REGENXBIO Advances AFFINITY DUCENNE Gene Therapy Trial to Pivotal Stage with Positive Phase 1/2 Results

Curran M. Simpson

According to a recent announcement, REGENXBIO has started dosing in the pivotal phase of its phase 1/2 AFFINITY DUCHENNE trial (NCT05693142), testing its investigational gene therapy RGX-202 for Duchenne muscular dystrophy (DMD). In addition, the company also released positive efficacy and safety data from the phase 1/2 portion of the study, and noted that it anticipates submitting a biologics license application (BLA) in 2026 for accelerated approval.¹

The trial, which began in 2023, includes 2 cohorts of patients, with the lower-dose cohort receiving 1x1014 genome copies (GC)/kg body weight and the higher-dose cohort receiving 2x1014 GC/body weight. The study was then expanded into a phase 1/2/3 trial to support a potential BLA submission. Following a positive end-of-phase 2 meeting with the FDA, the pivotal trial will assess the efficacy of RGX-202 at dose level (2x1014 GC/kg) in approximately 30 ambulatory patients aged 1 and older.

The findings, which include the first functional data of RGX-202, comprised of 12-month data from 3 dose level 1 patients aged 4-10 and 9-month data from 2 dose level 2 (pivotal dose) patients aged 8 to 12. RGX-202, a gene therapy that encodes key regions of naturally occurring dystrophin, resulted in positive impacts on disease trajectory, with treated patients demonstrating stable or improved function on the North Star Ambulatory Assessment (NSAA) and timed function tests relative to a matched external natural history cohort.

Participants in the pivotal dose cohort showed improved performance on the NSAA and timed function tests at nine months, surpassing external natural history controls, with the NSAA mean score increasing by 5.5 points. Similarly, all dose level 1 participants demonstrated improved performance at 12 months, exceeding external natural history controls. Additionally, dose level 1 participants achieved velocity changes in timed tasks that surpassed minimal clinically important difference (MCID) benchmarks at 12 months, a metric referenced by the FDA in the approval of the existing gene therapy.

"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,” Curran M. Simpson, president and chief executive officer at REGENXBIO, said in a statement.¹ "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."

Simpson added, "Based on the strength of the Phase I/II data and our positive discussions and alignment with the FDA, we are quickly advancing RGX-202 toward a BLA filing in 2026 using the accelerated approval pathway. We continue to evaluate opportunities to expand the RGX-202 program to benefit Duchenne patients worldwide."

In terms of biomarker data, results revealed a high expression and transduction of RGX-202 microdystrophin. At dose level 1, RGX-202 microdystrophin percent normal control was 60.6% for the 2 patients aged 4-7 and 10.4% for the 1 patient aged 8-11 years. For dose level 2, investigators observed 77.2% microdystrophin percent normal control in the 1 patient aged 4-7 and 39.7% in the 5 patients aged 8-11. According to REGENXBIO, the microdystrophin expression results in ambulatory patients aged at least 8 years were the highest reported microdystrophin levels across approved or investigational gene therapies.

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Overall, treatment with the gene therapy was considered well tolerated, with no serious adverse events (AEs) or AEs of special interest. The most common drug related AEs, which included nausea, vomiting, and fatigue, were all expected and resolved during the trial. Notably, across the 11 patients in dose level 1, dose level 2, and the younger cohort in dose level 2, there were no cases of myocarditis and no experiences of myositis.

In the pivotal stage of the study, which will be used for its future BLA submission, investigators will use proportion of participants whose RGX-202 microdystrophin expression is at least 10% at week 12 as the primary end point. Other secondary end points will include change from baseline on timed function tests including Time to Stand, 10-minute walk run, and Time to Climb. Additionally, this cohort, which comprises patients aged 1-4 years, will be evaluated using the Peabody Developmental Motor Scale-Third Edition, SV95C, and NSAA as an exploratory end point.

RGX-202, an adeno-associated virus (AAV) vector-based gene therapy, is intended to deliver a novel transgene which contains the functional elements of the C-Terminal (CT) domain seen in natural dystrophin. Presence of the CT domain has been shown in preclinical studies to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice.

Aravindhan Veerapandiyan, MD

"There remains a critical need for new therapeutic options for patients with Duchenne muscular dystrophy,” Aravindhan Veerapandiyan, MD, a pediatric neuromuscular neurologist at Arkansas Children’s Hospital and associate professor of pediatrics at the University of Arkansas for Medical Sciences, said in a statement.¹ "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. The safety, functional, and biomarker data shared today reinforce the positive feedback from families, highlighting improvements in patients' daily activities and underscoring the potential benefits of this treatment."

REFERENCE
1. REGENXBIO INITIATES PIVOTAL PHASE OF AFFINITY DUCHENNE® TRIAL OF RGX-202 GENE THERAPY AND REPORTS POSITIVE FUNCTIONAL DATA. News release. REGENXBIO. November 18, 2024. Accessed December 4, 2024. https://prnewswire.com/news-releases/regenxbio-initiates-pivotal-phase-of-affinity-duchenne-trial-of-rgx-202-gene-therapy-and-reports-positive-functional-data-302307989.html