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

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

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

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

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 • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology • HOXD1 • 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

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

SAFETY AND PRELIMINARY PHARMACODYNAMIC EFFECTS OF THE FERROPORTIN INHIBITOR VAMIFEPORT (VIT-2763) IN PATIENTS WITH NON-TRANSFUSION-DEPENDENT BETA THALASSEMIA (NTDT): RESULTS FROM A PHASE 2A STUDY (EHA 2022) - P2a | "There were no clinically meaningful changes from baseline in serum iron or TSAT levels in the placebo group, or in ferritin or hepcidin levels in any treatment group. Conclusion In this 12-week Phase 2a study, vamifeport had a favorable safety and tolerability profile and showed promising target engagement and pharmacodynamic effects on serum iron and TSAT levels versus placebo in adults with NTDT."

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

Innovative Adaptive Study Design in Transfusion-Dependent Beta-Thalassemia: Bayesian Design with Concurrent Randomization and Borrowing from Historical Data (ASH 2021) - P2b | "We designed a Phase-2b, double-blind, randomized, placebo controlled, multi-center study with Vamifeport (NCT04938635) to assess the efficacy and safety of multiple doses of a new therapy in adults with transfusion-dependent beta-thalassemia...However, with a robustification weight of 0.5 the type-I errors can be controlled in line with regulatory requirements. Discussion A proposed Bayesian design with robustified informative prior for the control arm helps reduce patients' burden of randomization to control arm and reduce overall sample size for a rare disease trial when recruitment and trial duration are challenging."

Beta-Thalassemia • Genetic Disorders • Rare Diseases

Iron is a modifier of the phenotypes of JAK2-mutant myeloproliferative neoplasms. (PubMed, Blood) - "Alterations of iron availability primarily affected the pre-megakaryocyte erythrocyte progenitors (pre-MegE), which constitute the iron-responsive stage of hematopoiesis in JAK2-mutant mice. The orally administered ferroportin inhibitor vamifeport and the minihepcidin PR73 normalized hematocrit and hemoglobin levels in JAK2-V617F and E12 mutant mouse models of PV, suggesting that ferroportin inhibitors and minihepcidins could be used in the treatment of PV patients."

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

Genetic Iron Overload Aggravates and Pharmacological Iron Restriction Improves MDS Pathophysiology in a Preclinical Mouse Model (ASH 2022) - "Our results show for the first time in a preclinical mouse model of MDS that iron excess driven by ineffective erythropoiesis has pathological implication in transfusion-independent MDS. These effects are likely aggravated by transfusions causing additional iron overload. Finally, iron restriction achieved through pharmacologic FPN inhibition by the oral FPN inhibitor vamifeport significantly improves MDS pathophysiology, uncovering the therapeutic potential of early prevention of NTBI formation in MDS."

Preclinical • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Myelodysplastic Syndrome • Oncology • NUP98

Efficacy and Safety Study of Multiple Doses of VIT-2763 in Adults With Transfusion-dependent Beta-thalassemia (clinicaltrials.gov) - P2b | N=0 | Withdrawn | Sponsor: Vifor (International) Inc. | N=80 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Beta-Thalassemia • Genetic 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. | Active, not recruiting ➔ Recruiting

Enrollment open • 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) - P2a | N=24 | Active, not recruiting | Sponsor: Vifor (International) Inc. | Suspended ➔ Active, not recruiting

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