Viltolarsen Raises Dystrophin Levels, Aids Muscles in DMD Boys in Phase 2 Trial

NS Pharma’s lead candidate viltolarsen safely and effectively increases dystrophin levels and promotes improvements in boys with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping, final data from a Phase 2 trial show.

“As a pediatric neurologist who specializes in the treatment of DMD, I am encouraged by the dystrophin increases observed in this study and the potential of viltolarsen to address the underlying cause of DMD,” Vamshi Rao, MD, a study author and trial investigator at Ann & Robert H. Lurie Children’s Hospital of Chicago, said in a press release.

The trial’s results, “Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A Phase 2 Randomized Clinical Trial,” were published in the journal JAMA Neurology.

These findings are being confirmed in up to 74 boys (ages 4–7) with DMD amenable to exon 53 skipping in the Phase 3 RACER53 trial (NCT04060199). This international study, which recently enrolled its first patient in Japan, is currently recruiting in the U.S., Canada, Europe and elsewhere; information on contacts and clinical sites can be found here.

DMD is caused by mutations in the DMD gene, resulting in no to very little production of dystrophin, a protein that acts like an anchor in muscle cells to keep them together and connect them with surrounding structures.

Viltolarsen (NS-065/NCNP-01) is an exon-skipping therapy designed to treat DMD patients whose disease-causing mutations are amenable to exon 53 skipping, which accounts for about 8% of all Duchenne cases. Exons are like pieces of a puzzle that contain information to produce proteins.

Injected directly into the bloodstream, viltolarsen works by “masking” exon 53 and allowing the other pieces of the puzzle in the DMD gene to attach in a way that enables the production of a shorter but functional version of dystrophin.

The dose-finding Phase 2 clinical trial (NCT02740972) evaluated viltolarsen in 16 boys (ages 4–9) with Duchenne amenable to exon 53 skipping and able to walk.

Participants, recruited in the U.S. and Canada, had a mean age of 7.4 and most (94%) were white. They were randomly assigned to either 40 mg/kg (low dose; eight boys) or 80 mg/kg (high dose; eight boys) of viltolarsen, once a week for 24 weeks (nearly six months).

Two boys in the low-dose and three in the high-dose group received a placebo for the study’s first four weeks, after which they were switched to their respective viltolarsen dose.

The trial’s main goals were assessing treatment safety and tolerability, and dystrophin production in muscle biopsies collected at the study’s beginning and end (at 24 weeks).

Secondary goals included additional dystrophin-associated measures and assessment of muscle function and strength, which were compared with 65 age-matched boys from a natural history study (a study of disease course in patients not using disease-modifying therapies).

Results showed that both doses of viltolarsen significantly increased dystrophin levels, with boys now producing a mean of 5.7% (low dose) and 5.9% (high dose) of normal dystrophin levels. Most boys (88% or 14) reached dystrophin levels greater than 3% of normal.

“These increases were seen in patients as young as four years of age and after six months or less of treatment, which underscores the impressive results seen in this study,” said Paula Clemens, MD, the study’s lead author and an investigator at the University of Pittsburgh School of Medicine.

A significant increase in the percentage of dystrophin-positive muscle fibers was also seen in both dose groups, with patients treated with the higher dose showing a greater increase.

Compared to the matched control group, all 16 boys showed significant improvements in timed function tests, including time to stand from supine (lying with the face and torso facing up), time to run or walk 10 meters, and the six-minute walk test, which measures the distance a person can walk in six minutes.

No significant differences, however, were found between viltolarsen-treated boys and the control group in time to climb four stairs, the North Star Ambulatory Assessment score (which assesses motor abilities), and muscle strength.

“Viltolarsen-treated participants showed improvement or stabilization of function,” the researchers wrote, “whereas the [external matched group] exhibited a decline in all timed function tests, except for time to climb 4 stairs.”

Viltolarsen was well-tolerated, with no reports of serious adverse events or deaths during the study. There also were no dose reductions, interruptions, or discontinuations due to treatment side effects, the most common of which were cough, common cold, nasal congestion, bruising, joint pain, diarrhea, and vomiting.

After completing this trial’s 24 weeks, patients were invited to continue treatment in an open-label extension study (NCT03167255) that runs through August 2021.

“We are deeply committed to the development of viltolarsen and offering healthier futures to DMD patients and families,” said Tsugio Tanaka, the president of NS Pharma (a subsidiary of Nippon Shinyaku).

Viltolarsen was approved in Japan to treat DMD patients amenable to exon 53 skipping in March. It is under priority review by the U.S. Food and Drug Administration for the same indication, with a decision expected between July and September. For now, eligible patients in the U.S. may request to be treated with viltolarsen under an expanded access program.

“Based on these results we are optimistic that, if it is approved [worldwide], viltolarsen will become an important new treatment option for DMD patients and healthcare providers,” Tanaka said.