Phase 2 REVIVE Trial Success: Rusfertide for Polycythemia Vera Treatment

Protagonist Therapeutics, Inc. has recently shared findings from the Phase 2 REVIVE study on rusfertide, a potential treatment for polycythemia vera (PV), published in the New England Journal of Medicine (NEJM). PV is a myeloproliferative neoplasm impacting around 160,000 patients in the U.S., characterized by elevated red blood cells and other blood components, often leading to cardiovascular issues and systemic symptoms like fatigue and night sweats. Existing treatments aim to maintain hematocrit levels below 45%, yet many patients still rely on frequent phlebotomies due to suboptimal control, aggravating iron deficiency and other symptoms.

Rusfertide, a peptide mimetic of the natural hormone hepcidin, has shown promise as a novel approach to treat PV by specifically targeting erythrocytosis. The Phase 2 REVIVE study indicated that rusfertide effectively controlled erythrocytosis, kept hematocrit levels under 45%, eliminated the need for frequent phlebotomies, and alleviated disease-related symptoms among PV patients. The treatment was generally well-tolerated, with common adverse events being mild to moderate injection site reactions and no serious laboratory abnormalities reported.

Dr. Ronald Hoffman from the Icahn School of Medicine highlighted that maintaining hematocrit control with reduced phlebotomy requirements can significantly improve patient outcomes, mitigating iron deficiency and other debilitating symptoms. The clinical trial’s results reflect rusfertide's potential to serve as a new therapeutic option, especially for those who struggle with existing treatments that can exacerbate fatigue and other issues.

The REVIVE trial involved a three-part study with 70 participants in Part 1 and 59 in Part 2, where patients were randomized to receive either rusfertide or placebo. The primary efficacy endpoint was to assess the proportion of responders who managed their hematocrit levels without requiring phlebotomy during the double-blind, randomized withdrawal phase. Rusfertide demonstrated a significantly higher response rate compared to placebo, with 69.2% of patients in the Full Analysis Set and 60% in the Randomized Analysis Set showing positive outcomes in maintaining hematocrit control and reducing phlebotomies.

In the subsequent open-label extension (OLE) phase of the trial, some patients sustained benefits from rusfertide treatment for over 2.5 years, reducing the need for phlebotomies long-term. This prompted the initiation of the THRIVE study, which extends rusfertide treatment up to a total of five years. Additionally, rusfertide usage correlated with improved serum ferritin levels, indicating better systemic iron management and reduced severity of PV-related symptoms like fatigue and itching.

Protagonist Therapeutics is conducting the global Phase 3 VERIFY trial to further evaluate rusfertide's efficacy, symptom burden, and safety for patients with uncontrolled hematocrit who are dependent on phlebotomy despite standard treatments. This trial aims to enroll 250 patients worldwide.

Protagonist has entered a collaboration and license agreement with Takeda to co-develop and co-commercialize rusfertide, marking a significant step toward providing PV patients with a new, potentially effective therapeutic option.