

As previously disclosed, one patient in the high-dose cohort underwent a heart transplant at Month 5.

This patient had advanced disease including diminished LV ejection fraction on echocardiogram and markedly elevated LV filling pressure prior to treatment. His clinical course was characteristic of Danon Disease progression.

Analysis of the explanted heart revealed significant fibrosis consistent with advanced Danon Disease.

Myocardial tissue from the explanted heart at 5 months post-treatment displayed 100% LAMP2B protein expression by immunohistochemistry throughout non-fibrotic cardiac regions including the ventricles and other essential targeted areas.

RP-A501 is an investigational gene therapy product being developed for Danon Disease and the first potential gene therapy for monogenic heart failure.

It consists of a recombinant adeno-associated serotype 9 capsid containing a functional version of the human LAMP2B transgene (AAV9.LAMP2B).

RP-A501 is currently being evaluated in a Phase 1 clinical trial, from which preliminary data of the low-dose cohort showed it was generally well tolerated and provided evidence of improved cardiac function in patients.