Gene Therapies Advance in Danon Disease, CLN2 Batten Disease


Both REGENXBIO and Rocket Pharmaceuticals have announced trial updates in their gene therapy programs for rare diseases.

Although 2022 is winding down, progress is still being made with gene therapies in development for rare diseases, with both Rocket Pharmaceuticals and REGENXBIO announcing updates for their gene therapy programs in Danon disease and late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease (the most common form of Batten disease), respectively.

Rocket Pharmaceuticals has had an end-of-Phase 1 meeting with the FDA regarding next steps for the adeno-associated virus (AAV)-based gene therapy RP-A501.1 The company reviewed the phase 1 data with the FDA and proposed a study design and endpoints for the next phase of study and a phase 2 dose was determined.

“I am pleased to announce that following discussions with FDA, we anticipate proceeding with a dose of 6.7e13 GC/kg, and we anticipate utilizing a single arm open-label trial design with a robust natural history comparator, pursuant to the FDA’s acknowledgment of the challenges associated with executing a randomized controlled trial in Danon Disease," Gaurav Shah, chief executive officer, Rocket Pharma, said in a statement.1 “The FDA has also expressed an openness to considering a biomarker-based composite endpoint supported by functional and quality-of-life assessments as measures of patient benefit. We look forward to continued dialogue with the FDA on the design for our proposed pivotal trial, including discussion of appropriate external controls for the study and appropriate endpoints to support accelerated approval.”

RP-A501 has continued to be well-tolerated and show some improvements in patients with Danon disease in an ongoing phase 1 trial (NCT03882437).2 Recent data from the low-dose, pediatric cohort showed that 2 patients with 6 and 11 months of follow-up had no complement-related adverse events (AEs) and minimal complement activation. Improvements have been seen across tissue, laboratory, and imaging-based biomarkers, New York Health Association class, and Kansas City Cardiomyopathy Questionnaire scores.

WATCH NOW: Joseph Rossano, MD, on the Potential of Gene Therapy in Danon Disease

“We are now in discussion with the FDA about a trial design that will enable evaluation of 2 pediatric patients treated with drug product manufactured at our in-house cGMP AAV facility as an initial component of a modestly-sized global pivotal study. We are very encouraged by the highly collaborative ongoing dialogue with the FDA for RP-A501 in Danon Disease and subject to the continued dialogue and agreement with the FDA anticipate initiating the initial component of the global study in the first half of 2023,” Shah added.1

REGENXBIO announced updates for 2 of their gene therapy candidates being developed for CLN2 disease, RGX-181 and RGX-381. The single patient in an investigator-initiated study has been dosed with RGX-181, which uses the company’s NAV AAV9 vector to deliver the TPP1 gene to the central nervous system, at the Hospital de Clinicas in Porto Alegre, Brazil.3 As of December 20, 2022, the therapy has been well-tolerated with no treatment-relatedserious adverse events (AEs).

"We are pleased to have the opportunity to participate in the first-in-human study of RGX-181 for patients with CLN2," Roberto Giugliani MD, PhD, Hospital de Clinicas, said in a statement.3 "Patients with this devastating disease need new treatment options with the potential for longer lasting effects on the CNS, and we hope that this gene therapy benefits this patient community," added Carolina Fischinger, MD, PhD, primary investigator of the single-patient study.

RGX-381 has made progress into clinical trials, with the UK Health Authority accepting a clinical trial application for a first-in-human, dose-escalation, phase 1/2 trial to assess the therapy’s safety, tolerability, and effect on ocular manifestations of CLN2 disease. The trial, which is expected to initaite in the first half of 2023, will be conducted at Great Ormond Street Hospital in London.

"REGENXBIO continues to make excellent progress advancing our AAV Therapeutics pipeline, and we are pleased to share the advancement of two more programs that may support our '5x'25' strategy to have five AAV Therapeutics either on the market or in late-stage development by 2025," Steve Pakola, MD, chief medical officer, REGENXBIO, added to the statement.3 "With strong preclinical data highlighting the ability of both RGX-181 and RGX-381 to support widespread distribution and expression of the TPP1 enzyme that is lacking in patients with CLN2 disease, we believe that these programs have the potential to provide much-needed new treatment options for children with this devastating disease."

1. Rocket Pharmaceuticals provides update on anticipated registration path for RP-A501 in Danon Disease following end-of-phase 1 FDA meeting. News release. Rocket Pharmaceuticals. December 22, 2022.
2. Rocket Pharmaceuticals announces positive updates from phase 1 clinical trial for RP-A501 in Danon disease at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2022. News release. Rocket Pharmaceuticals. September 30, 2022.
3. REGENXBIO reports update on advancement of programs for CLN2 disease. News release. REGENXBIO. December 21, 2022.
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