Vanda Pharmaceuticals announces the publication of an article titled "Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S

WASHINGTON, Feb. 24, 2025 — Vanda Pharmaceuticals Inc. (Vanda) (Nasdaq: VNDA) today announced the publication of an article entitled "Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S" in Molecular Therapy Nucleic Acids1, a Cell Press partner journal, that describes the development of a novel antisense oligonucleotide (ASO) therapeutic, VCA-894A, for a patient with a rare variant in the IGHMBP2 gene causing Charcot-Marie-Tooth disease Type 2S (CMT2S).

In 1886, Jean-Martin Charcot, Pierre Marie, and Henry Tooth independently described this hereditary motor and sensory neuropathy in their patients, paving the way for Charcot-Marie-Tooth (CMT) disease research.2,3 It was not until 1968 that a distinction was made in CMT disease, creating the classification of CMT1 and CMT2.4 Since then, CMT disease (OMIM: 616155) has been used as a model disease to describe genetic heterogeneity.5 However, the high genetic and allelic heterogeneity of CMT disease poses a challenge for both diagnosis and treatment.

VCA-894A is being developed for a patient who was first diagnosed at the age of 5 with a rare subtype of CMT disease known as CMT2S.6 CMT2S is an inherited neuromuscular disorder that progressively leads to muscle weakness and loss of motor function, and has an estimated prevalence of less than 1 in 1,000,000 worldwide.7 The severity and clinical presentations of CMT2S are influenced by the diverse genetic variants associated with CMT disease, emphasizing the importance of principal and modifying genes in human diseases. VCA-894A targets a patient-specific IGHMBP2 variant and restores expression levels of IGHMBP2, highlighting the exciting potential of this approach for personalized therapeutics for rare diseases.

"More than two decades after the human genome was first sequenced, we are now able to perform routine and affordable sequencing of the genome for any individual, enabling the discovery of genetic causes of disease and facilitating the development of targeted therapeutics. Our efforts to develop an antisense oligonucleotide treatment for a patient with a specific genetic mutation causing the neuromuscular disorder CMT2S is a demonstration of how these novel technologies can be leveraged to develop a new treatment paradigm – moving away from the one-treatment-fits-all perspective and towards the development of personalized medicines," said Mihael H. Polymeropoulos, M.D., Vanda's President, CEO and Chairman of the Board.

The article1 published today discusses the development of this novel breakthrough therapeutic customized to a specific genetic mutation of a patient with CMT2S. The effects of VCA-894A were confirmed in Hesperos' Human-on-a-Chip® neuromuscular junction model with patient-derived cells where VCA-894A demonstrated significant improvements in neuromuscular function, including reduced muscle fatigue and improved synaptic transmission between motor neurons and skeletal muscle myotubes. The use of a microphysiological system to evaluate the effects of a genetically tailored treatment represents a significant advancement in precision medicine and the use of human relevant methods of evaluation.

VCA-894A has been granted an orphan designation by the FDA and it is expected to soon be administered to the specific patient for whom it was developed. The experimental platform described in today's article has the potential to unlock the development of treatments that can address significantly unmet medical needs based on genetic understandings and precision medicine.

For access to the full study, visit DOI: 10.1016/j.omtn.2025.102479.

References:

• Smieszek, S. et al. Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S. Mol Ther Nucleic Acids 36, 102479 (2025).
• Charcot, J. M. & Marie, P. Sur Une Forme Particulière d'atrophie Musculaire Progressive : Souvent Familiale Débutant Par Les Pieds et Les Jambes et Atteignant plus Tard Les Mains. vol. 6 (Revue de médecine, 1886).
• Tooth, H. H. The Peroneal Type of Progressive Muscular Atrophy. Dissertation, University of Cambridge. (1886).
• Dyck, P. J. Lower Motor and Primary Sensory Neuron Diseases With Peroneal Muscular Atrophy. Arch Neurol 18, 603 (1968).
• Lupski, J. R. et al. Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy. New England Journal of Medicine 362, 1181–1191 (2010).
• Cassini, T. A. et al. Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice-site and Charcot-Marie-Tooth phenotype with early onset symptoms. Mol Genet Genomic Med 7, (2019).
• Charcot-Marie-Tooth disease type 2S. Orpha.net (2025). https://www.orpha.net/en/disease/detail/443073

About Vanda Pharmaceuticals Inc.

Vanda is a leading global biopharmaceutical company focused on the development and commercialization of innovative therapies to address high unmet medical needs and improve the lives of patients. For more on Vanda Pharmaceuticals Inc., please visit www.vandapharma.com and follow us on X @vandapharma.

About VCA-894A

VCA-894A is a 2'-O-methoxyethyl (MOE) phosphorothioate oligonucleotide sodium salt. VCA-894A specifically targets a cryptic splice site variant within IGHMBP2, which causes CMT2S. ASOs may have broad applicability in addressing a number of disorders, from nervous system treatments to systemic treatments.