Development of a Clinical Hemoglobin Modulator

临床血红蛋白调节剂的开发

• 批准号: 10175025
• 负责人: Douglas V Faller
• 金额: $ 184.38万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10175025
• 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血液疾病，是 他指定的是不断增长的全球健康伯恩。疾病减少产量或改变 成年血红蛋白A的β链的结构，并引起溶血性贫血，慢性器官 损害和早期死亡率。胎儿球蛋白（HBF）是正常血红蛋白的另一种类型，是 在胎儿发育过程中表达，但在婴儿期被抑制。数十年的研究表明 HBF的任何增量增加都会降低镰状细胞疾病和β-的严重程度 地中海贫血。胎儿血红蛋白（γ-珠蛋白链）的药理增强，是 被认为是一种治疗方式，以减少潜在的病理。我们应用了 吞吐量筛查以研究EMA或FDA目前批准的药物库 医疗条件确定了一小部分先前未识别的药物，这些药物诱导了 胎儿球蛋白基因，并验证了他们在患者红细胞祖细胞中的作用 灵长类动物和转基因小鼠。一种疗法，benserazide，诱导胎儿球蛋白高达30倍 在贫血狒狒中间歇性口服治疗过于基线，被发现废除了 抑制胎儿基因启动子Bcl11a的4个潜在的分子复制品， LSD-1，KLF-1和HDAC3，引起“化学基因编辑”。 Benserazide在欧洲和加拿大已使用了40年，用作氨基酸脱羧酶 抑制剂，以增强组合片剂中另一种活性剂的PK，以治疗 帕金森氏病，具有良性安全性，被认为是慢性剂量的安全 每天1300毫克。该建议将在人类等效剂量下评估Benserazide 从贫血狒狒和转基因小鼠中推断出活性剂量，以耐受性，以供耐受性 药代动力学和胎儿球蛋白表达测定最多24例β地中海贫血患者 中间和多达12例镰状细胞疾病的患者。 目的包括： 目的I：评估24个β地中海贫血的3剂Benserazide的耐受性和PK 中间患者（BTI）患者，在3剂降级队列中，并进行了12个膨胀队列 几周 AIM II：研究Benserazide在诱导的HBF表达中的初步活动，最多16个BTI 患者，以及一群镰状细胞疾病的患者，从基线变化： iia。 F-重新细胞，F细胞，MFI，HBF，总血红蛋白和血细胞比容 iib。溶血标记的测定（STFR，LDH，胆红素） 该研究应为进行分子的明确pH2或3个临床试验提供基础 针对这两种全球血液疾病的有针对性疗法。