Viltolarsen, known by the brand name Viltepso, is a specialized medication for Duchenne muscular dystrophy (DMD). It represents an advancement in treating this genetic muscle-wasting condition. The drug aims to mitigate the effects of DMD in specific patients by targeting the underlying genetic defect. It is part of a newer class of therapies designed to restore some level of protein function.
Understanding Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a genetic disorder that primarily affects males. It is characterized by progressive muscle weakness and degeneration. This condition arises from mutations in the dystrophin gene, located on the X chromosome, which is responsible for producing the dystrophin protein.
Dystrophin is a large protein that maintains the structure and function of muscle cells. It acts as a connection between the internal framework of a muscle cell and its outer membrane, protecting muscle fibers from damage during contraction and relaxation. Without adequate functional dystrophin, muscle cells are more susceptible to injury, leading to their gradual replacement by fibrous and fatty tissue, which results in loss of muscle strength and function. Over time, this damage leads to significant physical limitations, including loss of ambulation, and can eventually affect heart and respiratory muscles, leading to life-threatening complications.
How Viltolarsen Works: The Science of Exon Skipping
Genes are composed of segments called exons, which contain instructions for building proteins, interspersed with non-coding regions called introns. During protein production, the cell’s machinery reads the gene and splices together the exons to form a complete messenger RNA (mRNA) molecule, which serves as a blueprint for the protein. In DMD, certain genetic mutations, often deletions of one or more exons, disrupt this assembly process, leading to a “frameshift” error. This frameshift prevents the cell from reading the genetic instructions correctly, resulting in a non-functional or severely truncated dystrophin protein.
Viltolarsen works through a mechanism called “exon skipping” to correct this frameshift error. It is an antisense oligonucleotide (ASO), a short, synthetic strand of genetic material that binds to specific RNA sequences. For patients with DMD mutations amenable to exon 53 skipping, viltolarsen specifically targets exon 53 of the dystrophin pre-mRNA.
When viltolarsen binds to exon 53, it “masks” this exon from the cellular machinery involved in splicing. This masking causes the cell to skip over exon 53 during mRNA assembly. This allows the remaining exons to be joined, restoring the “reading frame.” The cell can then produce a shortened, but partially functional, dystrophin protein. This truncated dystrophin, though not full-length, retains functional domains that stabilize muscle fibers and lessen muscle damage.
Viltolarsen is for patients with a confirmed mutation in the dystrophin gene amenable to exon 53 skipping, which accounts for about 8% to 10% of all DMD patients.
Benefits and Practical Considerations
Viltolarsen aims to increase dystrophin protein production in patients with specific genetic mutations. Clinical trials have shown that viltolarsen can significantly increase dystrophin levels in muscle tissue. For instance, in a Phase 2 clinical trial involving boys aged 4 to 9, dystrophin levels increased from 0.6% of normal at baseline to approximately 5.9% of normal after 25 weeks. Most participants (88%) achieved dystrophin levels greater than 3% of normal.
Studies have also evaluated the drug’s impact on motor function. A four-year extension study showed viltolarsen-treated participants had stabilized motor function over the first two years and significantly slowed disease progression over the next two years, compared to a natural history control group. For example, the mean time to run or walk 10 meters increased by 2 seconds in the viltolarsen-treated group, compared to a 6-second increase in the control group. Improvements were also observed in the time to stand from a lying position and the time to climb four stairs.
Viltolarsen, marketed as Viltepso, is administered as an intravenous (IV) infusion over 60 minutes, typically once weekly. The U.S. Food and Drug Administration (FDA) granted accelerated approval for viltolarsen in August 2020, based on the observed increase in dystrophin production. Accelerated approval allows earlier access to drugs for serious conditions when there is a reasonable likelihood of clinical benefit, but continued approval may depend on further verification in confirmatory trials.
Viltolarsen has been well-tolerated in clinical studies. Common side effects include upper respiratory tract infection, injection site reactions, cough, and fever. While kidney toxicity was not frequently observed in clinical trials, it is a potential concern with some antisense oligonucleotides, and kidney function should be monitored in patients receiving viltolarsen. No serious adverse events or treatment discontinuations due to side effects were reported in the long-term extension study.