A new drug application (NDA) has been submitted to the FDA seeking the approval of rusfertide for the treatment of adult patients with polycythemia vera (PV).1
This NDA submission was based on findings from the phase 3 VERIFY study (NCT05210790) and the phase 2 REVIVE study (NCT04057040). Data from part 1a of the VERIFY study showed that rusfertide, a first-in-class hepcidin mimetic, met the trial’s primary end point and all 4 key secondary end points, demonstrating durable hematocrit control and a reduction in phlebotomy requirements. In part 1a, the overall response rate (ORR) was 32.9% in the rusfertide arm (n = 113/147) vs 76.9% in the placebo arm (n = 48/146; P < .0001).2 Additionally, 62.6% of patients in the rusfertide arm achieved hematocrit levels lower than 45% vs 14.4% of those in the placebo arm (P < .0001).
VERIFY Trial: Key Highlights
- The trial met its primary end point with a significantly higher ORR of 76.9% with rusfertide compared with 32.9% with placebo (P < .0001); the trial also met all 4 of its key secondary end points.
- Rusfertide provided rapid and durable control of hematocrit levels below 45% and phlebotomy ineligibility through week 52, including for patients who switched from placebo to rusfertide after week 32.
- Rusfertide maintained a favorable safety profile through 52 weeks of treatment, with most adverse effects being grade 1 or 2 and treatmentdiscontinuation rates remaining low at 7.5% in part 1a and 2.6% in part 1b.
“Submitting this NDA marks a major inflection point in the decade long journey that started with a hepcidin mimetic program at Protagonist,” Dinesh V. Patel, PhD, president and CEO of Protagonist Therapeutics, stated in a news release.1 “Rusfertide has practice-changing potential that could become standard of care [SOC] for patients with PV who currently rely on burdensome and often ineffective therapies.”
Previously, in August 2025, the FDA granted breakthrough therapy designation to rusfertide for the treatment of erythrocytosis in patients with PV.3
What is the mechanism of action of rusfertide?
In addition to the reduction in phlebotomy requirements, rusfertide is designed to manage erythrocytosis (red blood cell overproduction) by mimicking the natural hormone hepcidin to regulate iron homeostasis.1 By maintaining hematocrit levels below 45%, the therapy seeks to prevent life-threatening thrombotic effects, such as stroke and pulmonary embolism, and alleviate symptoms like severe fatigue and pruritus.
What was the design of the VERIFY trial?
VERIFY enrolled 293 patients with PV who had uncontrolled hematocrit levels and were phlebotomy dependent despite receiving SOC treatments, such as hydroxyurea, interferon, or ruxolitinib (Jakafi).1,2 The trial is an ongoing, 3-part, global, randomized, placebo-controlled study. Patients were evaluated based on the efficacy and safety of once-weekly, subcutaneously self-administered rusfertide plus SOC compared with placebo plus SOC.
The primary end point of the study was the proportion of patients achieving a response during weeks 20 to 32. A response was defined as the absence of “phlebotomy eligibility,” which required patients to maintain a confirmed hematocrit level of less than 45% (and not more than 3% higher than their baseline) or a hematocrit level below 48%. Secondary end points included the proportions of patients who met phlebotomy requirements, had maintained hematocrit levels below 45%, and had improvements in patient-reported outcome measurements.2
What additional findings were seen with rusfertide in the VERIFY trial?
The NDA submission included 52-week data showing that rusfertide provided sustained hematocrit control after week 32.1 Findings presented at the 2025 ASH Annual Meeting demonstrated that patients in the rusfertide arm achieved durable responses, with an ORR that rose from 76.9% at week 32 to 84.1% at week 52.2 Additionally, patients who switched from the placebo arm to the rusfertide arm achieved durable control of responses and rapid responses, with an ORR of 77.9% at week 52.
“This is an important milestone toward our goal of addressing critical gaps that patients living with polycythemia vera face today,” Teresa Bitetti, president of the Global Oncology Business Unit at Takeda, added in the news release.1 “The comprehensive VERIFY study data underscore rusfertide’s strong clinical profile and potential to provide sustained hematocrit control [and reduce] phlebotomy and symptom burden. Our collaboration with Protagonist exemplifies how partnerships can advance innovative science, with a focus on making a meaningful difference for patients.”
References
- Takeda and Protagonist announce submission of new drug application (NDA) for rusfertide for treatment of polycythemia vera (PV). News release. Takeda. January 5, 2026. Accessed January 5, 2026. https://www.takeda.com/newsroom/newsreleases/2025/new-drug-application-pv/
- Kuykendall A, Bankar A, Pettit K, et al. Rusfertide or placebo plus current standard-of-care therapy for polycythemia vera: Durability of response and safety results through week 52 from the randomized controlled phase 3 VERIFY study. Blood. 2025;146(suppl 1):81. doi:10.1182/blood-2025-8
- Rusfertide receives breakthrough therapy designation for treatment of erythrocytosis in patients with polycythemia vera. News release. Access Newswire. August 25, 2025. Accessed January 5, 2026. https://www.accessnewswire.com/newsroom/en/healthcare-and-pharmaceutical/rusfertide-receives-breakthrough-therapy-designation-for-treatment-of-1064560
