A Pilot Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of escalating multiple oral doses of AG-348 in subjects with stable sickle cell disease

一项初步研究，旨在评估稳定型镰状细胞病受试者多次口服 AG-348 剂量的安全性、耐受性、药代动力学和药效学

• 批准号: 10929187
• 负责人: Swee Lay Thein
• 金额: $ 49.34万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10929187
• 关键词: Acute; Acute Pain; Affinity; Alloimmunization; Binding; Biological Availability; Blood; Bone Marrow Transplantation; Cell membrane; Clinical; Complication; Data; Deoxygenated Sickle Hemoglobin; Disease; Dissociation; Dose; Drug Kinetics; Drug Targeting; Enzyme Activators; Enzymes; Erythrocytes; Event; FDA approved; Fetal Hemoglobin; Frequencies; Glycolysis; Hemoglobin; Histocompatibility; Hospitalization; Human; Iron Overload; Laboratory Study; Oral; Organ; Oxygen; Pain; Pathway interactions; Pharmacodynamics; Phosphoenolpyruvate; Pilot Projects; Polymers; Process; Production; Pyruvate; Pyruvate Kinase; Reaction; Reporting; Risk; Role; Safety; Sickle Cell; Sickle Cell Anemia; Sickle Cell Trait; Source; Supportive care; Syndrome; System; Testing; Transfusion; curative treatments; diphosphoglycerate; enzyme substrate; hydroxyurea; in vivo; novel; polymerization; pre-clinical; prescription opioid; pyruvate kinase deficiency; sickle cell crisis; sickling; small molecule; therapeutic target

Sickle cell disease (SCD) is a multisystem disorder associated with episodes of acute clinical events and progressive organ damage. Episodic pain, triggered by micro-vasoocclusion induced by sickled red blood cells, is the most common acute complication and the leading cause of hospitalization. Management strategies for SCD have evolved very slowly, and treatment of acute pain is still limited to supportive therapy with opioid medication. Until recently in 2017, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce frequency of acute painful crises but not universally effective. In addition to HU, transfusions with normal red blood cells are widely used to treat severe sickle crises, but this strategy has limitations (not uniformly accessible, accompanied by risks of alloimmunization, hemolytic transfusion reactions and transfusional iron overload). The only curative treatment is bone marrow transplantation, but this option carries significant risks and is limited by the availability of histocompatible donors. As the root cause of SCD is polymerization of deoxy-HbS, there is a strong rationale for exploring agents that could inhibit/reduce the polymerization process itself. HbS polymerizes only when deoxygenated, its oxygenation is influenced by a few factors, one key factor being the 2,3- diphosphoglycerate (2,3-DPG) concentration in the red blood cell. Increased intracellular 2,3-DPG decreases oxygen binding and stabilizes the deoxygenated form (T form) of hemoglobin. In addition, increased 2,3-DPG concentration decreases intracellular red cell pH further promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of ATP production in red blood cells. Pyruvate kinase (PK) is a key enzyme in the final step of glycolysis; PK converts phosphoenolpyruvate to pyruvate, creating 50% of the total red cell ATP that is essential for maintaining integrity of the red cell membrane. Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3-DPG, that favours polymerization of deoxy-HbS. In humans with SCD, and even in sickle carriers who are generally asymptomatic, reduced oxygen affinity will favour deoxygenation of HbS and its polymerisation, and thus sickling. Indeed, the combination of PK deficiency and sickle cell trait causing an acute sickling syndrome has been previously reported in two cases. Current approaches to reduce HbS polymerization include fetal haemoglobin induction via multiple strategies and drugs that targets HbS polymerization through increasing affinity of hemoglobin for oxygen (eg. Voxelotor / GBT440). Increasing red cell PK (PK-R) activity, leading to a decrease in intracellular 2,3-DPG concentration, presents a potentially attractive therapeutic target for thwarting HbS polymerization and acute sickle pain. AG-348 is a novel, orally bioavailable, small molecule allosteric activator of PK-R, that was recently FDA approved for the treatment of pyruvate kinase deficiency. Overview of the preclinical AG-348 data and other data support dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation at all multiple ascending doses tested, supporting the potential role of AG-348 in the treatment of sickle cell disease. The overall objective of the present study is to determine the clinical safety and tolerability of AG-348 in subjects with SCD.

镰状细胞病（SCD）是一种与急性临床事件和进行性器官损伤相关的多系统疾病。由镰状红细胞引起的微血管闭塞引发的阵发性疼痛是最常见的急性并发症，也是住院的主要原因。 SCD 的管理策略发展非常缓慢，急性疼痛的治疗仍然仅限于阿片类药物的支持治疗。直到 2017 年最近，唯一批准的 SCD 疗法是羟基脲 (HU)，该药物可减少急性疼痛危象的发生频率，但并非普遍有效。除 HU 外，输注正常红细胞也被广泛用于治疗严重的镰状细胞危象，但该策略具有局限性（并非普遍可行，伴有同种免疫、溶血性输血反应和输血铁超载的风险）。唯一的治疗方法是骨髓移植，但这种选择存在很大的风险，并且受到组织相容性供体的可用性的限制。 由于 SCD 的根本原因是脱氧 HbS 的聚合，因此有充分理由探索可以抑制/减少聚合过程本身的药物。 HbS 仅在脱氧时聚合，其氧合受几个因素影响，其中一个关键因素是红细胞中的 2,3-二磷酸甘油 (2,3-DPG) 浓度。 细胞内 2,3-DPG 的增加会减少氧结合并稳定血红蛋白的脱氧形式（T 形式）。此外，增加 2,3-DPG 浓度会降低细胞内红细胞 pH 值，进一步促进 HbS 聚合。 2,3-DPG 是糖酵解途径中的中间底物，是红细胞中 ATP 产生的唯一来源。丙酮酸激酶（PK）是糖酵解最后一步的关键酶； PK 将磷酸烯醇丙酮酸转化为丙酮酸，产生红细胞 ATP 总量的 50%，这对于维持红细胞膜的完整性至关重要。 PK 活性降低导致上游酶底物（包括 2,3-DPG）积累，有利于脱氧 HbS 的聚合。在患有 SCD 的人类中，甚至在通常无症状的镰状细胞携带者中，氧亲和力的降低将有利于 HbS 的脱氧及其聚合，从而促进镰状化。事实上，之前已报道过两例 PK 缺陷和镰状细胞特征相结合导致急性镰状综合征的病例。 目前减少 HbS 聚合的方法包括通过多种策略诱导胎儿血红蛋白，以及通过增加血红蛋白与氧的亲和力来靶向 HbS 聚合的药物（例如 Voxelotor / GBT440）。增加红细胞 PK (PK-R) 活性，导致细胞内 2,3-DPG 浓度降低，为阻止 HbS 聚合和急性镰状痛提供了潜在的有吸引力的治疗靶点。 AG-348 是一种新型、口服生物可利用的 PK-R 小分子变构激活剂，最近被 FDA 批准用于治疗丙酮酸激酶缺乏症。临床前 AG-348 数据和其他数据的概述支持血液糖酵解中间体的剂量依赖性变化，与所有测试的多个上升剂量下的糖酵解途径激活一致，支持 AG-348 在治疗镰状细胞病中的潜在作用。本研究的总体目标是确定 AG-348 在 SCD 受试者中的临床安全性和耐受性。