VCA-894A, a novel antisense oligonucleotide, exhibits a mechanism of action that specifically targets a cryptic splice site variant within immunoglobulin mu-binding protein 2.
According to a recent announcement, the FDA has approved an investigational new drug application (IND) to study Vanda Pharmaceuticals’ investigational agent VCA-894A, an antisense oligonucleotide (ASO), in patients with Charcot-Marie-Tooth disease type 2S (CMT2S).1
In the update, Vanda did not release any details on the design of the potential trial and how it would go about assessing the candidate therapy. VCA-894A has a mechanism of action that specifically targets a cryptic splice site variant within immunoglobulin mu-binding protein 2 (IGHMBP2), otherwise considered the root cause of CMT2S. In mid-2023, the agent received orphan drug designation by the FDA.
"This is an important milestone in the pursuit of personalized medicine, which has the potential to enable the development of treatments tailored to one's genetic variants, in this case specifically for a patient with CMT2S causing genetic mutations," Mihael H. Polymeropoulos, MD, president, chief executive officer, and chairman of Vanda’s Board, said in a statement.1
CMT is a disease of the peripheral nerves that control muscles that can cause progressive loss of function and sensation in the hands, arms, legs, and feet. Considered a form of inherited peripheral neuropathy, CMT affects 133,000 people in the United States and roughly 3 million worldwide. The prevalence of the CMT2S variant is estimated to be less than 1 in 1,000,000 worldwide.
Although there is no approved disease-modifying therapy for CMT, physical therapy and moderate activity have been shown to help maintain muscle strength, endurance, and flexibility. When medically indicated, orthopedic surgery can correct deformity and help maintain mobility and function.
CMT encompasses a heterogeneous group of disorders that are classified into a demyelinating and an axonal variety: CMT1 for demyelinating neuropathies with autosomal dominant inheritance, CMT4 for autosomal recessive demyelinating forms, and CMT2 for primary axonal types with autosomal dominant or recessive transmission. Pure motor forms of CMT are characterized by the preservation of sensory nerves and are labelled distal Hereditary Motor Neuropathies (dHMNs), which can have autosomal dominant, autosomal recessive, or X-linked transmission.2
PXT3003, a novel fixed-dose synergistic combination of baclofen, naltrexone, and sorbitol, is the most advanced CMT agent in the pipeline, as a second phase 3 trial is ongoing. Otherwise known as the PREMIER study, this international, double-blind, 2-arm, placebo-controlled trial includes approximately 350 patients with CMT1A, the most common form of CMT, to assess the safety and efficacy of PXT3003 over a 15-month period.3
The dose of PXT3003 tested in PREMIER corresponds to the high dose tested in the pivotal phase 3 trial, PLEO-CMT (NCT02579759). That study randomly assigned 323 individuals with mild to moderate CMT1A to either 5 mL of high- or low-dose PXT3003 or placebo, twice daily for up to 15 months, with change in ONLS score at 12 and 15 months as the primary end point. The high-dose treatment arm was prematurely stopped in September 2017 because of an unexpected formulation issue, after which the FDA and European Medicines Agency requested an additional phase 3 study to confirm the efficacy and safety of PXT3003, leading to PREMIER.4
In December 2023, topline findings from PREMIER did not confirm the previous data. Using the Overall Neuropathy Limitation Scale (ONLS), patients with mild-to-moderate CMT1A experienced improvement on both treatment and placebo, rather than the slow deterioration typical of CMT1A’s natural progression. The unexpected improvement in the placebo group complicated the results, and increased the questions surrounding ONLS as a relevant end point in a short-term study.
Additional data suggested no deterioration in the condition of patients under the treatment, considered a positive sign according to the company. In addition, the trial reaffirmed the safety profile of the PXT3003 as a potential treatment for CMT. Pharnext plans to continue to analyze the data, particularly in collaboration with potential partners, and assess the next steps toward potential marketing authorization.5