Viltolarsen (NS-065/NCNP-01) is an experimental therapy being developed by NS Pharma, with its parent company Nippon Shinyaku, to treat Duchenne muscular dystrophy (DMD) with mutations amenable to exon 53 skipping.
It is administered as an infusion into the bloodstream.
NS Pharma announced in February 2020 that the FDA has accepted its New Drug Application (NDA) for viltolarsen under priority review. A decision on approval from the FDA is anticipated in the third quarter of 2020.
What is Duchenne muscular dystrophy?
DMD is a type of muscular dystrophy — a group of genetic disorders characterized by progressive muscle weakness and wasting. It is caused by mutations in the DMD gene, which provides the instructions necessary to make a structural protein called dystrophin that plays a crucial role in muscle health. Without dystrophin, muscles are easily damaged at each contraction. Affected people eventually lose the ability to walk, and even breathe without assistance.
The DMD gene is situated on the X chromosome. Because boys have only one X chromosome, Duchenne mostly affects boys. (The second X chromosome in girls can compensate for mutations in the DMD gene.)
Most genes are made of so-called exons and introns. Exons are pieces of genetic material that encode for proteins. They are separated by spacer regions, called introns, that do not encode for proteins. In order to make a protein from a gene, a temporary copy of the gene is made. This temporary copy is called messenger RNA or mRNA. The mRNA undergoes a process called splicing, in which the introns are removed and the exons are connected together. The resulting mature mRNA molecule is then ready to be used as a template for making protein by the cell.
In some Duchenne MD cases, certain regions of the DMD gene are missing. The remaining exons, as a result, do not fit together as they should when the introns are removed from the mRNA. This disrupts the coding sequence of the mRNA and leads to a non-functional dystrophin protein being produced.
How does viltolarsen work?
Viltolarsen contains an artificial piece of mRNA that masks exon 53, causing this exon to be “skipped” when mature mRNA is being made. This skip restores the so-called “reading frame” of the mRNA molecule. In other words, it ensures that the remaining exons fit together again, allowing the protein-making machinery of the cell to synthesize a shorter but still working dystrophin protein.
Because viltolarsen is specific to exon 53, the treatment is only effective in a subgroup of DMD patients who have a mutation that is amenable to exon 53 skipping.
Viltolarsen in clinical trials
A Phase 2 clinical trial (NCT02740972) assessed the safety and tolerability of viltolarsen administered once a week for six months against placebo in eight boys with DMD who were still able to walk. All were between ages 4 and 10, and all had a confirmed mutation amenable to exon 53 skipping.
Results of the trial demonstrated that viltolarsen restored dystrophin production in the patients’ muscles after 20 to 24 weeks of infusion. Mild and moderate adverse events were reported, but none were severe enough for anyone taking part to leave the study.
An open-label extension (NCT03167255) of this trial is ongoing in the U.S. and Canada, with patients receiving viltolarsen for an additional 144 weeks. Safety and tolerability are being assessed throughout the trial, which is expected to end in December 2020.
A Phase 1/2 clinical trial (Japic CTI-163291) evaluated viltolarsen in patients in Japan. In a press release, Nippon Shinyaku indicated that increases in dystrophin protein as a result of treatment were seen in 14 out of 16 boys with DMD, ages 5 to 12. A tendency toward greater muscle strength was also observed in patients on the treatment’s higher, 80 mg/kg, dose. No serious side effects were reported.
A Phase 3 clinical trial (NCT04060199), called RACER53, is enrolling ambulatory boys with DMD, ages 4 to 7, to further assess viltolarsen’s safety and efficacy. The trial aims to recruit 74 patients at multiple international sites including Japan and the US, who will be randomly assigned to once-weekly infusions of viltolarsen at 80 mg/kg or to a placebo for up to 48 weeks. Contact and enrollment information are available here.
This study’s primary goals are changes in muscle strength and function, assessed by measuring the time it takes patients to stand. Secondary outcome measures will include time to walk or run a set distance, as well as measures of range of motion. Blood samples will be taken to determine how viltolarsen is metabolized in the body.
RACER53 is expected to conclude in late 2024.
Viltolarsen has been designated a potential treatment for a rare pediatric disease and an orphan drug, and placed on fast-track development by the U.S. Food and Drug Administration (FDA), and given a SAKIGAKE designation and orphan drug title in Japan.
Last updated: Feb. 12, 2020
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