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Viltolarsen Well Tolerated in Patients With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping

Viltolarsen was both safe and effective for patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping, suggesting a potential treatment option, according to a phase 2 randomized clinical trial published online on May 26 in JAMA Neurology

Viltolarsen is an antisense oligonucleotide administered intraveneously as part of exon skipping therapy. Exon skipping therapy usually involves changing RNA splicing by forcing the exclusion of an exon near the DMD variant. This shifts a DMD out-of-frame variant to a milder form of muscular dystrophy—Becker muscular dystrophy—contributing to dystrophin protein production, noted Paula R. Clemens, MD, of the University of Pittsburgh School of Medicine and colleagues.

The researchers set out to assess the efficacy, tolerability, and safety of viltolarsen among patients with DMD amenable to exon 53 skipping. As primary outcomes, they wanted to determine if the therapy led to de novo dystrophin protein production in bicep muscles as measured by Western blot, and to assess its tolerability and safety. Secondary outcomes included clinical muscle function and strength, protein production, and additional evaluation of dystrophin mRNA.

The study participants were boys age 4 to 9 years with a confirmed diagnosis of DMD amenable to exon 53 skipping.

"To our knowledge, this is the first report of the efficacy and safety of exon-skipping therapy in patients with DMD younger than 5 years. Patients as young as 4 years exhibited improvements in dystrophin levels and timed motor tests following viltolarsen treatment," wrote the study authors.

Boys with DMD showed significant treatment-related dystrophin production in both the low dose (40mg/kg per week) and high dose  (80mg/kg week) viltolarsen cohorts, the researchers reported.

Moreover, viltolarsen was well-tolerated overall, and timed function assessments showed that the drug offered therapy-related clinical benefit, the authors added. 

Current treatment options for DMD are primarily used for symptom management, the researchers emphasized. Exon skipping therapy may provide the opportunity to restore some degrees of functional dystrophin, which is deficient in the disease, they added.

Preclinical research has demonstrated that viltolarsen raises dystrophin protein levels and strongly promotes dose-dependent exon 53 skipping during pre-mRNA splicing. Recent research has shown the safety and efficacy of viltolarsen in nonambulatory and ambulatory patients with DMD, the investigators continued.

The researchers assessed 16 boys with DMD at sites in the United States and Canada. Mean age was 7.4 years, and the cohort was 94 percent white.

The study involved a one month randomized clinical safety trial and a subsequent five month open-label therapy period for patients, who were four to nine years of age, with DMD amenable to exon 53 skipping. The research team gathered data from December 2016 to February 2018, and assessed it from April 2018 to May 2019.

Limitations of the study included the small cohort size and that the use of an external control cohort was less rigorous than that used in a placebo-controlled randomized design study. Another limitation of the study was that over the time of the investigation improvements in muscle function varied, the authors acknowledged.

Disclosures: Clemens disclosed relationships with NS Pharma, Amicus Therapeutics, Sanofi

Genzyme, TRiNDS, ReveraGen BioPharma, Spark Therapeutics, Pfizer, Roche, and UCB.

Link Up For More Information:

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; Epub 2020 May 26.