Oral Therapeutic for Beta-Thalassemia

描述（由申请人提供）：β地中海贫血综合征是一种常见的遗传性疾病，由影响成人血红蛋白基因的分子突变引起，并导致输血并发症导致早期死亡。这些情况可以通过重新激活患者血液中胎儿血红蛋白 (Hb F) 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，三分之二的患有这些疾病的患者已经实现了 HbF 的药物再诱导。一些接受治疗的患者经历了生化和临床/血液学的改善，并且几年来不再依赖输血。第一种 SCFA 疗法丁酸盐和苯丁酸盐需要静脉输注或大量药物（20-30 克/天），难以长期使用。与rhu-EPO刺激红细胞生成和与丁酸盐诱导胎儿珠蛋白表达的联合治疗产生了累加效应，表明这两种作用对于β地中海贫血的最佳确定性治疗是必要的。 在第一阶段 STTR 期间，申请组织开发了一种新的 SCFA（ST-7 钠），与第一代药物相比，它在诱导 Hb F 和刺激红细胞增殖方面具有显着优势，具有口服生物利用度，并且药代动力学证明以可耐受剂量（成人 0.5-1 克）每天一次口服给药的可行性。该药物已被证明在 Hb F 诱导灵长类动物模型和人类珠蛋白基因转基因小鼠中有效且安全。 在此 II 期 STTR 申请中，我们建议进行 FDA 要求的额外临床前开发研究，以获得这种领先的红细胞生成 HbF 诱导剂（ST-7 钠）的 I 期临床试验的研究新药状态。该提案的目标是： 1) 进行 ST-7 钠刺激 HbF 和红细胞生成的 IND 所需的临床前毒理学研究； 2) 准备红细胞生成Hb F诱导剂I期临床试验的IND申请； 3) 评估其他四种新型 Hb F 诱导化合物在狒狒中的药代动力学和药效学，作为潜在的备用疗法。

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.