Protagonist and Takeda Announce Positive Topline Results from Phase 3 VERIFY Study of Rusfertide in Polycythemia Vera
Introduction to the VERIFY Study
Protagonist Therapeutics, Inc. and Takeda have announced the successful topline results of the Phase 3 VERIFY study, which evaluated rusfertide, an investigational hepcidin mimetic peptide therapeutic, in patients with polycythemia vera (PV). In this study, patients who were dependent on phlebotomy (the removal of blood to manage elevated red blood cell levels) were randomly assigned to receive either rusfertide or a placebo, alongside their standard of care treatment. The study met its primary endpoint and all four key secondary endpoints, providing significant insights into the potential of rusfertide as an effective treatment for PV.
Rusfertide, which has received Orphan Drug designation and Fast Track designation from the U.S. Food & Drug Administration (FDA), represents a novel approach to managing PV. The drug works by mimicking hepcidin, a naturally occurring hormone involved in regulating iron homeostasis and red blood cell production. By targeting the root cause of PV—an overproduction of red blood cells—rusfertide aims to help manage the disease more effectively than current treatments.
Study Design and Key Findings
The VERIFY study involved a randomized, placebo-controlled design, where patients were treated with either rusfertide or placebo for a period of 32 weeks. The study included a range of PV patients, primarily those who were phlebotomy-dependent and had not achieved adequate control of hematocrit levels with standard treatments.
The primary endpoint of the study was met with compelling results. A significantly higher proportion of patients who received rusfertide showed a clinical response (77%) compared to those on placebo (33%) during weeks 20 to 32 (p<0.0001). A clinical response was defined as the absence of phlebotomy eligibility, meaning that patients treated with rusfertide did not require the same frequency of blood removal to manage elevated hematocrit levels.
In addition to the primary endpoint, all four key secondary endpoints were also met, reinforcing the efficacy of rusfertide in managing PV. These secondary endpoints included:
- Phlebotomy Reduction: The first key secondary endpoint, which was the pre-specified primary endpoint for European Union (EU) regulators, showed a significant reduction in phlebotomies. The rusfertide arm had a mean of 0.5 phlebotomies per patient compared to 1.8 phlebotomies per patient in the placebo arm (p<0.0001).
- Hematocrit Control: Patients in the rusfertide group also demonstrated better control of hematocrit levels, another key goal in PV treatment. This endpoint was statistically significant, highlighting the drug’s ability to maintain more stable red blood cell counts over time.
- Patient-Reported Outcomes: Two additional key secondary endpoints focused on patient-reported outcomes, including fatigue and quality of life. The PROMIS Fatigue SF-8a scale and the MFSAF TSS-74 scale, both of which assess fatigue and symptoms related to PV, showed statistically significant improvements in patients treated with rusfertide.
Safety Profile of Rusfertide
The safety profile of rusfertide in the VERIFY study was consistent with previous clinical trials. The drug was generally well tolerated, with the majority of adverse events being grade 1-2 injection site reactions, which are common for injectable treatments. Importantly, there were no new safety concerns identified during the study.
Furthermore, no evidence of an increased risk of cancer was observed in the rusfertide-treated patients when compared to those receiving placebo. This is particularly significant, as PV patients are already at higher risk of developing blood-related cancers, such as leukemia, and it is crucial to ensure that any new treatment does not exacerbate this risk.
Protagonist and Takeda Announce Positive Topline Results from Phase 3 VERIFY Study of Rusfertide in Polycythemia Vera
Implications for Polycythemia Vera Treatment
Polycythemia vera is a chronic myeloproliferative disorder characterized by the overproduction of red blood cells, leading to an increased risk of thrombosis (blood clots) and cardiovascular events. The disease often requires phlebotomy, a process where blood is removed to reduce hematocrit levels, along with cytoreductive therapies. However, phlebotomy can be burdensome for patients, leading to severe fatigue, iron deficiency, and other quality-of-life issues.
The ability of rusfertide to reduce the need for frequent phlebotomies represents a significant advancement in the treatment of PV. By helping to control hematocrit levels more effectively and reducing the burden of phlebotomy, rusfertide has the potential to significantly improve the lives of patients living with this condition. As such, these positive results provide a strong foundation for the ongoing development of rusfertide as a potential treatment option for PV.
Next Steps and Future Prospects
The results of the VERIFY study position rusfertide as a promising treatment option for PV, with the potential to address significant unmet medical needs. Following the completion of the study, Protagonist and Takeda plan to present the detailed findings at upcoming medical conferences in 2025, which will allow the scientific community to review the full data set.
Protagonist’s Chief Medical Officer, Arturo Molina, M.D., M.S., expressed enthusiasm about the results, stating, “The positive results of the Phase 3 VERIFY study across the primary and all key secondary endpoints provide compelling evidence of the potential for rusfertide as a first-in-class erythrocytosis-specific agent.” He further noted that the company is grateful to the patients, study staff, and investigators who contributed to the study’s success.
Protagonist’s Long-Term Vision and Milestone Achievement
Protagonist’s CEO, Dinesh V. Patel, Ph.D., highlighted the significance of these findings for the company, noting, “This study marks a critical inflection point in Protagonist’s decade-long journey with the hepcidin program and validates our expertise in developing peptide-based medicines for unmet medical needs.” Under the collaboration agreement with Takeda, Protagonist will receive a $25 million milestone payment, which is contingent upon the completion of the VERIFY clinical study report.
These results also pave the way for regulatory submissions to health authorities, and Protagonist and Takeda are committed to bringing rusfertide to market as a potential new treatment for PV. Takeda’s President of R&D, Andy Plump, M.D., Ph.D., expressed excitement about the study results, stating, “We are encouraged by these results and excited about the potential of rusfertide to help patients living with PV.”
Conclusion
The Phase 3 VERIFY study has provided robust evidence supporting the efficacy and safety of rusfertide as a treatment for polycythemia vera. By significantly reducing the need for phlebotomy and improving hematocrit control, rusfertide offers a promising new therapeutic option for PV patients. With the completion of this study, both Protagonist and Takeda are poised to advance rusfertide through the regulatory process and bring this innovative treatment to those who need it most.
About VERIFY
The Phase 3 VERIFY trial (NCT05210790) is an ongoing, three-part, global, randomized, placebo-controlled trial evaluating rusfertide in 293 patients with polycythemia vera over a 156-week period. The trial is evaluating the efficacy and safety of once-weekly, subcutaneously self-administered rusfertide in patients with uncontrolled hematocrit who are phlebotomy dependent despite standard of care treatment, which could include hydroxyurea, interferon and/or ruxolitinib.
The primary endpoint of the study was the proportion of patients achieving a response during weeks 20-32, which was defined as the absence of “phlebotomy eligibility.” To meet phlebotomy eligibility, patients in the study were required to have: confirmed hematocrit ≥45% that was ≥3% higher than their baseline hematocrit value, or hematocrit ≥48%.
All patients have completed their participation in the randomized, placebo-controlled portion of the trial evaluating the efficacy and safety of rusfertide plus current treatment versus placebo plus current treatment and are now in the open-label portions of the trial.
About Protagonist
Protagonist Therapeutics is a discovery through late-stage development biopharmaceutical company. Two novel peptides derived from Protagonist’s proprietary discovery platform are currently in advanced Phase 3 clinical development, with New Drug Application submissions to the FDA expected in 2025. Icotrokinra (formerly, JNJ-2113) is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor (“IL-23R”) which is licensed to JNJ Innovative Medicines (“JNJ”), formerly Janssen Biotech, Inc. Following icotrokinra’s joint discovery by Protagonist and JNJ scientists pursuant to the companies’ IL-23R collaboration, Protagonist was primarily responsible for development of icotrokinra through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond.
Rusfertide, a mimetic of the natural hormone hepcidin, is currently in Phase 3 development for the rare blood disorder polycythemia vera (PV). Rusfertide is being co-developed and will be co-commercialized with Takeda Pharmaceuticals pursuant to a worldwide collaboration and license agreement entered into in 2024 under which the Company remains primarily responsible for development through NDA filing. The Company also has a number of pre-clinical stage oral drug discovery programs addressing clinically and commercially validated targets, including IL-17 oral peptide antagonist PN-881, oral hepcidin program, and oral obesity program.
More information on Protagonist, its pipeline drug candidates and clinical studies can be found on the Company’s website at www.protagonist-inc.com.
About Takeda
Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline.
As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.
