VCA-894A granted FDA’s orphan drug status for treating CMT2S

Therapy was designed to target a cryptic splice site variant that causes the disease

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The U.S. Food and Drug Administration (FDA) has granted orphan drug status to Vanda Pharmaceuticals’ VCA-894A for treating Charcot-Marie-Tooth disease type 2S (CMT2S).

An orphan drug designation seeks to encourage the development of therapies for rare diseases — those affecting fewer than 200,000 people in the U.S. — through benefits such as seven years of market exclusivity if approved, development support, and exemption from FDA fees.

“This designation is an important milestone, which we believe may enable the development of individualized treatments tailored to one’s genetic variants for patients with CMT2S,” Mihael H. Polymeropoulos, MD, CEO and chairman of the board at Vanda, said in a company press release.

Charcot-Marie-Tooth disease (CMT) comprises a group of inherited neurological disorders of the peripheral nervous system, the network of nerves that control movement and sensation (touch, heat, cold) to the arms and legs. It’s mainly divided into demyelinating CMT, also known as CMT type 1, and axonal CMT, or CMT type 2 (CMT2).

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Treating CMT2S with VCA-894A

CMT2S is caused by mutations in both copies of the IGHMBP2 gene, which contains instructions for a protein of the same name that has key role in protein production and cell division. The disease typically manifests in early childhood, causing progressive muscle weakness and wasting in both the upper and lower limbs.

VCA-894A is a so-called antisense oligonucleotide, or ASO, a type of small lab-made molecule that can interfere with the process by which a gene is expressed to generate a protein.” Specifically, ASOs complement a target RNA, a molecule generated from DNA that serves as a template for protein production. According to Vanda, ASOs enable the personalized treatment of rare disease by modulating gene activity.

VCA-894A was designed to target a cryptic splice site variant that causes CMT2S. Such mutations likely lead to CMT2S by the loss of motor neurons (nerve cells) and the deterioration of the peripheral nervous system, according to the company.

A splice site variant is a genetic change that can disrupt a process called RNA splicing, wherein immature RNA molecules are processed by removing small bits of sequence, called introns, and connecting the remaining exons. Such variants alter the protein-coding sequence. Cryptic splice sites are not typically used in normal RNA molecules and are only selected due to a mutation.