Rusfertide Shows Superior Efficacy in Phase 3 Polycythemia Vera Trial

Close-up of a blood sample showing polycythemia vera cells: © sawaratch - stock.adobe.com

The phase 3 VERIFY study (NCT05210790) demonstrated that rusfertide (PTG-300), a hepcidin mimetic, significantly outperformed placebo in achieving clinical response among phlebotomy-dependent patients with polycythemia vera (PV).¹

Patients were randomized to receive either rusfertide or placebo as an add-on to standard-of-care treatment. Notably, rusfertide met the primary end point and all 4 key secondary end points of the trial, according to positive topline results.

For the primary end point of the proportion of patients achieving a response, which was defined as the absence of phlebotomy eligibility, there was a significantly higher proportion of clinical responders among rusfertide-treated patients with PV at 77% vs those who received placebo at 33% during weeks 20 to 32 (P <.0001).

The first key secondary end point looking at the pre-specified primary end point for European Union (EU) regulators, was also met. Here, there was a mean of 0.5 phlebotomies per patient treated with rusfertide vs 1.8 phlebotomies per patient given placebo during weeks 0 to 32 (P <.0001).

“The positive results of the phase 3 VERIFY study across the primary and all key secondary end points provide compelling evidence of the potential for rusfertide as a first-in-class erythrocytosis-specific agent to address unmet medical needs in patients with PV who are unable to achieve adequate hematocrit control despite standard of care treatments,” said Arturo Molina, MD, MS, chief medical officer of Protagonist, in a press release.

The additional 3 pre-specified key secondary end points examined hematocrit control and patient-reported outcomes using PROMIS Fatigue SF-8a3 and MFSAF TSS-74. Each was also reached with statistical significance in the study.

For safety, treatment with rusfertide was generally well tolerated, with findings in line with previous trials of the agent. There were no new safety findings identified, most adverse events (AEs) were grade 1/2 injection site reactions, and all serious AEs were not related to rusfertide. Additionally, there was no evidence of an increased risk of cancer among the patients given rusfertide vs those given placebo.

“We plan to submit additional details of these promising results for presentation at upcoming medical conferences in 2025. We are immensely grateful to the patients, study staff and principal investigators who made the VERIFY study possible,” added Molina.

About the Phase 3 VERIFY Trial of Rusfertide

Rusfertide is a first-in-class investigational hepcidin mimetic peptide therapeutic. The agent has been granted orphan drug and fast track designations from the FDA.

“Based on this preclinical data, the phase 2 randomized study [REVIVE; NCT04057040] was conducted in patients with PV who required phlebotomies with or without cytoreductive treatment. In that phase 2 study, the investigators saw that about 60% of patients became phlebotomy-independent. To confirm the results from the phase 2 study, we are now conducting a global, phase 3, placebo-controlled, randomized trial,” explained Aniket Bankar, MD, hematologist at Princess Margaret Cancer Center in Toronto, Canada, in an interview with Targeted Oncology^TM.

VERIFY is an ongoing, 3-part, global, randomized, placebo-controlled, phase 3 trial comparing the efficacy and safety of rusfertide when given at a starting dose of 20 mg subcutaneously once a week to placebo plus ongoing therapy for patients with PV. Experts are assessing treatment with rusfertide when given to 293 patients with polycythemia vera over a 156-week period.²

The study includes patients with uncontrolled hematocrit who are phlebotomy dependent despite standard of care treatment, which could include hydroxyurea, interferon and/or ruxolitinib. All patients enrolled in the trial have completed their participation in the randomized, placebo-controlled portion of the study, which examined the efficacy and safety of rusfertide plus current treatment vs placebo plus current treatment. Now, these patients are in the open-label portions of the trial.

The proportion of patients achieving a response during weeks 20 to 32 served as the primary end point of the study.

“We are encouraged by these results and excited about the potential of rusfertide to help patients living with PV. These patients may experience a high treatment burden, and severe symptoms can impact their quality of life,” said Andy Plump, MD, PhD, president of research and development at Takeda, in a press release.¹ “We are deeply committed to bringing additional treatment options to those living with blood cancers, including myeloid cancers such as PV.”

REFERENCES:

1. Protagonist and Takeda announce positive topline results from phase 3 VERIFY study of rusfertide in patients with polycythemia vera. News release. March 3, 2025. Accessed March 3, 2025. https://tinyurl.com/4as8vkx7

2. Bankar A, Pettit K, Shatzel J, et al. VERIFY: A randomized controlled phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera (PV). J Clin Oncol. 2024;42(suppl 16):34. doi:10.1200/JCO.2024.42.17_suppl.34