FDA Grants Orphan Status to Novel JAK2 Inhibitor for Polycythemia Vera

The US FDA has granted orphan drug designation to VGT-1849B, an investigational selective JAK2 inhibitor, for the treatment of polycythemia vera (PV).¹

This designation is a significant regulatory milestone that facilitates the development of therapies for rare diseases and signals a promising new direction in the management of this chronic myeloproliferative disorder. The investigational drug's novel mechanism, a selective peptide nucleic acid-based antisense oligonucleotide (ASO), aims to provide a more targeted therapeutic approach with a potentially improved safety profile compared to current JAK inhibitor therapies.

Polycythemia vera is a rare, chronic myeloproliferative neoplasm characterized by the overproduction of myeloid lineage cells, particularly erythrocytes, which can lead to increased blood viscosity, thrombosis, and a heightened risk of cardiovascular events. The disease is also associated with the release of pro-inflammatory cytokines, contributing to symptoms like pruritus and fatigue. In more than 95% of patients, the disease is driven by the JAK2 V617F gain-of-function mutation, which results in aberrant and uncontrolled JAK2 signaling. The prevalence of PV in the United States is estimated to be between 44 and 57 per 100,000 people.

Existing treatments for PV often focus on controlling hematocrit levels to prevent complications. Therapies targeting the JAK-STAT pathway, which is aberrantly activated by the JAK2 mutation, have demonstrated efficacy in managing both hematologic parameters and disease-related symptoms. However, current JAK inhibitors, such as ruxolitinib (Jakafi), fedratinib (Inrebic), momelotinib (Ojjaara), and pacritinib (Vonjo), are not exclusively selective for JAK2. Due to the highly conserved structure of the catalytic sites of protein kinases, these drugs can inhibit other JAK family members (JAK1, JAK3, and TYK2) or other kinases, leading to off-target effects and a spectrum of adverse events, including an increased risk of infection.

VGT-1849B is being developed to address these limitations. Unlike small-molecule JAK inhibitors, VGT-1849B is a peptide nucleic acid-based ASO that utilizes a unique OliPass Peptide Nucleic Acid (OPNA) backbone chemistry. This design allows it to selectively target and bind to JAK2 mRNA, effectively reducing JAK2 protein production. By intervening at the mRNA level, VGT-1849B is designed to specifically downregulate the JAK2 protein, including the mutant V617F variant, without inhibiting other kinases. This precision is expected to suppress the aberrant hematopoiesis, reducing the production of red blood cells, neutrophils, and platelets while potentially mitigating the systemic toxicities associated with off-target kinase inhibition.

If clinical development proves successful, the highly selective nature of VGT-1849B could translate into a more favorable safety profile, which would be a significant advantage for patients with PV. A treatment that minimizes the risk of infection and other side effects could substantially improve a patient's quality of life and long-term adherence to therapy. The agent also offers the potential for a convenient, infrequent dosing schedule, which could further enhance patient compliance and overall management of this chronic condition.

The FDA’s Orphan Drug Designation is a regulatory status granted to drugs and biologics that are intended for the treatment, diagnosis, or prevention of rare diseases or conditions that affect fewer than 200,000 people in the US.² This designation provides various incentives to the drug developer, including tax credits, user fee waivers, and a period of market exclusivity upon approval. This status underscores the significant medical need for new therapeutic options in PV and signals that the FDA has acknowledged VGT-1849B's potential to address this need.

FAQs

What is polycythemia vera (PV)?

Polycythemia vera is a rare, chronic myeloproliferative neoplasm, a type of blood cancer, where the bone marrow produces too many red blood cells, as well as sometimes white blood cells and platelets. This overproduction leads to increased blood viscosity, which raises the risk of blood clots (thrombosis) and serious cardiovascular events. Patients often experience symptoms like pruritus (itching) and fatigue due to the release of pro-inflammatory cytokines. In over 95% of cases, PV is caused by a specific genetic mutation called JAK2 V617F, which results in uncontrolled signaling in the JAK-STAT pathway. The estimated prevalence of PV in the United States is between 44 and 57 per 100,000 people.

What is VGT-1849B and how does it work?

VGT-1849B is a novel, investigational selective JAK2 inhibitor that has been granted orphan drug designation by the FDA for the treatment of polycythemia vera. Unlike current small-molecule JAK inhibitors, VGT-1849B is a peptide nucleic acid-based antisense oligonucleotide (ASO) that utilizes OliPass Peptide Nucleic Acid (OPNA) backbone chemistry. This unique design allows it to selectively target and bind to JAK2 mRNA, thereby reducing the production of the JAK2 protein, including the mutant V617F variant. By intervening at the mRNA level, VGT-1849B aims to specifically downregulate the JAK2 protein without affecting other kinases, offering a more targeted therapeutic approach.

How does VGT-1849B differ from existing JAK inhibitor therapies for PV?

Existing JAK inhibitor therapies, such as ruxolitinib, fedratinib, momelotinib, and pacritinib, are not exclusively selective for JAK2. Due to the conserved structure of protein kinase catalytic sites, these drugs can inhibit other JAK family members (JAK1, JAK3, and TYK2) or other kinases, leading to off-target effects and a range of adverse events, including an increased risk of infection. VGT-1849B, as a selective peptide nucleic acid-based ASO, is designed to specifically target and reduce JAK2 mRNA, which should result in highly selective inhibition of JAK2 protein production. This precision is expected to avoid the off-target effects seen with current treatments, potentially leading to a more favorable safety profile.

This article was generated with assistance from Google Gemini and NotebookLM. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCES:

1. Vanda Pharmaceuticals Announces FDA Granted Orphan Drug Designation for VGT-1849B, a Novel and Selective Candidate for the Treatment of Polycythemia Vera. News release. Vanda Pharmaceuticals. August 28, 2025. Accessed August 28, 2025. https://tinyurl.com/32zau7ba

2. Designating an Orphan Product: Drugs and Biological Products. US FDA. Updated August 12, 2024. Accessed August 28, 2025. https://tinyurl.com/5ckfaxtv