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

镰状细胞病（SCD）是一种与急性临床事件发作和进行性器官损害相关的多系统疾病。镰状红细胞引起的微血管闭塞引起的阵发性疼痛是最常见的急性并发症，也是住院治疗的主要原因。SCD的治疗策略发展非常缓慢，急性疼痛的治疗仍然局限于阿片类药物的支持治疗。直到最近的2017年，唯一被批准的治疗SCD的药物是羟基脲（HU），它可以减少急性疼痛危机的频率，但不是普遍有效。除了HU外，正常红细胞输注也被广泛用于治疗严重镰状危象，但这一策略有局限性（不统一可及，伴有同种异体免疫、溶血性输血反应和输铁过载的风险）。唯一的治疗方法是骨髓移植，但这种选择有很大的风险，并且受到组织相容供体的限制。

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.