RGX-202 Gene Therapy Reduces CK, Yields Detectable Microdystrophin in Patients With DMD


RGX-202 delivers a slightly larger form of microdystrophin than other gene therapies, including the CT domain of dystrophin.

Aravindhan Veerapandiyan, MD

Aravindhan Veerapandiyan, MD

Credit: UAMS Health

RGX-202 investigational gene therapy was well-tolerated, reduced creatine kinase (CK) levels and produced detectable microdystrophin in patients with Duchenne muscular dystrophy (DMD).

Data on RGX-202 from the AFFINITY DUCHENNE phase 1/2 trial (NCT05693142) were presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, by Aravindhan Veerapandiyan, MD, assistant professor, pediatric neurology, University of Arkansas.

“The absence of functional dystrophin results in muscle cell damage during contraction, inflammation, fibrofatty replacement of muscle tissue, and ultimately cell death,” Veerapandiyan and colleagues wrote in their poster. “This reflects clinically in progressive weakness of skeletal muscle, eventual loss of ambulation, and weakness of cardiac muscle and the diaphragm which can present as cardiomyopathy and respiratory failure.”

The poster went over preclinical data that showed dose-dependent improvements in muscle function in mdx mice compared to non-treated mdx mice. In vehicle treated BL10 wildtype mice, a 2x1014 GC/kg dose (dose level 2) restored grip strength and treadmill performance.

“RGX-292 is the only gene therapy designed to deliver a transgene for a microdystrophin that includes the functional elements of the C-terminal domain found in naturally occurring dystrophin,” Veerapandiyan and colleagues wrote.

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Clinical Takeaways

  1. RGX-202 gene therapy showed good tolerance in patients with DMD, with no significant serious adverse events reported, suggestive of a good safety profile in this population.
  2. Biomarker data revealed reductions in creatine kinase levels and notable microdystrophin expression in treated patients, indicating potential therapeutic benefits.
  3. With promising results from the AFFINITY study, including robust microdystrophin expression and sarcolemma localization, RGX-202 is poised for further evaluation.

Data from the AFFINITY study were from 3 participants aged 4.4 to 12.1 years when treated with dose level 1 (1x1014 gc/kg) and 2 participants aged 8.1 years to 12.1 years when treated with dose level 2 of RGX-202 delivered via intravenous infusion. Post-therapy follow-up is 3 weeks to 9 months as of the data cutoff date of February 6, 2024. All patients that reached 3-month follow-up have completed the immunosuppression regimen of eculizumab, sirolimus, and corticosteroids as per study protocol.

The therapy has been well-tolerated in these patients with no significant serious adverse events.Biomarker data were available for 3 participants, with ages 4.4, 10.5, and 6.6 years at dosing. These patients had Western Blot expression of 38.8%, 11.1%, and 83.4% of normal at 3 months, respectively, and CK level reductions of –43%, -44%, and –93% from baseline at10 weeks.

“Robust RGX-202 microdystrophin expression was observed at 3 months, with comparable results obtained via Western Blot and LC-MS,” Veerapandiyan and colleagues wrote. “RGX-202 microdystrophin is localized to the sarcolemma at 3 months.”

Immunofluorescence was used to detect RGX-202 localization to the sarcolemma, and capillary Western Blot analysis was performed on biceps brachii biopsies collected at baseline and at 12 weeks post-administration.

Following these 5 patients treated with dose levels 1 and 2 of RGX-202, REGENXBIO plans to proceed the AFFINITY DUCHENNE study to an expansion cohort at dose level 2. The study is enrolling boys with genetically confirmed DMD aged 4 to 11 years. Participants must be able to perform a 100-meter walk without assistive devices and must have no preexisting antibodies to AAV8.

“We're bringing into the busy arena of gene therapy for DMD a new configuration, a product which we think has interesting differentiation. We're using AAV8 as a serotype and using our own microdystrophin, which has been designed and optimized very carefully. For instance, this is a microdystrophin which is slightly larger than the ones that have been used so far,” Olivier Danos, PhD, chief scientific officer, REGENXBIO, previously told CGTLive®.

Click here to view more coverage of the 2024 MDA Conference.

Veerapandiyan A, Rao V, Dastgir J, et al. RGX-202, an investigational gene therapy for the treatment of Duchenne muscular dystrophy: Interim clinical data. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Orlando, FL. Poster #M150
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