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.

镰状细胞疾病（SCD）是一种多系统疾病，与急性临床事件和进行性器官损伤有关。发作性疼痛是由最常见的急性并发症和住院的主要原因引起的微血管血管cly牙引发的。 SCD的管理策略的发展非常缓慢，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FDA批准Lglutamine（Endari）以及Crizanlizumab（Adakveo）（Adakveo）和Voxelotor（Oxbryta）的最新批准为止，SCD的唯一认可的SCD疗法是羟基脲（HU），是羟基脲（HU），均被指示降低了急性疼痛的频率，但并不是痛苦的频率。 由于SCD的根本原因是脱氧 - 血红蛋白S（HBS）的聚合，因此探索可以抑制或减少聚合过程本身的剂量的基本原理。2HBS仅在脱氧时进行聚合。它的氧合受到一些因素的影响，其中一个关键因素是RBC中2,3-二磷酸甘油酸（2,3-DPG）浓度。细胞内2,3-DPG的增加可降低氧结合并稳定血红蛋白的脱氧形式（t形式）。此外，升高的2,3-DPG浓度降低了炎性细胞pH，进一步促进了HBS聚合。 2,3- DPG是糖酵解途径中的中间底物，糖酵解途径是RBC中三磷酸腺苷（ATP）的唯一来源。丙酮酸激酶（PK）是糖酵解的最后一步的关键酶。 PK将磷酸烯醇丙酮酸转化为丙酮酸，从而创造了50％的红细胞ATP，这对于维持RBC膜的完整性至关重要。降低的PK活性导致上游酶底物的积累，其中包括2,3-DPG，由于稳定​​血红蛋白的脱氧形式（t形式），因此有利于聚合。在患有SCD的人，甚至在通常无症状的镰状载体中，氧气亲和力降低都会有利于HBS及其聚合的脱氧，因此可恶。实际上，PK缺乏症和镰状细胞性状的组合在两种情况下以前已经报道。 当前减少HBS聚合的方法包括胎儿血红蛋白（HB F）通过多种策略和药物诱导，这些策略和药物通过增加血红蛋白对氧气的亲和力（例如，voxelotor）而靶向HBS聚合。提高红细胞PK（PKR）活性，导致细胞内2,3-DPG浓度的降低，为挫败HBS聚合和急性镰刀疼痛的新的且潜在的具有吸引力的治疗靶标提供了一种新的且潜在的治疗靶标。 Mitapivat（AG-348）是PKR的口服生物利用的小分子变构激活剂，目前正在II / III期临床试验中研究PK缺乏症的人类（NCT02476916，NCT03548220 II非转灌关依赖性thalassymia的人类临床试验（NCT03692052）。最近发表的PK缺乏受试者的结果似乎很有希望，并且可以接受该药物的安全性。在所有多个升剂剂量下，临床前的mitapivat数据和其他数据支持血液糖酵解中间体的剂量依赖性变化与糖酵解途径激活一致，这支持了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受试者中多种升级剂量的Mitapivat的临床安全性和耐受性。我们已经观察到所有受试者每天两次两次MITAPIVAT剂量的可接受的安全性，对于十名受试者而言100 mg BID，与PKD患者中观察到的一系列不良反应相当。此外，我们的I阶段研究提供了Mitapivat在SCD中有效性的初步证据，血红蛋白水平的升高和大多数SCD受试者观察到的溶血标志物的降低以及某些受试者报告的症状的主观改善。本研究的目的是通过稳定的SCD受试者评估长期治疗的安全性和耐受性。