Vanda Pharmaceuticals Inc. announced that the U.S. Food and Drug Administration has granted Orphan Drug Designation for VGT-1849B, a selective peptide nucleic acid-based JAK2 inhibitor for treating polycythemia vera (PV). The designation provides regulatory benefits for developing therapies addressing rare medical conditions.
Novel Antisense Approach Targets JAK2 Mutation
VGT-1849B represents a novel therapeutic approach using antisense oligonucleotide (ASO) technology with OliPass Peptide Nucleic Acid (OPNA) backbone chemistry. The compound was derived from peptide nucleic acid (PNA) by introducing cationic lipid moieties onto nucleobases, which markedly improves cell permeability and RNA affinity through covalent attachment of cationic lipid groups.
The therapy selectively targets JAK2 mRNA to reduce downstream signaling and JAK2V617F-driven autonomous cell proliferation. By targeting JAK2 with high precision, VGT-1849B effectively reduces JAK2 protein production without off-target kinase effects. The inhibition of JAK2 suppresses hematopoiesis, consequently reducing red blood cell, neutrophil, platelet, and lymphocyte production.
Addressing Unmet Medical Need in Polycythemia Vera
Polycythemia vera is a chronic myeloproliferative disorder characterized by aberrant hematopoiesis of myeloid lineage with exuberant red cell production and increased release of pro-inflammatory cytokines. More than 95% of PV patients harbor the JAK2 V617F gain-of-function mutation leading to aberrant JAK2 production. The prevalence of PV in the United States is estimated to affect 44 to 57 per 100,000 people.
Potential Safety Advantage Over Current JAK Inhibitors
While several JAK inhibitors are available including Jakafi®, Inrebic®, Ojjaara®, and Vonjo®, none are solely selective to JAK2. Due to the highly conserved structure of the catalytic sites of protein kinases, existing JAK2 inhibitors may bind to off-target kinases, leading to increased toxicity and worse overall safety profiles.
The adverse side effects from JAK inhibition emphasize the importance of selectively targeting JAK2 while avoiding inhibition of other JAK family members. By specifically targeting JAK2, VGT-1849B aims to reduce the risk of infection and toxic effects seen with inhibitors that also block JAK1, JAK3, TYK2, or other kinases outside the JAK family.
Unique OPNA Technology Platform
The OPNA technology underlying VGT-1849B offers several advantages over conventional RNA therapeutics. For therapeutic intervention, OPNA potently binds to target pre-mRNA, induces exon skipping, and yields an mRNA splice variant. Unlike other types of RNA therapeutics, OPNA does not require formulation aid for in vivo therapeutic activity, potentially enabling convenient infrequent dosing.
If approved, VGT-1849B could offer targeted efficacy with an improved safety profile and convenient dosing schedule. The ability of VGT-1849B to reduce JAK2 protein may alleviate the disease burden that patients with PV face while maintaining a favorable safety profile, potentially resulting in higher quality of life for patients.
