Viltolarsen (NS-065/NCNP-01) is an experimental therapy that NS Pharma is developing, with its parent company Nippon Shinyaku, to treat Duchenne muscular dystrophy (DMD) resulting from mutations amenable to exon 53 skipping. It is an infusion that doctors administer into the bloodstream.
NS Pharma announced in February 2020 that the U.S. Food and Drug Administration (FDA) accepted its request (called a new drug application or NDA) to review viltolarsen for possible approval. An FDA decision is anticipated in late summer or early autumn 2020.
What is DMD?
Duchenne is the most common form 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. Dystrophin plays a crucial role in muscle health; without it, each contraction damages muscles. People with the disease eventually lose the ability to walk and, eventually, to breathe without assistance.
The DMD gene resides on the X chromosome. Because males have only one X chromosome (inherited from the mother), DMD mostly affects boys. (Females have two X chromosomes — one from each parent — and the second 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. Introns are spacer regions that do not encode for proteins, they separate exons. To make a protein from a gene, cells make a temporary copy of the gene. This temporary copy is called messenger RNA or mRNA. The mRNA undergoes a process called splicing, in which cells remove introns and connect the exons together. The resulting mature mRNA molecule is then ready for cells to use as a template to make a protein.
In some DMD 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. This disrupts the coding sequence of the mRNA, and causes the cell to produce a non-functional dystrophin protein.
How does viltolarsen work?
Viltolarsen contains an artificial piece of mRNA that masks exon 53, causing cells to “skip” this exon when they are making mature mRNA. 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 a cell’s protein-making machinery to synthesize a shorter but working dystrophin protein.
Because viltolarsen is specific to exon 53, the treatment is effective only in those 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 once-weekly viltolarsen for six months against placebo in 16 boys with DMD who were still able to walk. All were ages 4 to 10, and had a confirmed mutation amenable to exon 53 skipping.
Trial results demonstrated that viltolarsen restored dystrophin production in the patients’ muscles after 20 to 24 weeks of infusion. Patients reported mild and moderate side effects, mostly often cough and upper respiratory tract infection. None were severe enough to cause anyone taking part to leave the study.
A Phase 1/2 clinical trial (Japic CTI-163291) evaluated viltolarsen in 16 boys with DMD, ages 5 to 12, in Japan. Nippon Shinyaku reported that treatment led to increases in dystrophin protein in muscle in 14 patients, according to a press release. Researchers also observed a tendency toward greater muscle strength in patients on the treatment’s higher, 80 mg/kg dose. No serious side effects were reported.
Ongoing clinical trials
An open-label extension (NCT03167255) of the NCT02740972 trial is ongoing in the U.S. and Canada, with all of the 16 children who enrolled in the parent study continuing with viltolarsen, once a week by intravenous infusion, for an additional 144 weeks (about three years). Researchers are assessing the treatment’s safety and effectiveness (measured via changes in time to stand), and the trial is due to conclude in December 2020.
A Phase 3 clinical trial (NCT04060199), called RACER53, is currently recruiting boys ages 4 to 7 with DMD, who are still able to walk, to further assess viltolarsen’s safety and effectiveness. The trial intends to enroll up to 74 patients at multiple sites, including the US, Japan and select countries across Asia and Europe; information is available here. Researchers will randomly assign patients to either once-weekly infusions of viltolarsen at 80 mg/kg, or a placebo, for up to 48 weeks.
This study’s primary goals are changes in muscle strength and function, as measured by the time it takes patients to stand. Secondary outcome measures include time to walk or run a set distance, as well as measures of range of motion. Researchers will also take blood samples to determine how the body metabolizes viltolarsen. This Phase 3 study is expected to be complete in December 2024.
The FDA designated viltolarsen a potential rare pediatric disease treatment and an orphan drug as did the European Commission (EC) and placed it on fast-track development. Japan gave it a SAKIGAKE designation and orphan drug title.
Last updated: June 12, 2020
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