vamifeport (VIT-2763) / CSL Behring - LARVOL DELTA

Safety and pharmacodynamics of the ferroportin inhibitor vamifeport in patients with non-transfusion-dependent β-thalassemia: results from a randomized phase 2a study. (PubMed, Orphanet J Rare Dis) - P2 | "In this 12-week study, vamifeport had a favorable safety/tolerability profile, with no changes in hemoglobin levels ≥ 1.0 g/dL, and promising pharmacodynamic effects versus placebo in adults with β-NTDT."

Clinical • Journal • P2a data • PK/PD data • Beta-Thalassemia • Genetic Disorders • Hematological Disorders

Combination Therapy with Luspatercept and the Ferroportin Inhibitor Vamifeport Is Superior to Either Drug Alone in Improving Anemia and Reducing Myeloid Skewing in MDS (ASH 2023) - "In conclusion, our results show that iron restriction by vamifeport enhances the erythroid maturation action of luspatercept, likely by improving iron utilization in erythroid cells and ameliorating their survival. Furthermore, vamifeport improves the myeloid skewing in the MDS model, suggesting disease-modifying activity as single agent as well as combined therapy with luspatercept. Together, these data prove that combo therapies aimed at restricting iron and boosting erythroid maturation may offer additive beneficial effects in MDS and provide pre-clinical evidence for combining iron restriction and TFG-β superfamily ligand-trap approaches as more effective therapeutic strategies for the treatment of MDS."

Combination therapy • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology • ITGAM • NUP98 • TGFB1

Iron Restriction Alleviates β-Thalassemia By Stimulating ULK1-Mediated Autophagy of Free α-Globin (ASH 2023) - "We showed previously that β-thalassemic erythroblasts can eliminate free α-globin by ULK1-mediated autophagy and that this process is stimulated by rapamycin inhibition of mTORC1, which phosphorylates ULK1 to inhibit its activity...Mechanistically, long-term administration of vamifeport was associated with inhibition of mTORC1, as evidenced by 32% reductions in the phosphorylation of its substrate, ribosomal protein S6 kinase (p=0.004), and activation of the heme-regulated eIF2α kinase (HRI), indicated by increased phosphorylation of eIF2α and/or accumulation of the HRI effector transcription factor ATF4...Additional mechanisms for iron regulation of mTORC1 activity are also possible. Our findings provide new insight into the mechanisms by which iron restriction alleviates β-thalassemia and illustrate how metabolic regulators of erythropoiesis impact the severity of β-thalassemia by eliminating free α-globin through a key protein quality control pathway."

Beta-Thalassemia • Genetic Disorders • Hematological Disorders • ATF4 • HBB • ULK1

Iron at the Crossroads Between Erythropoiesis and Megakaryopoiesis (ASH 2024) - "Dr. Skoda will describe the effects of iron deficiency and iron overload on the iron-responsive progenitor stages that decide between erythroid and megakaryocytic lineage choices and compare the effects of orally administered ferroportin inhibitor vamifeport and the minihepcidin PR73 on hemoglobin and iron parameters in JAK2 -V617F and E12 mutant mouse models."

Anemia • Essential Thrombocythemia • Genetic Disorders • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • JAK2

Rotenone induces ferroptosis and neurotoxicity through inhibition of SIRT1-Nrf2-ferroportin 1/GPX4 pathways in SH-SY5Y cells and mice. (PubMed, Chem Biol Interact) - "VIT-2763 and RSL4, the inhibitors of Fpn-1 and GPX4, counteracted the protective effects of SIRT1-Nrf2 axis against rotenone-induced ferroptosis. Finally, we revealed reduced expression of SIRT1-Nrf2 axis in rotenone-treated mice and activation SIRT1-Nrf2 by agonists ameliorated rotenone-induced ferroptosis of dopaminergic neuron and improved gait abnormality in mice. Taken together, we revealed that rotenone induced neuron ferroptosis through iron accumulation and lipid peroxidation via inhibition of SIRT1-Nrf2 axis, providing additional evidence for the mechanisms of pesticide-induced neurotoxicity and related PD."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • GPX4

Pharmacologic Inhibition of Erythrocyte Ferroportin Expression Exacerbates Plasmodium Infection. (PubMed, Microorganisms) - "In P. yoelii infected mice, VIT-2763 treatment suppressed hepcidin expression and increased ferroportin expression in hepatocytes, while reducing ferroportin protein levels in RBCs. VIT-2763 mediated exacerbation of P. yoelii infection reveals the tissue-specific regulation of ferroportin in hepatocytes and RBCs, underscoring the therapeutic potential of modulating the hepcidin-ferroportin axis as an intervention strategy in malaria."

Journal • Hematological Disorders • Hepatology • Infectious Disease • Liver Failure • Malaria

Effect of Food on the Oral Bioavailability of a Prolonged-release Formulation of Vamifeport in Healthy Adults (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: CSL Behring | Active, not recruiting ➔ Completed

Trial completion

Effect of Food on the Oral Bioavailability of a Prolonged-release Formulation of Vamifeport in Healthy Adults (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: CSL Behring | Recruiting ➔ Active, not recruiting

Enrollment closed

Effect of Food on the Oral Bioavailability of a Prolonged-release Formulation of Vamifeport in Healthy Adults (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: CSL Behring | Not yet recruiting ➔ Recruiting

Enrollment open

Effect of Food on the Oral Bioavailability of a Prolonged-release Formulation of Vamifeport in Healthy Adults (clinicaltrials.gov) - P1 | N=28 | Not yet recruiting | Sponsor: CSL Behring

New P1 trial

Pharmacokinetics and Pharmacodynamics of Two Prolonged-release Formulations of Vamifeport in Healthy Adults (clinicaltrials.gov) - P1 | N=22 | Completed | Sponsor: CSL Behring | Active, not recruiting ➔ Completed

Trial completion

Pharmacokinetics and Pharmacodynamics of Two Prolonged-release Formulations of Vamifeport in Healthy Adults (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: CSL Behring | Not yet recruiting ➔ Active, not recruiting

Enrollment closed

Pharmacokinetics and Pharmacodynamics of Two Prolonged-release Formulations of Vamifeport in Healthy Adults (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: CSL Behring

New P1 trial

Genetic iron overload aggravates and pharmacological iron restriction improves MDS pathophysiology in a preclinical study. (PubMed, Blood) - "Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared to single treatments, and offers additive beneficial effects in MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Psychiatry

Vamifeport: Monography of the First Oral Ferroportin Inhibitor. (PubMed, J Clin Med) - "Preliminary data in NTD thalassemic patients also confirm the safety and efficacy in decreasing iron level. In conclusion, vamifeport represents a new option in the panorama of drugs targeting the hepcidin-ferroportin axis, but its efficacy is still under investigation as a single agent."

Journal • Review • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease

The oral ferroportin inhibitor vamifeport prevents liver iron overload in a mouse model of hemochromatosis. (PubMed, Hemasphere) - "At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in Hfe C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the Hfe C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy."

Journal • Preclinical • Genetic Disorders • Hematological Disorders • Hepatology • HAMP

COMBINATION THERAPY WITH LUSPATERCEPT AND THE FERROPORTIN INHIBITOR VAMIFEPORT IS SUPERIOR TO EITHER DRUG ALONE IN IMPROVING MDS PATHOPHYSIOLOGY (EHA 2024) - "In conclusion, our results show that iron restriction by vamifeport enhances the erythroid maturation action ofluspatercept, likely by improving iron utilization in erythroid cells and ameliorating their survival. Furthermore,vamifeport improves the myeloid skewing in the MDS model, suggesting disease-modifying activity as singleagent as well as combined therapy with luspatercept. Together, these data prove that combo therapies aimedat restricting iron and boosting erythroid maturation may offer additive beneficial effects in MDS and providepre-clinical evidence for combining iron restriction and TFG-β superfamily ligand-trap approaches as moreeffective therapeutic strategies for the treatment of MDS."

Combination therapy • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology • ITGAM • NUP98 • TGFB1

Ferroportin inhibitor vamifeport (EHA 2024) - No abstract available

Hematological Disorders

Study to Assess Efficacy and Safety of VIT-2763 (Vamifeport) in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=25 | Completed | Sponsor: Vifor (International) Inc. | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study to Assess Efficacy and Safety of VIT-2763 (Vamifeport) in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Vifor (International) Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study to Assess Efficacy and Safety of VIT-2763 (Vamifeport) in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: Vifor (International) Inc. | Phase classification: P2a ➔ P2 | Trial completion date: Dec 2023 ➔ Apr 2024 | Trial primary completion date: Nov 2023 ➔ Apr 2024

Phase classification • Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

VITHAL: Safety, Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Preliminary Efficacy of VIT-2763 in β-thalassaemia (clinicaltrials.gov) - P2 | N=35 | Completed | Sponsor: Vifor (International) Inc. | Phase classification: P2a ➔ P2 | N=25 ➔ 35

Enrollment change • Phase classification • Beta-Thalassemia • Genetic Disorders

Ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of β-thalassemia with blood transfusions. (PubMed, Haematologica) - "When given alone or combined with blood transfusions, vamifeport also ameliorated anemia, ineffective erythropoiesis, and dysregulated iron homeostasis. Administering vamifeport together with repeated blood transfusions additively ameliorated anemia and ineffective erythropoiesis in this mouse model, providing preclinical proof-of-concept for the efficacy of combining vamifeport with blood transfusions in β-thalassemia."

Journal • Preclinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders

Study to Assess Efficacy and Safety of VIT-2763 (Vamifeport) in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2a | N=24 | Recruiting | Sponsor: Vifor (International) Inc. | Trial completion date: Sep 2023 ➔ Dec 2023 | Trial primary completion date: Aug 2023 ➔ Nov 2023

Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Structures of ferroportin in complex with its specific inhibitor vamifeport. (PubMed, Elife) - "The introduction of point mutations in the binding pocket of vamifeport reduces its affinity to FPN, emphasizing the relevance of the structural data. Together, our study reveals conformational rearrangements of FPN that are of potential relevance for transport, and it provides initial insight into the pharmacological targeting of this unique iron efflux transporter."

Journal • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease