Protagonist Therapeutics and Takeda Reveal Comprehensive Phase 3 VERIFY Study Results for Rusfertide in Polycythemia Vera at ASCO 2025
Protagonist Therapeutics,and Takeda Pharmaceutical Company Limited have announced detailed findings from the Phase 3 VERIFY clinical trial evaluating rusfertide, an investigational hepcidin mimetic peptide therapeutic, in patients suffering from polycythemia vera (PV). The study, a randomized, placebo-controlled trial, met its primary and all key secondary endpoints, demonstrating significant clinical benefits of rusfertide when added to the current standard of care. These promising results were shared as a late-breaking oral presentation (LBA3) during the plenary session at the 61st American Society of Clinical Oncology (ASCO) Annual Meeting, held today at 2:09 pm Central Daylight Time.
Understanding Polycythemia Vera and Current Treatment Challenges
Polycythemia vera is a rare chronic blood disorder characterized primarily by the excessive production of red blood cells (erythrocytosis). This overproduction leads to an increased volume and thickness of the blood (higher viscosity), which significantly elevates the risk of life-threatening thrombotic complications such as stroke, deep vein thrombosis (DVT), and pulmonary embolism. Besides these serious risks, patients with PV often endure debilitating symptoms including profound fatigue, difficulty concentrating, night sweats, and intense itching (pruritus), all of which negatively impact quality of life and daily functioning.
A central goal in the management of PV is to control hematocrit levels — the proportion of red blood cells relative to total blood volume. Maintaining hematocrit below 45% is critical, as studies have shown this threshold significantly reduces the risk of thrombotic events. Despite current treatment strategies, which typically include phlebotomy (blood removal) and cytoreductive therapies such as hydroxyurea or interferon, many patients continue to experience poorly controlled hematocrit levels, ongoing symptoms, and frequent phlebotomy requirements. This unmet medical need has driven the development of novel therapies aimed at more effectively regulating red blood cell production and iron metabolism in PV patients.
Rusfertide: A Novel Mechanism of Action
Rusfertide is a first-in-class, investigational hepcidin mimetic peptide therapeutic designed to target the underlying iron dysregulation in PV. Hepcidin is a natural hormone that regulates iron homeostasis by limiting iron availability for red blood cell production. By mimicking hepcidin’s activity, rusfertide aims to reduce excess red blood cell production by restricting iron, a vital component needed for erythropoiesis.
The VERIFY study was designed to evaluate the efficacy and safety of rusfertide as an add-on treatment to standard of care in PV patients who are dependent on frequent phlebotomies, with or without concurrent cytoreductive therapy. The trial enrolled patients with poorly controlled hematocrit levels who required frequent blood removal to manage their condition.
Study Design and Key Findings
The VERIFY trial was a randomized, placebo-controlled Phase 3 study in which patients were assigned to receive either once-weekly subcutaneous injections of rusfertide or placebo, alongside their existing standard therapies. The primary endpoint was the proportion of patients achieving a clinical response, defined as not meeting the criteria for phlebotomy eligibility during Weeks 20 through 32 of the study. This endpoint is a critical marker indicating control over hematocrit levels and reduced dependency on phlebotomy.
The results were striking: 76.9% of patients treated with rusfertide plus standard care achieved the primary clinical response, compared to only 32.9% of patients receiving placebo plus standard care (p<0.0001). This robust response was consistent regardless of patients’ baseline risk status or whether they were on concurrent cytoreductive therapies, highlighting rusfertide’s broad applicability.
Secondary endpoints also strongly favored rusfertide treatment:
- The average number of phlebotomies per patient over 32 weeks was dramatically reduced in the rusfertide group (0.5 phlebotomies) compared to the placebo group (1.8 phlebotomies), a statistically significant difference (p<0.0001).
- Only 27% of patients receiving rusfertide required any phlebotomy during the study period, versus 78% in the placebo group.
- Hematocrit control was significantly better in the rusfertide arm, with 62.6% of patients maintaining hematocrit below 45%, compared to just 14.4% in the placebo arm (p<0.0001).
- Rusfertide showed meaningful improvements in patient-reported outcomes, including fatigue and overall symptom burden, as measured by PROMIS Fatigue scores and the Myeloproliferative Neoplasm Symptom Assessment Form (MFSAF) Total Symptom Score, with statistically significant improvements (p<0.03). This is notable as rusfertide is the first investigational treatment to demonstrate significant improvement in these patient-centered measures in PV.
Safety Profile and Tolerability
Rusfertide was generally well tolerated throughout the trial. Most adverse events were low grade and non-serious. Injection site reactions were the most common side effect, occurring in 55.9% of patients, followed by anemia (15.9%) and fatigue (15.2%). Importantly, there were no serious adverse events attributed to rusfertide treatment.
Concerns around increased cancer risk, which can be an issue in PV patients, were also addressed. The incidence of reported cancer events during the trial was low, with only one patient (0.7%) in the rusfertide arm experiencing a cancer event compared to seven patients (4.8%) in the placebo arm, indicating no increased oncogenic risk from rusfertide during the study period.
Expert Commentary
Dr. Andrew T. Kuykendall, M.D., Lead Investigator of the VERIFY study and Associate Member of the Department of Hematology at Moffitt Cancer Center, emphasized the clinical significance of these findings. “PV poses significant challenges for patients, including debilitating symptoms and the risk of serious thrombotic events, and hematocrit control is crucial to improving patient outcomes. The VERIFY study demonstrated that treatment with rusfertide controls hematocrit levels in phlebotomy-dependent patients, including those on cytoreductive therapies. These results suggest rusfertide has the potential to become part of the standard of care treatment for patients with PV.”
Similarly, Dinesh V. Patel, Ph.D., President and CEO of Protagonist Therapeutics, highlighted the importance of this breakthrough. “These findings underscore rusfertide’s potential as a first-in-class erythrocytosis-specific treatment for PV and validate more than a decade of scientific innovation originating from Protagonist’s peptide technology platform. We thank all the patients, study staff, and investigators for their participation and look forward to advancing rusfertide in partnership with Takeda to potentially transform PV treatment worldwide.”
Phuong Khanh (P.K.) Morrow, M.D., Head of the Oncology Therapeutic Area Unit at Takeda, added, “These promising pivotal data strongly support rusfertide’s potential benefit for a broad spectrum of PV patients who may be receiving current standard of care therapies but are not achieving adequate hematocrit control. We eagerly anticipate additional VERIFY trial data later this year as we work toward regulatory approval and continue our collaboration with Protagonist to bring this innovative therapy to patients globally.
The positive results from the VERIFY study represent a major step forward in the treatment landscape for polycythemia vera. By addressing the core pathological mechanism of erythrocytosis through iron regulation, rusfertide offers a novel approach that could reduce patients’ reliance on frequent phlebotomy and improve symptom control and quality of life.
The companies are now preparing to submit these comprehensive results to regulatory authorities and continue evaluating rusfertide’s potential in ongoing and future clinical trials. If approved, rusfertide may become the first erythrocytosis-specific therapeutic designed to directly address the unmet needs of PV patients, improving both clinical outcomes and patient-reported quality of life measures.
