Rusfertide sharply cut the need for phlebotomy in polycythaemia vera

Rusfertide, an injectable drug that mimics the body's own iron-regulating hormone hepcidin, sharply reduced how often people with polycythaemia vera needed their blood drawn to control the disease, according to the phase 3 VERIFY trial [s1]. The result addresses a long-standing frustration in a blood cancer whose standard treatment — repeatedly removing blood by phlebotomy — is effective but burdensome, and one that many patients still fail to control [s1].

Polycythaemia vera is a myeloproliferative neoplasm, a disorder of the bone marrow in which the body overproduces red blood cells. The resulting thickening of the blood raises the risk of clots, strokes and heart attacks, so the central goal of care is to keep the haematocrit — the proportion of blood made up of red cells — below 45% [s1]. That is done with phlebotomy, often alongside cytoreductive drugs, but a substantial group of patients remains "phlebotomy-dependent," needing frequent venesection to stay in range [s1].

What the trial did

VERIFY randomly assigned patients who required frequent phlebotomy, in a 1:1 ratio and under double-blind conditions, to receive either rusfertide or placebo, with or without background cytoreductive therapy [s1]. The analysis reported here covers Part 1a, a 32-week comparison [s1]. In all, 293 patients took part — 147 assigned to rusfertide and 146 to placebo [s1]. The trial is registered as NCT05210790 and is now active but no longer recruiting [s2].

The primary endpoint was a "clinical response," defined as the absence of eligibility for phlebotomy across weeks 20 to 32 — in other words, keeping the haematocrit controlled without needing blood removed during that window [s1]. Key secondary measures included the average number of phlebotomies, the share of patients keeping haematocrit below 45%, and patient-reported fatigue and symptom scores [s1].

What it found

The difference was large. A clinical response was achieved by 113 patients on rusfertide — 77% — compared with 48 patients, or 33%, on placebo (P<0.0001) [s1]. Rusfertide also cut the mean number of phlebotomies to 0.5 (standard deviation 1.2), against 1.8 (SD 1.5) on placebo (P<0.0001) [s1]. And it was far better at holding the haematocrit target: 92 patients (63%) maintained a haematocrit below 45%, versus 21 patients (14%) on placebo (P<0.0001) [s1].

Beyond the blood counts, the drug moved the measures that patients feel. Rusfertide produced a statistically significant improvement over placebo on both the PROMIS Fatigue short-form score and the Myelofibrosis Symptom Assessment Form total symptom score, with P values of 0.0252 and 0.0240 respectively [s1]. On safety, the most common adverse events were injection-site reactions, anaemia and fatigue, and no deaths were reported in the trial [s1].

How to read it

The strength of VERIFY is that its primary endpoint is not a laboratory surrogate alone but a clinically meaningful one: whether a patient could get through the measurement window without needing a phlebotomy, which is the daily reality the treatment is meant to change [s1]. The effect on that endpoint, and on the haematocrit-control and phlebotomy-count measures, was consistent and large, and the symptom scores moved in the same direction [s1]. Rusfertide works by a different mechanism from existing cytoreductive drugs — it restricts the iron supply that feeds red-cell production rather than suppressing the marrow broadly — which is why it was tested on top of standard care rather than against it [s1].

The appropriate caution is that the data reported here cover a 32-week window [s1]. Polycythaemia vera is a lifelong disease, and the outcomes that matter most over years — strokes, heart attacks, blood clots, and progression to more aggressive marrow diseases — are not what a 32-week phlebotomy-avoidance endpoint directly measures. Injection-site reactions and anaemia are the kind of on-treatment effects that will need watching as longer follow-up accrues [s1]. For context on how the field has tried to control these neoplasms with older agents, see our coverage of interferon versus hydroxyurea in myeloproliferative neoplasms.

What to watch

The questions now are about durability and hard outcomes: whether the phlebotomy benefit holds over the longer phases of the trial, whether tighter haematocrit control translates into fewer clotting events, and how the anaemia signal behaves with continued dosing [s1]. VERIFY has shown that a hepcidin-mimic drug can take much of the phlebotomy burden off patients who are hardest to control; whether that convenience also buys protection from the disease's most dangerous complications is the next thing the trial will have to demonstrate [s1][s2].

This article describes research and is not medical advice. Treatment of polycythaemia vera is a decision for patients and their haematologists.