Puzzling Preliminary Results Announced for Viltolarsen’s Confirmatory Trial in Duchenne Muscular Dystrophy

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Following the mixed results, NS Pharma is working with the FDA to determine how to proceed with viltolarsen.

According to an announcement from NS Pharma, preliminary results from the phase 3 RACER53 study (NCT04060199), a confirmatory trial of viltolarsen (Viltepso; NS Pharma), showed no significant difference between active and placebo groups on the primary end point of velocity after 48 weeks. Despite this, the company believes there may be additional factors at play for why both the viltolarsen and placebo-treated groups showed increases in Time to Stand from Supine.1

NS Pharma is currently conducting further detailed analyses, including post-hoc data analyses, and plans to work closely with regulatory authorities to determine how to proceed based on the results of the analysis and in the best interests of patients. Viltolarsen, an exon 53 skipping therapy delivered via weekly intravenous infusion, was approved by the FDA in 2020 under the accelerated approval pathway, becoming the second therapy to reach market for patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.

RACER53, a 77-patient study assessing once weekly 80 mg/kg dose of viltolarsen vs placebo, was intended to confirm the clinical benefit of viltolarsen. Preliminary safety data from the 48-week trial showed that all adverse events for viltolarsen were mild or moderate in nature. No treatment-emergent AEs led to discontinuation of the drug throughout the study.

"We are currently conducting further detailed data analyses and identifying factors that may have influenced the results (e.g. age, treatment period, and effect of concomitant drugs including glucocorticoid therapy),” Tsugio Tanaka, MSc, president at NS Pharma, said in a statement.1 "Considering the results of prior clinical studies, we have confidence that viltolarsen can be a beneficial treatment for amenable patients with Duchenne."

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Viltolarsen was approved based on data from a phase 2 clinical trial (NCT02740972) and its long-term extension, details of which were originally published in JAMA Neurology in 2020. Among 16 participants age 4 to 9, significant drug-induced dystrophin production was observed in both viltolarsen dose cohorts (40 mg/kg per week: mean, 5.7% [range, 3.2—10.3] of normal; 80 mg/kg per week: mean, 5.9% [range, 1.1–14.4] of normal), with 15 (94%) patients achieving dystrophin levels greater than 2% of normal and 14 of 16 (88%) achieving levels greater than 3% of normal.2,3

Years later, data from the 4-year long-term extension were published in the Journal of Neuromuscular Diseases. All 16 participants from the initial 24-week study enrolled in the extension study. For the primary efficacy outcome, viltolarsen-treated patients showed stabilization of motor function over the first 2 years and significant slowing of disease progression over the following 2 years compared with the Cooperative International Neuromuscular Research Group Duchenne Natural History Study control group which declined.4

To date, that was the only study of an exon 53 skipping agent used to demonstrate significant functional benefit over 4 years with comparison to a group-matched, prospectively collected, control group. “Based on the efficacy and safety data reported here, combined with the previously reported significant increase in dystrophin levels in these same participants, viltolarsen can be an important part of the treatment strategy for DMD patients who have mutations that are amenable to exon 53 skipping,” the study authors wrote.

At the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, data from that same study showed that viltolarsen-treated patients had significant improvement of pulmonary function compared with standard of care treatment after 48 weeks. Overall, patients treated with active therapy had a 5.15% (±2.3) mean change from baseline in percent predicted forced vital capacity compared with a decrease of –0.93% (±1.5) for those on standard-of-care treatment (P = .03). Notably, viltolarsen-treated patients also demonstrated a sustained performance of upper limb 2.0 over the treatment period.5

REFERENCES
1. NS Pharma Shares Preliminary Results of Viltolarsen (NS-065 / NCNP-01) Phase 3 Clinical Trial (RACER53 Study). NS Pharma. May 27, 2024. Accessed May 28, 2024. https://www.biospace.com/article/releases/ns-pharma-shares-preliminary-results-of-viltolarsen-ns-065-ncnp-01-phase-3-clinical-trial-racer53-study-/
2. FDA approves targeted treatment for rare duchenne muscular dystrophy mutation. News release. US Food and Drug Administration. August 12, 2020. Accessed May 28, 2024. https://www.prnewswire.com/news-releases/fda-approves-targeted-treatment-for-rare-duchenne-muscular-dystrophy-mutation-301111213.html
3. Clemens PR, Rao VK, Connolly AM, et al. Safety, tolerability, and efficacy of viltolarsen in boys with duchenne muscular dystrophy amenable to exon 53 skipping: a phase 2 randomized clinical trial. JAMA Neurol. 2020;77(8):982—991. doi:10.1001/jamaneurol.2020.1264
4. Clemens PR, Vamshi R, Connolly AM, et al. Efficacy and safety of viltolarsen in boys with Duchenne muscular dystrophy: results from the phase 2, open-label, 4-year extension study.
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