Evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamics of long-term mitapivat dosing in subjects with stable sickle cell disease

稳定型镰状细胞病受试者长期服用 mitapivat 的安全性、耐受性、药代动力学和药效学评估

• 批准号: 10699750
• 负责人: Swee Lay Thein
• 金额: $ 113.3万
• 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/10699750
• 关键词: Acute; Acute Pain; Adenosine Triphosphate; Adverse effects; Affinity; Binding; Blood; Cardiopulmonary; Clinical; Complication; Data; Disease; Dose; Drug Kinetics; Drug Targeting; Enzymes; Erythrocytes; Evaluation; Event; Fetal Hemoglobin; Fibrinogen; Frequencies; Glycolysis; Hemoglobin; Hemoglobin concentration result; Hospitalization; Human; Membrane; Monitor; Oral; Organ; Oxygen; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase II Clinical Trials; Phase II/III Clinical Trial; Phosphoenolpyruvate; Plant Roots; Polymers; Process; Production; Publishing; Pyruvate; Pyruvate Kinase; Reporting; Role; Safety; Sickle Cell; Sickle Cell Anemia; Sickle Cell Trait; Sickle Hemoglobin; Source; Supportive care; Symptoms; Syndrome; Testing; Thalassemia; diphosphoglycerate; enzyme substrate; functional status; health related quality of life; hydroxyurea; pharmacokinetics and pharmacodynamics; phase 1 study; polymerization; pre-clinical; prescription opioid; pyruvate kinase deficiency; response; 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 microvascular vaso-occlusion 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 the FDA approval of Lglutamine (Endari) in 2017 and the more recent approvals of crizanlizumab (Adakveo) and voxelotor (Oxbryta) in 2019, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce frequency of acute painful crises but which is not universally effective. As the root cause of SCD is polymerization of deoxy-hemoglobin S (HbS), there is a strong rationale for exploring agents that could inhibit or reduce the polymerization process itself.2 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 RBC. 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 intraerythrocyte pH, further promoting HbS polymerization. 2,3- DPG is an intermediate substrate in the glycolytic pathway, the only source of adenosine triphosphate (ATP) production in RBCs. 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 RBC membrane. Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3-DPG which favors polymerization as it stabilizes the deoxygenated form (T form) of hemoglobin. In humans with SCD, and even in sickle carriers who are generally asymptomatic, reduced oxygen affinity will favor deoxygenation of HbS and its polymerization, 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 hemoglobin (Hb F) induction via multiple strategies and drugs that targets HbS polymerization through increasing affinity of hemoglobin for oxygen (e.g. voxelotor). Increasing red cell PK (PKR) activity, leading to a decrease in intracellular 2,3-DPG concentration, presents a new and potentially attractive therapeutic target for thwarting HbS polymerization and acute sickle pain. Mitapivat (AG-348) is an orally bioavailable small molecule allosteric activator of PKR, currently being studied in Phase II/III clinical trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 / AG348- C-007), as well as in an ongoing Phase II clinical trial in humans with non-transfusion-dependent thalassemia (NCT03692052). The recently published results in PK deficient subjects appear promising, and the safety profile of the drug was acceptable. Overview of the preclinical mitapivat 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 mitapivat in the treatment of SCD. We recently completed our Phase I study (NCT04000165, Study 19-H-0097) to determine the clinical safety and tolerability of multiple escalating doses of mitapivat in subjects with SCD. We have observed an acceptable safety profile for mitapivat doses up to 50 mg twice daily (BID) for all subjects and 100 mg BID for ten subjects, with a range of adverse effects comparable to those observed in PKD patients. Furthermore, our Phase I study has provided preliminary evidence of efficacy for mitapivat in SCD, with increases in hemoglobin level and decreases in hemolytic markers observed in the majority of SCD subjects and subjective improvements in symptoms reported by some subjects. The objective of the present study is to evaluate the safety and tolerability of long-term treatment with a stable dose of mitapivat 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。在 FDA 于 2017 年批准 L 谷氨酰胺 (Endari) 以及最近于 2019 年批准 crizanlizumab (Adakveo) 和 voxelotor (Oxbryta) 之前，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频率，但这并不普遍有效。 由于 SCD 的根本原因是脱氧血红蛋白 S (HbS) 的聚合，因此有必要探索能够抑制或减少聚合过程本身的药物。2 HbS 仅在脱氧时聚合；其氧合受多种因素影响，其中一个关键因素是红细胞中 2,3-二磷酸甘油酸 (2,3-DPG) 的浓度。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 浓度会降低红细胞内 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，是红细胞中三磷酸腺苷 (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 活性降低会导致上游酶底物的积累，包括 2,3-DPG，它有利于聚合，因为它可以稳定血红蛋白的脱氧形式（T 形式）。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 (Hb F)，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）。增加红细胞 PK (PKR) 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一个新的且具有潜在吸引力的治疗靶点。 Mitapivat (AG-348) 是一种口服生物可利用的 PKR 小分子变构激活剂，目前正在 PK 缺陷人类中进行 II/III 期临床试验（NCT02476916、NCT03548220 / AG348-C-006; NCT03559699 / AG348-C-007） ），以及正在进行的 II 期临床试验患有非输血依赖性地中海贫血的人 (NCT03692052)。最近发表的针对 PK 缺陷受试者的结果似乎很有希望，并且该药物的安全性是可以接受的。临床前 mitapivat 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，与所有测试的多个递增剂量下的糖酵解途径激活一致，支持 mitapivat 在 SCD 治疗中的潜在作用。 我们最近完成了 I 期研究（NCT04000165，研究 19-H-0097），以确定 SCD 受试者多次递增剂量的 mitapivat 的临床安全性和耐受性。我们观察到所有受试者的 mitapivat 剂量高达 50 mg 每天两次 (BID) 和 10 名受试者的 100 mg BID 的安全性可接受，其一系列不良反应与在 PKD 患者中观察到的不良反应相当。此外，我们的 I 期研究提供了 mitapivat 对 SCD 疗效的初步证据，在大多数 SCD 受试者中观察到血红蛋白水平增加和溶血标记物减少，以及一些受试者报告的症状的主观改善。本研究的目的是评估稳定剂量的 mitapivat 对 SCD 受试者长期治疗的安全性和耐受性。