Vamifeport hydrochloride(Vamifeport hydrochloride) - 药物靶点：FPN1_在研适应症：β地中海贫血，全身性肉碱缺乏症，镰状细胞血症_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Vamifeport

靶点

FPN1

作用机制

FPN1抑制剂(膜铁转运蛋白-1抑制剂)

治疗领域

神经系统疾病心血管疾病遗传病与畸形+ [3]

在研适应症

β地中海贫血全身性肉碱缺乏症镰状细胞血症

非在研适应症

非输血依赖性地中海贫血输血依赖性β地中海贫血

原研机构

Vifor Pharma AG

在研机构

Vifor (International) AGVifor Fresenius Medical Care Renal Pharma France S.A.S.

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C21H21FN6O2

InChIKeyKNYVRFXIVWUGBZ-UHFFFAOYSA-N

CAS号2095668-10-1

关联

6

项与 Vamifeport hydrochloride 相关的临床试验

NCT05077436 / Completed临床1期

A Randomised, Open-Label, Food Effect and Formulation Bioavailability Study of Two Vamifeport Oral Formulations in Healthy Male and Female Adults

Two different vamifeport oral formulations will be administered in fed and fasted state to assess the vamifeport food-drug interaction and to assess the relative bioavailability (the proportion of drug entering the circulation) of 2 different vamifeport oral formulations in healthy adult participants.
Participants will be randomly allocated to one of four treatment sequences, with four dosing periods each, where different combinations of both formulations will be administered following fasted and fed state.
The total study duration for each participant is up to 7 weeks and 4 days.

开始日期2021-10-14

申办/合作机构

Vifor (International) AG

NCT04938635 / Withdrawn临床2期

A Phase 2b, Double-blind, Randomised, Placebo-controlled, Multicentre Study to Assess the Efficacy and Safety of VIT-2763 Multiple Doses in Adults With Transfusion-dependent Beta-thalassaemia

The main purpose of this study is to evaluate the efficacy of 3 multiple doses of VIT-2763 as measured by the reduction in red blood cell (RBC) transfusion burden from Week 13 to Week 24, to identify the most efficacious and safe dose.

开始日期2021-09-20

申办/合作机构

Vifor (International) AG

[+1]

NCT04817670 / Completed临床2期

A Phase 2a, Double-blind, Randomised, Placebo-controlled, Efficacy, and Safety Study of Multiple Doses of VIT-2763 in Subjects With Sickle Cell Disease

The purpose of this study is to investigate the effect of VIT-2763 on markers of hemolysis (breakdown in red blood cells) in sickle cell disease (SCD). The safety, tolerability and clinical beneficial effects of VIT-2763 for the treatment of SCD are also explored.

开始日期2021-06-18

申办/合作机构

Vifor (International) AG

[+1]

100 项与 Vamifeport hydrochloride 相关的临床结果

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100 项与 Vamifeport hydrochloride 相关的转化医学

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100 项与 Vamifeport hydrochloride 相关的专利（医药）

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10

项与 Vamifeport hydrochloride 相关的文献（医药）

2023-10-01·Haematologica

Ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of β-thalassemia with blood transfusions.

Article

作者: Altermatt, Patrick ; Nyffenegger, Naja ; Flace, Anna ; Dürrenberger, Franz ; Kalleda, Natarajaswamy ; Doucerain, Cédric ; Ingoglia, Giada ; Manolova, Vania

β-thalassemia is an inherited anemia characterized by ineffective erythropoiesis. Blood transfusions are required for survival in transfusion-dependent β-thalassemia and are also occasionally needed in patients with non-transfusion-dependent β-thalassemia. Patients with transfusion-dependent b-thalassemia often have elevated transferrin saturation (TSAT) and non-transferrin-bound iron (NTBI) levels, which can lead to organ iron overload, oxidative stress, and vascular damage. Vamifeport is an oral ferroportin inhibitor that was previously shown to ameliorate anemia, ineffective erythropoiesis, and dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia, under non-transfused conditions. Our study aimed to assess the effects of oral vamifeport on iron-related parameters (including plasma NTBI levels) and ineffective erythropoiesis following blood transfusions in Hbbth3/+ mice. A single dose of vamifeport prevented the transient transfusion-mediated NTBI increase in Hbbth3/+ mice. Compared with vehicle treatment, vamifeport significantly increased hemoglobin levels and red blood cell counts in transfused mice. Vamifeport treatment also significantly improved ineffective erythropoiesis in the spleens of Hbbth3/+ mice, with additive effects observed when treatment was combined with repeated transfusions. Vamifeport corrected leukocyte counts and significantly improved iron-related parameters (serum transferrin, TSAT and erythropoietin levels) versus vehicle treatment in Hbbth3/+ mice, irrespective of transfusion status. In summary, vamifeport prevented transfusion-mediated NTBI formation in Hbbth3/+ mice. 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.

2023-03-21·eLife

Structures of ferroportin in complex with its specific inhibitor vamifeport.

Article

作者: Lehmann, Elena Farah ; Liziczai, Márton ; Langini, Cassiano ; Sundstrom, Hanna ; Altermatt, Patrick ; Manolova, Vania ; Dürrenberger, Franz ; Drożdżyk, Katarzyna ; Manatschal, Cristina ; Dutzler, Raimund

A central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular iron exporter, and the peptide hormone hepcidin, which inhibits Fe²⁺ transport and induces internalization and degradation of FPN. Dysregulation of the FPN/hepcidin axis leads to diverse pathological conditions, and consequently, pharmacological compounds that inhibit FPN-mediated iron transport are of high clinical interest. Here, we describe the cryo-electron microscopy structures of human FPN in complex with synthetic nanobodies and vamifeport (VIT-2763), the first clinical-stage oral FPN inhibitor. Vamifeport competes with hepcidin for FPN binding and is currently in clinical development for β-thalassemia and sickle cell disease. The structures display two distinct conformations of FPN, representing outward-facing and occluded states of the transporter. The vamifeport site is located in the center of the protein, where the overlap with hepcidin interactions underlies the competitive relationship between the two molecules. 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.

2022-08-18·Blood

The oral ferroportin inhibitor vamifeport improves hemodynamics in a mouse model of sickle cell disease

Article

作者: Doucerain, Cédric ; Dürrenberger, Franz ; Flace, Anna ; Buehler, Paul W. ; Nyffenegger, Naja ; Ingoglia, Giada ; Zennadi, Rahima ; Manolova, Vania ; Kalleda, Natarajaswamy ; Buzzi, Raphael M. ; Schaer, Dominik J.

AbstractSickle cell disease (SCD) is an inherited hemolytic anemia caused by a single point mutation in the β-globin gene of hemoglobin that leads to synthesis of sickle hemoglobin (HbS) in red blood cells (RBCs). HbS polymerizes in hypoxic conditions, leading to intravascular hemolysis, release of free hemoglobin and heme, and increased adhesion of blood cells to the endothelial vasculature, which causes painful vaso-occlusion and organ damage. HbS polymerization kinetics are strongly dependent on the intracellular HbS concentration; a relatively small reduction in cellular HbS concentration may prevent HbS polymerization and its sequelae. We hypothesized that iron restriction via blocking ferroportin, the unique iron transporter in mammals, might reduce HbS concentration in RBCs, thereby decreasing hemolysis, improving blood flow, and preventing vaso-occlusive events. Indeed, vamifeport (also known as VIT-2763), a clinical-stage oral ferroportin inhibitor, reduced hemolysis markers in the Townes model of SCD. The RBC indices of vamifeport-treated male and female Townes mice exhibited changes attributable to iron-restricted erythropoiesis: decreased corpuscular hemoglobin concentration mean and mean corpuscular volume, as well as increased hypochromic and microcytic RBC fractions. Furthermore, vamifeport reduced plasma soluble VCAM-1 concentrations, which suggests lowered vascular inflammation. Accordingly, intravital video microscopy of fluorescently labeled blood cells in the microvasculature of Townes mice treated with vamifeport revealed diminished adhesion to the endothelium and improved hemodynamics. These preclinical data provide a strong proof-of-concept for vamifeport in the Townes model of SCD and support further development of this compound as a potential novel therapy in SCD.

100 项与 Vamifeport hydrochloride 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
β地中海贫血	临床前	以色列	Vifor (International) AG	2020-06-11
β地中海贫血	临床前	黎巴嫩	Vifor (International) AG	2020-06-11
β地中海贫血	临床前	黎巴嫩	Vifor (International) AG	2020-06-11
β地中海贫血	临床前	希腊	Vifor (International) AG	2020-06-11
β地中海贫血	药物发现	希腊	Vifor (International) AG	2020-06-11
非输血依赖性地中海贫血	药物发现	黎巴嫩	Vifor (International) AG	2020-06-11
非输血依赖性地中海贫血	药物发现	意大利	Vifor (International) AG	2020-06-11
非输血依赖性地中海贫血	药物发现	希腊	Vifor (International) AG	2020-06-11
非输血依赖性地中海贫血	药物发现	以色列	Vifor (International) AG	2020-06-11
非输血依赖性地中海贫血	药物发现	泰国	Vifor (International) AG	2020-06-11

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04364269 (VITHAL, CTgov)	临床2期	β地中海贫血 \| 非输血依赖性地中海贫血	35	Placebo	選觸醖壓鹹顧簾衊積淵(構鏇鬱膚齋鬱衊鬱觸構) = 鏇膚衊積餘衊製製鑰齋艱範壓夢廠鬱獵淵糧鹽 (膚鹹範糧衊網膚網構構, 壓願膚顧蓋憲鏇遞鹽遞 ~ 淵範網鹽夢蓋鏇繭範顧) 更多	-	2023-12-14
NCT04364269 (EHA2022) 人工标引	临床2期	输血依赖性β地中海贫血	25	Vamifeport hydrochloride (QD)	(觸憲選糧簾製鑰獵遞糧) = 範繭觸壓鏇繭齋齋窪選淵齋壓顧壓獵襯遞憲遞 (淵鹹簾顧願鹽壓衊鹽觸 ) 更多	积极	2022-05-12
NCT04364269 (EHA2022) 人工标引	临床2期	输血依赖性β地中海贫血	25	Vamifeport hydrochloride (BID)	(淵簾蓋廠壓壓製遞淵夢) = 積繭醖顧蓋範鬱壓齋鹹顧廠膚鏇鹹憲鹹積襯糧 (淵廠構鏇憲遞顧鹹鑰蓋 ) 更多	积极	2022-05-12