Phase 2 Galactic53 Data Point to Viltolarsen’s Impact on Respiratory and Motor Function in DMD

Amy Harper, MD

A recently presented analysis of the phase 2 Galactic53 clinical trial (NCT04956289) showed that treatment with viltolarsen (Viltepso; NS Pharma), an FDA-approved exon-skipping therapy, provides respiratory and motor function benefits for ambulatory and nonambulatory patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 53 skipping.¹

Presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held October 15-18, in Savannah, Georgia, this was the first study of viltolarsen evaluating pulmonary and upper limb function in both ambulatory and nonambulatory patients with DMD. In total, the trial comprised of 20 patients aged at least 8 years old who were treated with viltolarsen 80 mg/kg/week. Investigators compared outcomes of treated patients to controls (n = 48) from the CINRG Duchenne Natural History Study.

Led by Amy Harper, MD, an associate professor at Virginia Commonwealth University, percent predicted forced vital capacity (FVC%p) was higher at week 49 for viltolarsen-treated patients in comparison with controls. These findings were consistent for both ambulatory (n = 10; 8.3% [±3.3] vs 1.2% [2.1]) and nonambulatory (n = 10; 1.6% [±3.0] vs –3.2% [±2.0]) participants, respectively. At week 49, PCF was higher for viltolarsen compared with the DNHS controls in both ambulatory and nonambulatory participants, while performance of the upper limb (PUL) 2.0 scores remained stable with treatment.

Coming into the study, the baseline characteristics of those on viltolarsen and those included in the control cohort were well-matched. Overall, 19 of the 20 viltolarsen-treated patients reported treatment-emergent adverse events (TEAEs), 4 of which were treatment-related. During the study, no serious AEs were reported, and no participants discontinued.

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A few weeks before AANEM 2024, investigators published results from GALACTIC53 in Scientific Reports. Additional data revealed that 90% (9 of 10) of nonambulatory participants receiving viltolarsen had an increase or stabilization in FVC%p from baseline, and 60% (6 of 10) of participants maintained FVC%p values greater than 50% at week 49. At that time point, the least square (LS) mean change from baseline in the total North Star Ambulatory Assessment (NSAA) score for ambulatory participants in the viltolarsen group was +2.2 (SE, 0.8) points, compared with –2.5 (SE, 1.4) for the CINRG DNHS cohort. Of note, the NSAA was added later in the CINRG DNHS study and thus, only 3 participants had data available for comparison with the viltolarsen group.²

This study had several limitations common to early-phase and rare disease studies, including a small sample size and the absence of a placebo control group. While the CINRG DNHS control cohort provides a useful comparison in a phase II study of a rare disease, it is less rigorous than a placebo-controlled trial. The control group was matched to viltolarsen participants based on age, ambulatory status, and steroid use, but the selection of controls by ambulatory status was not prespecified. Additionally, the CINRG DNHS control data was collected between 2006 and 2016, five years before Galactic53 began; however, there were no significant changes in DMD care guidelines during this time.

Viltolarsen was approved under the accelerated approval pathway in 2020 using data from a phase 2 study as the leading evidence. Earlier this year, the company announced mixed results around its phase 3 RACER53 study (NCT04060199), a trial aimed to confirm the clinical benefit of the therapy.³

The trial, which featured 77 patients with DMD, showed no significant difference between viltolarsen and placebo on the primary end point of velocity after 48 weeks. Preliminary safety data showed that all AEs for viltolarsen were mild or moderate in nature. At the time, NS Pharma wrote that there may be additional factors at play that may explain the some of the puzzling results. The company stated it will continue to conduct further analyses, including post-hoc data analyses, and plans to work with regulatory authorities to determine how to proceed based on the results of the analysis and in the best interests of patients.

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REFERENCES
1. Harper AD, Orevutera NK, Crozier Ra, Magnus K, Clemens PA. Safety, pulmonary function, and motor function in ambulatory and nonambulatory participants with Duchenne muscular dystrophy treated with viltolarsen: results from the Galactic53 clinical trial. Presented at: 2024 AANEM annual meeting; October 15-18; Savannah, GA. ABSTRACT 253
2. Harper AD, Topaloglu H, Mercuri E, et al. Safety and efficacy of viltolarsen in ambulatory and nonambulatory males with Duchenne muscular dystrophy. Scientific Reports. 2024;14:23488. doi:10.1038/s41598-024-70783-y
3. NS Pharma Shares Preliminary Results of Viltolarsen (NS-065 / NCNP-01) Phase 3 Clinical Trial (RACER53 Study). NS Pharma. May 27, 2024. Accessed November 26, 2024. https://www.biospace.com/article/releases/ns-pharma-shares-preliminary-results-of-viltolarsen-ns-065-ncnp-01-phase-3-clinical-trial-racer53-study-/