Selective Antisense Oligonucleotide-based JAK2 Inhibitor Receives FDA Orphan Drug Designation for Polycythemia Vera

The FDA granted orphan drug designation to VGT-1849A (Vanda Pharmaceuticals Inc), a selective antisense oligonucleotide (ASO)-based JAK2 inhibitor for the treatment of polycythemia vera (PV), a rare hematologic malignancy that causes the bone marrow to overproduce red blood cells.^1,2

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PV is a chronic myeloproliferative disorder that occurs when a mutation in a gene causes an issue with blood cell production.^1,2 The rare disease is estimated to affect around 1 in 2000 individuals that reside in the US.¹ PV typically develops at a slow pace and is not discovered at initial time of development. Many individuals with PV do not have noticeable signs or symptoms, which include headache, dizziness, fatigue, and blurred vision. Additional symptoms include itchiness after a warm bath or shower; numbness, tingling, burning, or weakness in hands, feet, arms, or legs; bloating or pain in left upper abdomen; unusual bleeding; painful swelling of one joint; shortness of breath; and difficulty breathing when lying down. PV can cause life threatening outcomes if not treated.²

The study authors noted that more than 95% of individuals harbor the JAK2 V617F gain-of-function mutation leading to aberrant JAK2 production. JAK2 inhibitors, like ASO VGT-1849A, can be used to treat certain blood cancers, including PV. These inhibitors work by targeting and reducing the activity of the JAK2 protein, which is involved in the production of blood cells. By inhibiting JAK2, these drugs can help to control the excessive production of blood cells associated with PV and other related disorders.¹

As a ASO that selectively targets JAK2, VGT-1849A aims to reduce increased activity of JAK2 that could cause hematologic malignancies. If approved, VGT-1849A could provide targeted efficacy and an improved safety profile compared to currently available small molecule inhibitors targeting the JAK2 protein kinase. These include ruxolitinib (Jakafi; Incyte Corporation), fedratinib (Inrebic; Bristol Myers Squibb), momelotinib (Ojjaara; GlaxoSmithKline) and pacritinib (Vonjo; CTI BioPharma) which lack sole selectivity for the target protein which could result in off target and toxic effects.¹

"This orphan designation for VGT-1849A is an important milestone in precision medicine-based therapeutics in the space of hematological malignancies. This milestone marks the second precision medicine therapeutic for Vanda following the development of VCA-894A for Charcot-Marie-Tooth³ that is expected to begin clinical testing in the coming months," said Mihael H. Polymeropoulos, M.D., Vanda's President, CEO and Chairman of the Board, in a news release.”¹

The study authors noted that VGT-1849A could reduce JAK2 activity, lessening the disease burden faced by individuals with PV while providing a favorable safety profile.¹

REFERENCES

1. Vanda Pharmaceuticals Announces Orphan Drug Designation Granted for VGT-1849A, a Novel and Selective Antisense Oligonucleotide Candidate for the Treatment of Polycythemia Vera. Vanda Pharmaceuticals Inc. News release. December 20, 2024. Accessed December 20, 2024. https://prnmedia.prnewswire.com/news-releases/vanda-pharmaceuticals-announces-orphan-drug-designation-granted-for-vgt-1849a-a-novel-and-selective-antisense-oligonucleotide-candidate-for-the-treatment-of-polycythemia-vera-302337333.html.

2. Polycythemia vera. Mayo Clinic. News release. February 11, 2022. Accessed December 20, 2024. https://www.mayoclinic.org/diseases-conditions/polycythemia-vera/symptoms-causes/syc-20355850.