Oral Therapeutic for Beta-Thalassemia

描述(申请人提供)：贝塔地中海贫血综合征是一种常见的遗传疾病，由影响成人血红蛋白基因的分子突变引起，并导致输血并发症的早期死亡。这些情况可以通过重新激活患者血液中胎儿血红蛋白(HbF)的产生来改善。在临床试验中，使用第一代短链脂肪酸(SCFA)疗法，三分之二的这些疾病患者已经实现了HBF的药理学重新诱导。一些接受治疗的患者经历了生化和临床/血液学方面的改善，并在几年内摆脱了输血。最初的SCFA疗法，丁酸盐和苯丁酸酯，需要静脉输注或大量药物(20-30克/天)，这很难长期使用。联合应用rhu-EPO刺激红细胞生成和丁酸盐诱导胎儿珠蛋白表达产生相加效应，表明这两种作用对于最佳的最终治疗β地中海贫血是必要的。 在第一阶段STTR期间，申请组织开发了一种新的SCFA(ST-7钠)，它比第一代药物具有显著的优势，在诱导Hb F和刺激红系细胞增殖方面具有显著优势，具有口服生物利用度，并且药动学表明，以可耐受的剂量(成人0.5-1克)每天口服一次是可行的。该试剂已在灵长类动物模型中被证明是有效和安全的，用于诱导Hb F和在转基因人类珠蛋白基因的小鼠中。 在这一第二阶段的STTR应用中，我们建议进行FDA要求的额外的临床前开发研究，以获得这种促红细胞生成素诱导剂(ST-7钠)的第一阶段临床试验的研究新药状态。这项建议的目标是：1)进行ST-7钠的IND所需的临床前毒理学研究，以刺激HBF和红细胞生成；2)准备IND应用于促红细胞生成剂Hb F诱导剂的I期临床试验；3)评估其他四种新型Hb F诱导剂作为潜在的备用疗法在狒狒身上的药代动力学和药效学。

DESCRIPTION (provided by applicant): The beta thalassemia syndromes are prevalent genetic disorders caused by molecular mutations affecting the genes for adult hemoglobin and cause early mortality from complications of blood transfusions. These conditions can be ameliorated by reactivating production of fetal hemoglobin (Hb F) in the patients' blood. Pharmacologic re-induction of HbF has been achieved in two-thirds of patients with these diseases in clinical trials, using first generation short-chain fatty acid (SCFA) therapeutics. Some of the treated patients experienced both biochemical and clinical / hematologic improvement, and became independent of blood transfusions for several years. The first SCFA therapies, butyrate and phenylbutyrate, required IV infusions or large amounts of drug (20-30 grams/day) which are difficult for long-term use. Combined therapy with rhu- EPO to stimulate erythropoiesis and with Butyrate to induce fetal globin expression produced additive effects, suggesting that both actions are necessary for an optimal definitive treatment for beta thalassemia. During the Phase I STTR, the applicant organization developed a new SCFA (sodium ST-7) which has substantial advantages over the first generation agents, in inducing Hb F and also stimulating erythroid cell proliferation, with oral-bioavailability, and with pharmacokinetics demonstrating feasibility for once/day oral administration at tolerable doses (0.5-1 gram for an adult). The agent has proven effective and safe in a primate model for Hb F induction and in mice transgenic for the human globin genes. In this Phase II STTR application, we propose to conduct the additional preclinical development studies required by the FDA to obtain Investigational New Drug status for Phase I clinical trials of this lead erythropoietic HbF-inducer (sodium ST-7). The goals of this proposal are: 1) To conduct the preclinical toxicology studies required for an IND for sodium ST-7 to stimulate HbF and erythropoiesis; 2) To prepare an IND application for phase I clinical trials of the erythropoietic Hb F-inducing agent; 3) To evaluate four other novel Hb F-inducing compounds for pharmacokinetics and pharmacodynamics in baboons, as potential back-up therapeutics.