Plenary: The VERIFY trial

The plenary session of ASCO 2025 featured the primary results of the randomized, phase III VERIFY study, evaluating the hepcidin mimetic peptide rusfertide in the treatment of patients with polycythaemia vera (PV)

PV is a JAK-driven myeloproliferative neoplasm that is characterized by excessive red blood cell (RBC) production. This erythrocytosis increases the blood viscosity, potentially resulting in life threatening thrombotic events such as deep vein thrombosis or pulmonary embolism. PV also comes with a significant symptom burden, including severe fatigue, concentration problems, night sweats and pruritus, negatively impacting the quality of life of patients. The traditional treatment for patients with PV consists of repeated phlebotomies to reduce the haematocrit level (<45%) and reduce the thrombotic risk. However, these repeated phlebotomies fail to control the haematocrit level in a significant proportion of patients and often result in a profound iron deficiency.

Rusfertide is a first-in-class peptide that mimics hepcidin, the master regulator that controls iron homeostasis in the bone marrow for RBC production. By closing ferroportin channels and limiting iron transport to the bone marrow, rusfertide reduces iron availability for erythropoiesis, thereby mitigating RBC overproduction. Previously, the phase II REVIVE study showed that rusfertide was able to control RBC counts and reduce the need for a phlebotomy in patients with phlebotomy-dependent PV.

The randomized, placebo-controlled, phase 3 VERIFY trial evaluated rusfertide in patients with PV requiring phlebotomies. In both arms of the study, patients were allowed to continue their established cytoreductive therapy (e.g., hydroxyurea, interferon, ruxolitinib). VERIFY convincingly met its primary endpoint with 76.9% of patients obtaining a clinical response (i.e., absence of phlebotomy eligibility and no phlebotomy procedures from weeks 20 to 32) as compared to 32.9% in the control arm (p< 0.0001). In addition, rusfertide significantly reduced the average number of phlebotomies that patients needed (1.8 vs. 0.5; p< 0.0001). Over the first 32 weeks of the study, 72.8% of patients in the rusfertide arm did not require a phlebotomy, while this was only the case for 21.9% in the placebo arm. Finally, significantly more patients in the rusfertide arm were able to maintain a hematocrit level below 45% during the first 32 weeks of treatment (62.6% vs. 14.4%; p< 0.0001).

VERIFY also evaluated the impact of rusfertide on the symptom burden and the quality of life of patients. At 32 weeks, rusfertide was associated with a significant improvement in the PROMIS Fatigue SF-8a total T score and demonstrated a significant improvement compared to placebo in the MFSAF TSS7 score, a score that specifically assesses PV-related symptoms such as fatigue, night sweats, itching, abdominal discomfort, pain under the ribs, early satiety, and bone pain.

In conclusion, the VERIFY study showed that rusfertide significantly reduces the phlebotomy requirement, maintains hematocrit control, and improves disease-related symptoms in patients with PV. This identifies rusfertide as a potential new standard of care in this setting. The VERIFY study is still ongoing, with participants continuing rusfertide in an open-label extension part. This will allow the investigators to assess the durability of the responses to rusfertide and evaluate the impact of this agent on the thrombotic risk of PV patients.