Takeda files NDA with FDA for rusfertide in polycythemia vera

Japan’s Takeda Pharmaceutical (TSE: 4502 / NYSE: TAK) and partner California-based Protagonist Therapeutics, Inc. (NASDAQ: PTGX) announced an NDA filing with the US FDA for rusfertide, a first-in-class hepcidin mimetic peptide, for the treatment of adults with polycythemia vera (PV). With the filing granted Priority Review treatment, the Prescription Drug User Fee Act (PDUFA) target action date has been set for Q3 2026. The priority review award adds to previous grants of Breakthrough Therapy Designation, Fast Track Designation, and Orphan Drug Designation for rusfertide.

The VERIFY Study and Supporting Clinical Data for Rusfertide

The NDA submission was primarily supported by the Phase III VERIFY study (NCT05210790), an ongoing three-part, global, randomized, placebo-controlled trial evaluating rusfertide in 293 patients with polycythemia vera over a 156-week period. The VERIFY study rusfertide results showed that the drug met its primary endpoint — the proportion of patients achieving a response during Weeks 20–32, defined as the absence of phlebotomy eligibility — and all four key secondary endpoints. Phlebotomy eligibility in the trial required a confirmed hematocrit of 45% or higher that was at least 3 percentage points above baseline, or a hematocrit of 48% or higher.

Patients receiving rusfertide plus current standard of care demonstrated a higher response rate compared to standard of care alone. The response encompassed hematocrit control, reduction in phlebotomy requirements, and improvement in patient-reported outcomes measuring fatigue and symptom burden. Through 52 weeks, the most common treatment-emergent adverse events among rusfertide-treated patients were injection site reactions (47.4%), anemia (25.6%), and fatigue (19.6%), predominantly grade 1 or 2. Serious adverse events occurred in 8.1% of rusfertide-treated patients overall.

The NDA also incorporated four-year efficacy and safety data from the Phase II REVIVE study (NCT04057040), which enrolled 70 patients in dose-finding, 59 in a blinded randomized withdrawal portion, and 58 in an open-label expansion, as well as from the long-term extension THRIVE study (NCT06033586), which continues to follow 46 patients who transitioned from REVIVE.

Rusfertide: the industry context

Protagonist Therapeutics discovered rusfertide using its proprietary constrained peptide platform and led development from early-stage work through Phase III. In January 2024, Takeda and Protagonist entered into a worldwide license and collaboration agreement for rusfertide with Takeda leading global regulatory submissions. Protagonist retains an option to co-commercialize rusfertide in the US through a 50/50 profit-and-loss-share structure.

PV is a myeloproliferative neoplasm characterized by erythrocytosis — the overproduction of red blood cells — which increases blood viscosity and elevates the risk of thrombotic events including stroke, deep vein thrombosis, and pulmonary embolism. The primary treatment goal is maintaining hematocrit below 45%. Current standard of care consists of therapeutic phlebotomy, low-dose aspirin, and cytoreductive agents such as hydroxyurea, pegylated interferon alfa, and ruxolitinib (Jakafi, Incyte). Ropeginterferon alfa-2b (Besremi, PharmaEssentia) received FDA approval in 2021 as the first interferon specifically indicated for PV regardless of treatment history. Despite these options, a substantial proportion of patients remain phlebotomy-dependent and continue to experience symptom burden including fatigue, pruritus, and night sweats. No therapy currently approved for PV treatment directly targets the hepcidin–ferroportin axis that governs iron-restricted erythropoiesis.

Rusfertide occupies a distinct mechanistic position. As a synthetic hepcidin mimetic, it binds ferroportin (SLC40A1) and induces its internalization, restricting iron availability for red blood cell production. No other hepcidin mimetic has reached NDA stage in any indication.

Several molecules targeting the same biological axis are in earlier-stage development, though these are being studied for iron-loading anemias instead of PV. Examples include Disc Medicine’s DISC-0974 (jatacimab), and CSL Vifor’s Vamifeport (VIT-2763), a small-molecule ferroportin inhibitor.