Development of a Clinical Hemoglobin Modulator

临床血红蛋白调节剂的开发

• 批准号: 10428368
• 负责人: Douglas V Faller
• 金额: $ 163万
• 依托单位: PHOENICIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428368
• 关键词: Adult; Amino Acids; Benign; Benserazide; Bilirubin; Biological Assay; Canada; Cells; Chemicals; Chronic; Clinical; Clinical Trials; Development; Disease; Dose; Drug Kinetics; Erythrocytes; Erythroid; Europe; Fetal Development; Fetal Hemoglobin; Genes; Genetic; HDAC3 gene; Half-Life; Hematocrit procedure; Hematological Disease; Hemoglobin; Hemoglobin A; Hemoglobinopathies; Hemolysis; Hemolytic Anemia; Human; Libraries; Medical; Medicine; Modality; Molecular; Oral; Oral Medicine; Organ; Papio; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Primates; Production; Research; Reticulocytes; Safety; Severities; Sickle Cell; Sickle Cell Anemia; Structure; Tablets; Therapeutic; Transgenic Mice; beta Thalassemia; cohort; decarboxylase inhibitor; fetal; gamma Globin; global health; high throughput screening; infancy; molecular targeted therapies; mortality; nonhuman primate; progenitor; promoter; small molecule; stem cells; thalassemia intermedia

The β-thalassemias and hemoglobinopathies are serious genetic blood diseases, which are WHO-designated as a growing global health burden. The disorders decrease production or alter the structure of the β-chain of adult hemoglobin A, and cause hemolytic anemia, chronic organ damage, and early mortality. Fetal globin (HbF) is another type of normal hemoglobin, which is expressed during fetal development but suppressed in infancy. Decades of research have shown that any incremental increase in HbF reduces the severity of sickle cell disease and β- thalassemia. Pharmacologic augmentation of fetal hemoglobin (γ-globin chain) production, is accepted as one therapeutic modality to reduce the underlying pathology. We applied high- throughput screening to study a library of drugs currently approved by the EMA or FDA for other medical conditions, identified a small panel of previously unrecognized drugs which induce the fetal globin gene, and validated their action in patients’ red blood cell progenitors, nonhuman primates, and transgenic mice. One therapeutic, Benserazide, induced fetal globin up to 30-fold over baseline with intermittent oral treatment in anemic baboons, and was found to abolish, suppress, or displace 4 potent molecular repressors of the fetal gene promoter, BCL11A, LSD-1, KLF-1, and HDAC3, causing “chemical gene editing”. Benserazide has been used for 4 decades in Europe and Canada as an amino acid decarboxylase inhibitor, to enhance the PK of another active agent in a combination tablet for treatment of Parkinson’s disease, has a benign safety profile and is considered safe at chronic doses up to 1300 mg per day. This proposal will evaluate Benserazide at human equivalent doses extrapolated from active dosing in anemic baboons and transgenic mice, for tolerability, pharmacokinetics, and fetal globin expression assays in up to 24 patients with beta thalassemia intermedia and up to 12 patients with sickle cell disease. The Aims include: Aim I: To evaluate tolerability and PK of 3 doses of Benserazide in 24 beta thalassemia intermedia (BTI) patients, in 3 dose-escalating cohorts and an expansion cohort treated for 12 weeks Aim II: To investigate preliminary activity of Benserazide in inducing HbF expression in up to 16 BTI patients, and in one cohort of patients with sickle cell disease, as change from baseline in: IIa. F-reticulocytes, F-cells, MFI, HbF, total hemoglobin and hematocrit IIb. Assays of markers of hemolysis (STfr, LDH, bilirubin) The study should provide a basis for conducting definitive Ph2 or 3 clinical trials of a molecularly targeted therapy for these two global blood disorders.

β-地中海贫血和血红蛋白病是严重的遗传性血液病， 被世卫组织指定为日益严重的全球卫生负担。这些疾病会减少生产或改变 成人血红蛋白A的β链结构，并引起慢性器官溶血性贫血 损伤和早期死亡。胎儿球蛋白（HbF）是另一种类型的正常血红蛋白， 在胎儿发育期间表达，但在婴儿期被抑制。几十年的研究表明 HbF的任何增量增加都会降低镰状细胞病的严重程度， 地中海贫血胎儿血红蛋白（γ-珠蛋白链）产生的药理学增加， 被接受为一种治疗方式，以减少潜在的病理。我们申请了高- 通量筛选，以研究EMA或FDA目前批准用于其他用途的药物库 医学条件，确定了一小组以前未被识别的药物， 胎儿珠蛋白基因，并验证了他们的行动，在患者的红细胞祖细胞，非人类 灵长类动物和转基因小鼠。一种治疗剂苄丝肼诱导胎儿珠蛋白高达30倍 贫血狒狒间歇性经口给药超过基线，发现消除， 抑制或取代胎儿基因启动子BCL 11 A的4种有效分子阻遏物， LSD-1、KLF-1和HDAC 3，导致“化学基因编辑”。 苄丝肼作为一种氨基酸脱羧酶在欧洲和加拿大已经使用了40年 抑制剂，以增强组合片剂中另一种活性剂的PK，用于治疗 帕金森氏病，具有良性的安全性，被认为是安全的慢性剂量高达 每天1300毫克。本提案将以人体等效剂量评价苄丝肼 从贫血狒狒和转基因小鼠的活性给药外推，耐受性， 多达24例β地中海贫血患者的药代动力学和胎儿珠蛋白表达测定 中间型和多达12例镰状细胞病患者。 这些目标包括： 目的I：评价3种剂量苄丝肼治疗24 β地中海贫血的耐受性和PK 中间型（BTI）患者，在3个剂量递增队列和一个扩展队列中治疗12 周 目的II：研究苄丝肼在多达16个BTI中诱导HbF表达的初步活性 患者和一个镰状细胞病患者队列中，以下指标较基线的变化： IIA. F网织红细胞、F细胞、MFI、HbF、总血红蛋白和红细胞压积 IIb.溶血标志物（STfr、LDH、胆红素）测定 该研究应为进行确定性的分子药物2期或3期临床试验提供基础。 针对这两种全球性血液疾病的靶向治疗。