FDA Grants Fast Track Designation to Givinostat for Polycythemia Vera

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The FDA has granted fast track designation to givinostat (Duvyzat), an orally administered histone deacetylase (HDAC) inhibitor, for the treatment of patients with polycythemia vera (PV).1

The agent is being evaluated in the ongoing phase 3 GIV-IN PV trial (NCT06093672), which aims to compare the efficacy and safety of givinostat to hydroxyurea in patients with JAK2 V617F–positive, high-risk PV, which is characterized by the clonal overproduction of erythroid, myeloid, and megakaryocytic lineages within the bone marrow. By targeting aberrant gene expression, givinostat may suppress pathologic cell proliferation associated with driver mutations such as JAK2 V617F, which are common in patients with PV.

“The FDA decision to grant givinostat fast track designation underscores the urgent need for innovative treatments for PV and highlights the potential of givinostat to make a meaningful difference,” Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco Group, stated in a news release. “We look forward to working closely with the FDA as we plan for completion of our phase 3 clinical trial.”

The FDA and European Medicines Agency both previously granted orphan drug designation to givinostat for PV. In the United States, the FDA previously approved givinostat for the treatment of patients 6 years of age or older with Duchenne muscular dystrophy.2

GIV-IN PV Trial Design and Eligibility Criteria

The ongoing, multicenter, randomized, phase 3 trial is evaluating the efficacy, safety, and tolerability of givinostat in patients at least 18 years of age with a confirmed diagnosis of PV per 2016 WHO criteria within 3 years of randomization.3 Patients must also harbor a JAK2 V617Fmutation and meet high-risk criteria for thrombosis, defined as being 60 years of age or older and/or a history of prior thrombosis. Additional inclusion criteria comprise a need for cytoreductive treatment at screening, demonstrated by hematocrit of more than 45% or less than 45% following a phlebotomy performed within 3 months; a white blood cell count of more than10 × 10⁹/L; or platelet count of more than 400 × 10⁹/L. Normalized hematocrit to less than 45% must be achieved by the time of randomization.

Patients pretreated with hydroxyurea and those meeting European LeukemiaNet (ELN) criteria for resistance or intolerance will be excluded, along with those who present with a QTcF interval of more than 450 milliseconds in males or more than 460 milliseconds in females; a documented history of QTc prolongation or ventricular arrhythmias; or prior treatment with a JAK2 or HDAC inhibitor.

Additional exclusion criteria include splanchnic thrombosis and/or cerebral venous sinus thrombosis; significant cardiovascular disease; inadequate liver or renal function; recent thromboembolic or cerebrovascular events; and use of any investigational agents within 30 days or 5 half-lives of randomization.

Patients are being randomly assigned to receive givinostat or hydroxyurea. The primary end point is the proportion of patients achieving response at week 48, defined as hematocrit less than 45% without phlebotomy in the prior 3 months; a white blood cell count of less than 10 × 10⁹/L; a platelet count less than 400 × 10⁹/L; and spleen size within normal range by imaging. Secondary end points include complete hematologic response (CHR) rate, time to first CHR, spleen size normalization at week 48, and safety and tolerability through week 48. After week 48, response will be assessed by the absence of progressive disease and the incidence of major hemorrhagic and thrombotic events.

References

1. Italfarmaco announces U.S. FDA grants fast track designation to givinostat in treatment of polycythemia vera. News Release. Italfarmaco. May 6, 2025. https://www.globenewswire.com/news-release/2025/05/06/3074789/0/en/Italfarmaco-Announces-U-S-FDA-Grants-Fast-Track-Designation-to-Givinostat-in-Treatment-of-Polycythemia-Vera.html
2. Duvyzat. Prescribing information. Updated March 2024. Accessed May 6, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217865Orig1s000lbl.pdf
3. Study on efficacy and safety of givinostat versus hydroxyurea in patients with polycythemia vera. ClinicalTrials.gov Updated December 6, 2024. Accessed May 6, 2025. https://clinicaltrials.gov/study/NCT06093672