ACVR1 signaling and hepcidin axis

Current understanding

ACVR1 (ALK2) signaling, activated by BMP6 and elevated inflammatory cytokines in MPN, drives hepatic hepcidin transcription and contributes to functional iron restriction and anemia of myelofibrosis. Pharmacologic ACVR1 inhibition (as a component of momelotinib’s mechanism, and now of gecacitinib hydrochloride’s dual JAK/ACVR1 activity) suppresses hepcidin and improves erythropoiesis, distinguishing this class from selective JAK inhibitors. The mechanism is increasingly leveraged in combination with JAK-STAT blockade and is being extended into the peri-transplant setting for aGVHD prophylaxis.

Evidence log

• 2026-10-04 — Momelotinib induces hemoglobin improvement and symptom control in PCM1::JAK2-associated myeloid neoplasm.: Case report of momelotinib yielding hemoglobin improvement in PCM1::JAK2-associated myeloid neoplasm supports that ACVR1-mediated hepcidin suppression can restore erythropoiesis even in rare JAK2-fusion-driven disease, not only JAK2V617F MF. (novelty: 3)
• 2026-09-01 — FDA Approves Mimrylo (rusfertide) for Polycythemia Vera: FDA approval of rusfertide (Mimrylo) on 2026-08-28 for erythrocytosis in PV is the first regulatory validation of a hepcidin-mimetic acting downstream of the ACVR1/BMP-hepcidin axis, establishing direct hepcidin agonism as a distinct therapeutic node from ACVR1 kinase inhibition. (novelty: 4)
• 2026-08-31 — FDA Approves First-of-its-Kind Drug for Polycythemia Vera (Rusfertide/Mimrylo): FDA approval of rusfertide (Mimrylo), the first hepcidin-mimetic drug, for inadequately controlled polycythemia vera clinically validates direct hepcidin agonism as a therapeutic strategy for iron/erythrocytosis control — the first regulatory endorsement of a hepcidin-axis intervention in MPN. (novelty: 4)
• 2026-06-15 — A Study of Rusfertide in Japanese Adults With Polycythemia Vera: Japanese open-label study of rusfertide (hepcidin mimetic) in PV evaluates long-term hematocrit control and phlebotomy reduction, extending the hepcidin-agonism therapeutic strategy (parallel to TMPRSS6 inhibition) to a new ethnic population over up to 244 weeks. (novelty: 3)
• 2026-06-01 — A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera: Sapablursen (ISIS 702843), a TMPRSS6-targeting antisense oligonucleotide, is being evaluated in PV to upregulate hepcidin and restrict iron-driven erythrocytosis — providing a mirror-image therapeutic use of the hepcidin axis (raising rather than lowering hepcidin) and engaging the regulatory circuit upstream via TMPRSS6/HJV rather than via ACVR1 kinase activity. (novelty: 4)
• 2026-02-05 — A Study of Elritercept Alone or Together With Ruxolitinib in Adults With Myelofibrosis: Elritercept early-phase trial in MF probes a SMAD2/3 ligand-trap mechanism that may indirectly affect iron-restricted erythropoiesis, offering a non-ACVR1-kinase route distinct from momelotinib/gecacitinib’s direct ACVR1 inhibition. (novelty: 4)
• 2026-02-04 — Treating Anemia in Myelofibrosis With Repurposed Drugs (Nelfinavir) That Restore Iron Delivery to the Bone Marrow: A phase I/II trial of repurposed HIV protease inhibitor nelfinavir tests whether restoring iron delivery to the marrow can improve MF anemia, suggesting a non-ACVR1 pharmacologic route to relieve iron-restricted erythropoiesis distinct from momelotinib/gecacitinib. (novelty: 4)
• 2026-02-27 — Efficacy and Safety of Gecacitinib Hydrochloride in Prophylaxis Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Myelofibrosis: cross-connection with jak-stat-signaling: Gecacitinib’s dual JAK/ACVR1 inhibition explicitly couples JAK-STAT blockade with ACVR1/hepcidin-axis suppression in a single agent, extending the precedent set by momelotinib. (novelty: 4)

Open questions

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