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

Ferritin Normalization Is Not Disease Control in HFE-Related Hemochromatosis: Residual Risk, Transferrin Saturation, and the Hepcidin-Ferroportin Axis. (PubMed, Eur J Haematol) - "It further explores novel hepcidin-ferroportin axis targeted treatments, including the hepcidin mimetic rusfertide, the oral ferroportin inhibitor vamifeport, and agents targeting TMPRSS6. Crucially, it highlights that these agents are still investigational and acknowledges that not all persistent morbidity in p.C282Y homozygotes stems from iron deposition. Nevertheless, the combination of high treatment burden, circulating iron toxicity unmeasured by ferritin, and continued tissue and organ risk post-ferritin normalization indicates that disease management in HFE-related hemochromatosis must look beyond ferritin alone, supporting the need for clinical trials to evaluate disease-targeted interventions rigorously."

Journal • Review • Diabetes • Genetic Disorders • Hematological Disorders • Hepatology • Immunology • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Osteoarthritis • Pain • Rheumatology • TMPRSS6

THE FERROCLEAR PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY: ADDRESSING PATIENT NEEDS IN HEREDITARY HEMOCHROMATOSIS THROUGH A NOVEL TARGETED APPROACH (EHA 2026) - P2 | "Vamifeport is a small-molecule, oral FPN inhibitor that acts as a hepcidin mimetic and has been shown to reduce dietary iron absorption and restore balanced iron distribution in organs...The FERROCLEAR study will provide data on whether modulating the FPN axis with a targeted pharmacologic approach can effectively reduce liver iron concentration and improve patient outcomes. The study details are available at ClinicalTrials.gov (NCT07332091)."

Clinical • P2 data • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hematological Disorders • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Solid Tumor

Efficacy and Safety of Vamifeport in Adult Participants With Homeostatic Iron Regulator Gene (HFE)-Related Hereditary Hemochromatosis (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: CSL Behring | N=50 ➔ 84

Enrollment change • Trial initiation date • Genetic Disorders • Hematological Disorders

Efficacy and Safety of Vamifeport in Adult Participants With Homeostatic Iron Regulator Gene (HFE)-Related Hereditary Hemochromatosis (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: CSL Behring

New P2 trial • Genetic Disorders • Hematological Disorders

CSL624_2001: Efficacy and safety of vamifeport in adult subjects with HFE-related hereditary hemochromatosis (clinicaltrialsregister.eu) - P1/2 | N=29 | Not yet recruiting | Sponsor: CSL Behring LLC

New P1/2 trial • Genetic Disorders • Hematological Disorders

Repurposing vamifeport for lupus nephritis. (PubMed, Nat Rev Rheumatol) - No abstract available

Journal • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology

Vamifeport, a clinical stage oral ferroportin inhibitor, alleviates murine lupus nephritis: A pilot study. (PubMed, Clin Immunol) - "We identified that vamifeport reduces ferroportin expression on primary monocytes and attenuates LN serum-induced inflammation in monocyte-derived macrophages (MDM), but not in human renal proximal tubular epithelial cells (ferroportin-expressing cells in the kidney). Collectively, our study suggests that vamifeport has a high potential to be further developed clinically as an adjunct therapeutic to treat LN."

Journal • Preclinical • Beta-Thalassemia • Genetic Disorders • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology

Efficacy and Safety of Vamifeport in Adult Participants With Homeostatic Iron Regulator Gene (HFE)-Related Hereditary Hemochromatosis (clinicaltrials.gov) - P2 | N=84 | Recruiting | Sponsor: CSL Behring | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders

Ferroportin Inhibition Attenuates Pulmonary Hypertension in Hypoxic Sickle Cell Disease Mice. (PubMed, Blood Adv) - "Indeed, attenuation of red cell sickling, less extra- and intravascular hemolysis and normalization of cardiopulmonary dysfunction was observed after vamifeport treatment. We suggest that induction of mild iron deficiency anemia may attenuate deadly sequelae of SCD, including cardiopulmonary dysfunction."

Journal • Preclinical • Cardiovascular • Genetic Disorders • Heart Failure • Hematological Disorders • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Sickle Cell Disease • HBB

Efficacy and Safety of Vamifeport in Adult Participants With Homeostatic Iron Regulator Gene (HFE)-Related Hereditary Hemochromatosis (clinicaltrials.gov) - P2 | N=84 | Not yet recruiting | Sponsor: CSL Behring

New P2 trial • Genetic Disorders • Hematological Disorders

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