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Vanda Pharmaceuticals' VGT-1849A, a Selective JAK2 Inhibitor, Receives FDA Orphan Drug Designation for Polycythemia Vera

• The FDA has granted Orphan Drug Designation to VGT-1849A, a selective antisense oligonucleotide JAK2 inhibitor, for treating polycythemia vera (PV). • VGT-1849A aims to reduce increased JAK2 activity, potentially lessening the disease burden for individuals with PV and offering a favorable safety profile. • Polycythemia vera, a rare hematologic malignancy, results in the overproduction of red blood cells in the bone marrow, affecting approximately 1 in 2000 US residents. • VGT-1849A could provide targeted efficacy and an improved safety profile compared to currently available small molecule inhibitors targeting the JAK2 protein kinase.

Vanda Pharmaceuticals' VGT-1849A, a selective antisense oligonucleotide (ASO)-based JAK2 inhibitor, has received Orphan Drug Designation from the FDA for the treatment of polycythemia vera (PV). PV is a rare hematologic malignancy characterized by the overproduction of red blood cells in the bone marrow.
PV is a chronic myeloproliferative disorder arising from gene mutations that disrupt normal blood cell production. Affecting approximately 1 in 2000 individuals in the US, PV often progresses slowly and may remain undetected initially. Common symptoms include headache, dizziness, fatigue, and blurred vision, along with itchiness after warm baths, numbness, abdominal bloating, unusual bleeding, joint swelling, and shortness of breath. Untreated PV can lead to life-threatening complications.

Mechanism of Action and Potential Benefits of VGT-1849A

More than 95% of PV patients harbor the JAK2 V617F gain-of-function mutation, leading to excessive JAK2 production. JAK2 inhibitors, such as VGT-1849A, are designed to target and reduce the activity of the JAK2 protein, thereby controlling the overproduction of blood cells associated with PV.
VGT-1849A, as a selective ASO targeting JAK2, aims to mitigate the increased JAK2 activity that drives hematologic malignancies. If approved, VGT-1849A promises targeted efficacy and an improved safety profile compared to existing small molecule JAK2 inhibitors like ruxolitinib, fedratinib, momelotinib and pacritinib. These current treatments lack sole selectivity for the JAK2 protein, potentially causing off-target and toxic effects.

Vanda Pharmaceuticals' Perspective

"This orphan designation for VGT-1849A is an important milestone in precision medicine-based therapeutics in the space of hematological malignancies," said Mihael H. Polymeropoulos, M.D., Vanda's President, CEO and Chairman of the Board. He also noted this milestone marks the second precision medicine therapeutic for Vanda following the development of VCA-894A for Charcot-Marie-Tooth.
The developers of VGT-1849A anticipate that the drug will reduce JAK2 activity, thereby alleviating the disease burden for PV patients while maintaining a favorable safety profile.
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Reference News

[1]
Selective Antisense Oligonucleotide-based JAK2 Inhibitor Receives FDA Orphan Drug ...
pharmacytimes.com · Dec 22, 2024

FDA granted orphan drug designation to VGT-1849A, a selective ASO-based JAK2 inhibitor for treating polycythemia vera (P...

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