REGENXBIO has initiated the pivotal Phase 3 portion of the AFFINITY DUCHENNE clinical trial, marking a significant step forward in the development of RGX-202, an investigational gene therapy for Duchenne muscular dystrophy (DMD). The first patient has been dosed in this critical trial, which aims to evaluate the efficacy and safety of RGX-202 in a larger patient population.
The Phase 3 trial (NCT05693142) will enroll approximately 30 ambulatory patients aged 1 year and older with DMD. The primary endpoint is the proportion of patients achieving at least 10% RGX-202 microdystrophin expression at 12 weeks post-treatment. Secondary endpoints include changes from baseline in timed function tests such as Time to Stand (TTStand), 10-Meter Walk/Run (10MWR), and Time to Climb (TTClimb) for patients aged 4 years and older. For younger patients (1-3 years), the Peabody Developmental Motor Scale-Third Edition (PDMS-3) and SV95C will be used. The North Star Ambulatory Assessment (NSAA) will be utilized as an exploratory endpoint.
Promising Phase 1/2 Data
REGENXBIO also announced positive 12-month efficacy data from three patients aged 4 to 10 years treated at dose level 1 (DL1, 1x10^14 GC/kg) and 9-month efficacy data from two patients aged 8 to 12 years treated at dose level 2 (DL2, 2x10^14 GC/kg) in the Phase 1/2 portion of the study. Compared to external natural history controls matched for age and baseline function, all five treated patients showed stability or improved function on the NSAA and timed function tests.
Notably, the two patients who received DL2 achieved a mean improvement of 5.5 points on the NSAA at 9 months post-treatment, exceeding the performance of the natural history control group. The three patients treated at DL1 also demonstrated improvements on timed function tests and the NSAA at 12 months, surpassing the minimal clinically important difference benchmark on change in timed task velocity.
Safety and Tolerability
Safety data from patients treated at DL1, DL2, and a younger cohort receiving DL2 indicated that RGX-202 was well-tolerated. There were no serious adverse events (AEs) or AEs of special interest, including central or peripheral neurotoxicity, drug-induced liver injury, or thrombocytopenia. The most common AEs related to the gene therapy were nausea, vomiting, and fatigue, which resolved without intervention. No cases of myocarditis or myositis were reported.
RGX-202: A Potential Game-Changer for DMD
RGX-202 is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a novel transgene encoding a shortened but functional microdystrophin protein to muscle cells. This microdystrophin contains the C-Terminal (CT) domain, which preclinical studies suggest improves muscle resistance to contraction-induced damage in dystrophic mice. The pivotal dose for the Phase 3 trial is 2x10^14 GC/kg, based on the Phase 2 data and discussions with the FDA.
"The initiation of our pivotal trial and newly released positive functional data are exciting milestones on our path to rapidly deliver RGX-202, the only next generation gene therapy in pivotal phase, to the Duchenne community," said Curran M. Simpson, president and CEO of REGENXBIO. He added, "The totality of our data demonstrates that RGX-202 provides evidence of improving outcomes for boys with Duchenne and altering the trajectory of this devastating disease, with consistent, robust expression of our novel microdystrophin translating into significant clinical benefit."
Accelerated Approval Pathway
REGENXBIO anticipates submitting a biologics license application (BLA) for RGX-202 in 2026 via the accelerated approval pathway. This pathway allows the FDA to approve drugs for serious conditions that fill an unmet medical need based on a surrogate endpoint, such as microdystrophin expression. The company hopes that the Phase 3 trial will provide sufficient evidence to support accelerated approval and ultimately offer a new treatment option for DMD patients.
Addressing an Unmet Need
DMD is a devastating genetic disorder characterized by progressive muscle degeneration and weakness. Mutations in the dystrophin gene lead to a lack of functional dystrophin protein, which is essential for maintaining muscle integrity. While existing therapies, including Sarepta Therapeutics' Elevidys, offer some benefit, there remains a significant unmet need for more effective treatments, particularly for younger patients. RGX-202 aims to address this need by delivering a functional microdystrophin gene to muscle cells, potentially slowing disease progression and improving patient outcomes.
"There remains a critical need for new therapeutic options for patients with Duchenne muscular dystrophy," said Aravindhan Veerapandiyan, MD, of Arkansas Children's Hospital. "I am very pleased to see the advancement of the RGX-202 program to the pivotal stage, which offers promise for a broader patient population and am highly encouraged by the functional data presented today demonstrating RGX-202's potential to alter the course of the disease."
