Rusfertide Leads to Controlled Hematocrit Levels and Fewer Phlebotomies in Polycythemia Vera

Naveen Pemmaraju, MD

Findings from 2 clinical trials showed that treatment with rusfertide (PTG-300) helped patients with polycythemia keep their hematocrit levels under 45% and significantly reduced their need for period therapeutic phlebotomies, according to a presentation from the Society of Hematologic Oncology Annual Meeting (SOHO).¹

Lead study author Naveen Pemmaraju, MD, an associate professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, provided the update.

Currently, there are few treatment options for patients with PV that can help to control hematocrit levels and reduce the need for phlebotomy and the incidence of thrombosis.

Rusfertide is an injectable synthetic mimetic of hepcidin, a natural hormone, that is currently in clinical development as a noncytoreductive treatment option for PV. Hepcidin regulates iron absorption, distribution, and storage, controlling the body’s production of red blood cells. The synthetic agent is suggested to offer greater potency, stability, and solubility than with the natural hormone.²

In June 2021, the FDA granted the agent a breakthrough therapy designation as a treatment option for patients with PV.³

The agent has been investigated in several clinical trials of patients with PV, including 2 phase 2 studies: REVIVE (NCT04057040) and PACIFIC (NCT04767802). These 2 clinical trials were placed on a clinical hold by the FDA in September 2021 after the identification of a nonclinical finding in a 26-week rasH2 transgenic mouse model study showing benign and malignant subcutaneous skin tumors.⁴ The full clinical was then lifted in October 2021 following a review by the FDA. New safety and stopping rules were added to the study protocols for the protection of patients in the ongoing studies. No other unexpected safety signals were reported during the review.⁵

The REVIVE study is a randomized phase 2 trial of patients with PV requiring phlebotomy consisting of 3 parts: a 28-week open-label dose-escalation phase in which the dose of rusfertide is titrated until hematocrit levels below 45% can be achieved; a 12-week blinded, randomized, withdrawal phase in which patients receive rusfertide or placebo; and an open-label extension lasting up to 3 years. Treatment was administered subcutaneously at doses between 10 mg and 120 mg weekly.

About 80 patients were enrolled in the trial. Patients were allowed to still be receiving cytoreductive therapy or hydroxyurea, interferon, or ruxolitinib (Jakafi) as long as they were on a relatively stable dose of therapy. Those with post-PV myelofibrosis or known immunodeficiency were excluded from the study.

The primary end point was the proportion of responders during the blinded, randomized, withdrawal portion of the trial. Secondary end points included the change in phlebotomy requirements and the number of patients achieving a response by week 29.

PACIFIC is an open-label, single-arm phase 2 trial of patients with PV and elevated hematocrit levels of about 48% where current therapies cannot control these levels. The study took place in 2 parts: an induction phase, in which patients received induction with 40-mg subcutaneous rusfertide twice weekly until hematocrit levels dipped below 45%, and a continuation phase with weekly dosing of rusfertide, with treatment lasting up to 52 weeks.

Approximately 20 patients were enrolled in the study who had all other causes of erythrocytosis ruled out. Those with clinically significant thrombosis, post-PV myelofibrosis, infection, immunodeficiency, active hepatitis or HIV, or a history of invasive malignancy were excluded from the study.

The trial sought to determine the safety and efficacy of rusfertide.

Pemmaraju will provide an update to findings, which has showed that patients were mostly able to be without phlebotomy and maintain hematocrit levels below 45% in the REVIVE study. Additionally, ferritin levels normalized with the use of rusfertide. In the PACIFIC study, hematocrit levels under 45% were maintained for about 6 weeks.

When dosing stopped in both studies with the clinical hold, patients required phlebotomy again, hematocrit levels increased, red blood cell counts rose, and serum ferritin levels dropped. After the hold was lifted, levels normalized and patients no longer required phlebotomy once again.

These data provide support for the ongoing, randomized phase 3 VERIFY trial (NCT05210790), which intends to enroll about 250 patients with PV who require frequent phlebotomy. In the first part of the study, patients will be randomly assigned in a blinded fashion to receive either rusfertide or placebo plus standard therapy for 32 weeks. The second part is an open-label phase where rusfertide treatment is ongoing for 124 weeks.

The primary end point is patients achieving a response and secondary end points include changes in phlebotomy, total fatigue scores, and myelofibrosis symptoms.

References

1. Pemmaraju N, Kuykendall A, Kremyanskaya M, et al. Rusfertide (PTG-300) treatment interruption reverses hematological gains and upon reinitiation, restoration of clinical benefit observed in patients with polycythemia vera. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Abstract MPN-469.
2. Product candidates: rusfertide (PTG-300). Protagonist Therapeutics. Accessed September 8, 2022. https://bit.ly/3ihxucZ
3. Protagonist Therapeutics receives FDA breakthrough therapy designation for rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 3, 2021. Accessed September 8, 2022. https://bit.ly/3vRx6Gd
4. Protagonist Therapeutics reports FDA clinical hold on rusfertide clinical development program. News release. Protagonist Therapeutics. September 17, 2021. Accessed September 8, 2022. https://bit.ly/3iUiLUY
5. Protagonist Therapeutics announces removal of FDA clinical hold on the rusfertide clinical development program. News release. Protagonist Therapeutics. October 11, 2021. Accessed September 8, 2022. https://bit.ly/2YF5nge