Rusfertide Improves Responses, Meets Primary End Point of REVIVE Trial in Polycythemia Vera

Arturo Molina, MD, MS

Treatment with rusfertide (PTG-300), a subcutaneous injectable hepcidin mimetic, led to a higher response rate of 69.2% vs 18.5% with placebo in patients with polycythemia vera (PV), meeting the primary end point of the phase 2 REVIVE trial (NCT04057040; P = .0003).¹

Responders included those who completed 12 weeks of double-blind treatment while maintaining hematocrit control without meeting criteria for phlebotomy or undergoing phlebotomy.

“Participants in our studies who required frequent phlebotomy, with or without cytoreductives, have now been treated with rusfertide for more than two years, remaining largely phlebotomy free,” Arturo Molina, MD, MS, chief medical officer of Protagonist, said in a press release. “Data from the REVIVE study suggest that rusfertide treatment results in a highly statistically significant reduction in the need for therapeutic phlebotomy in phlebotomy-dependent patients, leading to rapid, sustained, and durable control of hematocrit levels below 45%. Part 2 of REVIVE, the randomized withdrawal study, yielded no new safety findings while confirming previously reported efficacy and safety findings observed in the open-label portion of REVIVE [part 1].”

“These randomized withdrawal data from the REVIVE study indicate a dramatic difference in the experience of the treatment group versus the placebo group,” Ronald Hoffman, MD, the Albert A. and Vera G. List Professor of Medicine (Hematology and Oncology), director of the Myeloproliferative Research Program at the Icahn School of Medicine at Mount Sinai, and principal investigator of the study, said. “With robust and strongly positive results observed across a diverse set of patients, we now have further confirmation of rusfertide’s potential to serve as an important future treatment option for patients with PV.”

Patients with PV who have hematocrit levels above 45% are at a greater risk of thrombosis. Standard therapy for these patients includes therapeutic phlebotomy alone or in combination with cytoreductive agents. However, current therapies are not effective in reducing hematocrit levels below 45% and are not all well tolerated. Rusfertide is a hepcidin mimetic being developed as a non-cytoreductive option to maintain hematocrit levels below 45% in patients with PV.²

The phase 2 study enrolled patients with excessive erythrocytosis despite therapeutic phlebotomy (3 or more in the 6 months prior to enrolling) with or without cytoreductive therapy with a hematocrit level below 45% at study entry.

Eligible participants were first treated in a 28-week, open-label, dose-titration and efficacy evaluation phase (part 1).¹ Patients administered rusfertide in doses ranging from 10 mg to 120 mg weekly. Doses were adjusted each month to maintain hematocrit levels below 45%.²

Afterward, patients (n = 53) were randomly assigned 1:1 to rusfertide or placebo for another 12 weeks as part of the double-blind, placebo-controlled phase (part 2). Patients in this cohort had frequent phlebotomy requirements. Notably, 92.3% (n = 24/26) of patients in this cohort treated with rusfertide remained free from phlebotomy (P = .0003).

Additionally, the change from moderate or severe Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) symptom scores at baseline was statistically significant in fatigue, problems with concentration, inactivity, and itching during the 28-week, open-label portion of part 1 of the study.

A comparison of symptom assessments in part 2 was not made because most patients administered placebo had discontinued treatment prior to the 12-week MPN-SAF symptom assessment.

“All study subjects who participated in the REVIVE clinical trial had been previously unsuccessful in controlling their hematocrit using standard-of-care therapies alone,” Andrew Kuykendall, MD, Department of Malignant Hematology, Moffit Cancer Center, added. “These new data from REVIVE provide important insights into the role that rusfertide can potentially have within a future PV treatment paradigm, supporting patients and their physicians in achieving the treatment goal of hematocrit below 45%, in step with current National Comprehensive Cancer Network Clinical Practice Guidelines.”

Regarding safety, the agent was well tolerated, and no new adverse effects (AEs) were reported since the safety analysis was presented at the 2022 ASH Annual Meeting and Exposition. The most common AEs were localized injection site reactions.

Rusfertide is also under study in the ongoing, phase 3 VERIFY trial (NCT05210790) vs placebo in patients with PV maintaining hematocrit control and in improving symptoms of disease.³

“The new randomized withdrawal data confirm our previous efficacy and safety findings of rusfertide in PV and support our strong conviction that rusfertide can be a potentially transformational therapeutic option for polycythemia vera,” Dinesh V. Patel, PhD, president and chief executive officer of Protagonist, said. “With the completion of the REVIVE study, the company's topmost priority continues to be execution of the 250-patient global, pivotal, phase 3 VERIFY study in PV. The Protagonist team continues to work with full dedication alongside investigators, site staff and other partners with the shared aim of bringing this important potential therapy to PV patients.”

References

1. Protagonist Therapeutics announces highly statistically significant results from the randomized withdrawal portion of the REVIVE study of rusfertide in polycythemia vera. News release. Protagonist Therapeutics. March 15, 2023. Accessed April 3, 2023. https://www.yahoo.com/lifestyle/protagonist-therapeutics-announces-highly-statistically-113000427.html
2. Hoffman R, Ginzburg Y, Kremyanskaya M, et al. Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(suppl 16):7003. doi:10.1200/JCO.2022.40.16_suppl.7003
3. A phase 3 study of rusfertide in patients with polycythemia vera (VERIFY). ClinicalTrials.gov. Updated March 28, 2023. Accessed April 3, 2023. https://clinicaltrials.gov/ct2/show/NCT05210790