Pivotal Study Shows Significant Improvements in Hematocrit Control and Patient Outcomes
What does the future hold for patients with polycythemia vera (PV)? Takeda and Protagonist Therapeutics, Inc. have announced a significant milestone in the treatment of this rare blood disorder. The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for rusfertide, a first-in-class hepcidin mimetic peptide therapeutic. The FDA has also granted Priority Review, with a Prescription Drug User Fee Act (PDUFA) target action date in the third quarter of this year. This development marks a crucial step toward providing a new, effective treatment option for patients with PV, a condition characterized by the overproduction of red blood cells, which can lead to life-threatening thrombotic events.
Key Insights at a Glance
- Hematocrit Control: Rusfertide demonstrated significant improvements in hematocrit control, a primary treatment goal in PV.
- Phlebotomy Reduction: The therapy significantly reduced the need for phlebotomy, a burdensome and frequent treatment for PV patients.
- Patient Reported Outcomes: Rusfertide improved patient-reported outcomes, including fatigue and symptom burden.
- Regulatory Milestones: The NDA acceptance and Priority Review underscore the potential of rusfertide to address significant unmet needs in PV.
Why Hematocrit Control is Critical in Polycythemia Vera
Hematocrit control is the primary treatment goal in polycythemia vera, as it helps prevent life-threatening thrombotic events and alleviates burdensome symptoms. Achieving and maintaining hematocrit levels below 45% is essential to reduce the risk of stroke, deep vein thrombosis, and pulmonary embolism. Current treatments, such as phlebotomy and medications like hydroxyurea, often fall short in providing sustained control, leaving patients with limited therapeutic options. The urgent need for innovative treatments like rusfertide is clear, as it aims to address the underlying mechanism of iron dysregulation and reduce excess red blood cell production.
The FDA Review Window Narrows for Every Drug Candidate
Just as a sprinter accelerates toward the finish line, Takeda and Protagonist are racing against the FDA review clock to bring rusfertide to market. The acceptance of the NDA and the granting of Priority Review are significant milestones that highlight the potential of rusfertide to transform the treatment landscape for PV. The Prescription Drug User Fee Act (PDUFA) target action date in the third quarter of this year adds a sense of urgency, as the companies and the FDA work diligently to ensure that this innovative therapy reaches patients who need it most. The regulatory process is a critical phase, and the success of rusfertide in this stage will have far-reaching implications for the future of PV treatment.
Takeda and Protagonist’s Collaborative Effort to Advance Rusfertide
Takeda and Protagonist Therapeutics have joined forces to advance rusfertide, a first-in-class hepcidin mimetic peptide therapeutic. The Phase 3 VERIFY study, which included 293 patients with PV, demonstrated that rusfertide plus standard of care more than doubled clinical response rates compared to the standard of care alone. Key endpoints included hematocrit control, a reduction in phlebotomy requirements, and improvements in patient-reported outcomes such as fatigue and symptom burden. Rusfertide was generally well-tolerated, with the most common adverse events being injection site reactions, anemia, and fatigue, which were primarily mild to moderate. This collaborative effort underscores the commitment of both companies to addressing significant unmet needs in hematologic cancers.
Future Outlook
The future of polycythemia vera treatment is poised to evolve with the potential approval of rusfertide. The ongoing Phase 3 VERIFY study and the long-term Phase 2 REVIVE/THRIVE studies provide robust evidence of the therapy’s efficacy and safety. The FDA’s Priority Review and the PDUFA target action date in the third quarter of this year indicate that the regulatory process is progressing smoothly. As the review continues, the focus remains on ensuring that rusfertide can offer a meaningful improvement in clinical outcomes and quality of life for patients with PV.
Conclusion
The acceptance of the NDA for rusfertide by the FDA represents a significant step forward in the treatment of polycythemia vera. For healthcare providers and patients, this milestone brings hope for a new, effective therapy that can address the challenges of hematocrit control and reduce the burden of frequent phlebotomies. How is your healthcare practice preparing for this potential shift in treatment options? Join the conversation in the comments below.
About Rusfertide
Rusfertide is a first-in-class investigational subcutaneous treatment that mimics the action of hepcidin, a natural hormone that regulates iron homeostasis and red blood cell production. By targeting the underlying mechanism of iron dysregulation in polycythemia vera, rusfertide aims to reduce excess red blood cell production and help patients achieve sustained hematocrit control. Rusfertide is administered once weekly via subcutaneous self-injection and has been generally well-tolerated in clinical trials to date.
About VERIFY
The Phase 3 VERIFY study (NCT05210790) is an ongoing, three-part, global, randomized, placebo-controlled study evaluating rusfertide in 293 patients with polycythemia vera over a 156-week period, with treatment extension for participants who are continuing to derive benefit from rusfertide beyond the 156-week treatment period.
The study is evaluating the efficacy and safety of once-weekly, subcutaneously self-administered rusfertide in patients with uncontrolled hematocrit who are phlebotomy-dependent despite current standard of care treatment, which could include phlebotomy, 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 study evaluating the efficacy and safety of rusfertide plus current standard of care versus placebo plus current standard of care and are now in the open-label portions of the study.
About REVIVE and THRIVE
The Phase 2 REVIVE study (NCT04057040) evaluated rusfertide in adult patients with polycythemia vera and consisted of three parts, including 70 patients in the dose-finding Part 1 (28 weeks), 59 patients in the blinded, placebo-controlled, randomized withdrawal Part 2 (13 weeks) and 58 patients in the Part 3 open-label expansion (52 weeks). The THRIVE study (NCT06033586) is an ongoing, open-label extension study evaluating the long-term durability of response and safety profile of rusfertide in patients with polycythemia vera.
The study includes 46 patients who previously participated in REVIVE. Patients eligible to transition to the THRIVE study completed the open-label extension portion of REVIVE, ≥12 months of rusfertide therapy and had an end-of-treatment visit. THRIVE is designed to further assess the maintenance of hematocrit control, reduction in the need for therapeutic phlebotomy and overall safety of once-weekly, subcutaneous rusfertide over an additional two-year treatment period.
About Polycythemia Vera (PV)
Polycythemia vera (PV) is characterized by the overproduction of red blood cells (erythrocytosis), which increases blood viscosity, or thickness, and can result in life threatening thrombotic events such as stroke, deep vein thrombosis and pulmonary embolism. Hematocrit is the ratio of red blood cells to the total amount of blood in the body. Achieving and maintaining controlled hematocrit levels of <45% is the primary treatment goal in PV to prevent thrombotic events and alleviate burdensome symptoms, including severe fatigue, difficulty in concentrating, night sweats and pruritus.
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.
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 NDAs for both ICOTYDE™ (icotrokinra) and rusfertide under review at the FDA. ICOTYDE is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor (“IL-23R”), which is licensed to Janssen Biotech, Inc., a Johnson & Johnson company.
Following ICOTYDE’s joint discovery by Protagonist and Johnson & Johnson scientists pursuant to the companies’ IL-23R collaboration, Protagonist was primarily responsible for the development of ICOTYDE through Phase 1, with Johnson & Johnson assuming responsibility for development in Phase 2 and beyond.
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