CLINICAL TRIAL: A PHASE 2, OPEN-LABEL, SWITCH-OVER, DOSE-ESCALATION STUDY OF THE

临床试验：2 期、开放标签、转换、剂量递增研究

• 批准号: 7950694
• 负责人: Brendan Lee
• 金额: $ 2.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950694
• 关键词: Acute; Adult; Affect; Alternative Therapies; Amino Acids; Ammonia; Arginine; Benzoates; Blood; Brain; Carbamyl Phosphate; Caregivers; Catabolism; Child; Citrulline; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Diet; Dietary intake; Disadvantaged; Disease; Dose; Encephalopathies; Enzymes; Excretory function; Funding; Gastrointestinal tract structure; Glutamine; Glycerol; Glycine; Grant; Half-Life; Heterogeneity; Hospitalization; Human Genetics; Hydrolysis; Hyperammonemia; Impairment; Inborn Errors of Metabolism; Injection of therapeutic agent; Inpatients; Institution; Intervention; Kidney; Life; Ligase; Liver; Maintenance Therapy; Marketing; Metabolic; Mole the mammal; Mutation; Nature; Neonatal; Neurologic; Nitrogen; Odors; Oils; Oral; Oral Administration; Ornithine Carbamoyltransferase; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenylacetates; Phenylbutyrates; Plasma; Powder dose form; Prodrugs; Protein-Restricted Diet; Proteins; Recording of previous events; Research; Research Personnel; Resources; Safety; Severities; Sodium; Sodium phenylbutyrate; Source; Supplementation; Tablets; Taste Perception; Time; Treatment Protocols; Tubular formation; United States; United States National Institutes of Health; Urea; Urine; Venous; Visit; absorption; arginase; argininosuccinate lyase; argininosuccinate synthase; base; carbamoyl phosphate synthetase deficiency; diaries; effective therapy; enzyme deficiency; experience; glomerular filtration; infancy; late disease onset; liver transplantation; nitrogen compounds; open label; pharmacokinetic characteristic; pill; prevent; sodium phenylacetate; urea cycle; urinary; wasting

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urea cycle disorders (UCDs) are inborn errors of metabolism that can result from decreased or absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). These disorders prevent the conversion of waste nitrogen into urea and result in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of Buphenyl¿ (sodium phenylbutyrate) with citrulline or arginine. Although an effective treatment, Buphenyl¿ has some disadvantages, such as a high pill burden (approximately 40 tablets [20 g] per day for an adult or 4 tsp of powder for a 20 kg child), unpleasant taste, and high sodium content. There is some evidence from clinical trials of PBA for other indications that the high pill burden may decrease the likelihood of compliance with the treatment regimen. Glyceryl tri (4-phenylbutyrate) (GT4P), a prodrug of phenylbutyrate (PBA) (Buphenyl¿) and a pre-prodrug of the active compound phenylacetate (PAA), is under development as an alternative therapy to Buphenyl¿ in patients with UCDs. GT4P is expected to provide similar nitrogen-scavenging ability while eliminating the current issues of bad taste, odor, sodium content, and pill burden. This is a phase 2, open-label, switch-over, dose-escalation study in patients with UCDs who are taking Buphenyl¿ as maintenance therapy. For each patient, GT4P will be introduced as a replacement for Buphenyl¿ gradually over a dose-escalation phase of up to 9 weeks, which may include up to 10 inpatient visits. GT4P will be a safe, well-tolerated alternative to Buphenyl¿ for patients with urea cycle disorders. SPECIFIC AIMS The primary objective of this study is to evaluate the safety and tolerability of GT4P compared to Buphenyl¿ in patients with urea cycle disorders (UCDs). Secondary objectives are to assess: ¿ plasma and urine pharmacokinetic (PK) characteristics of GT4P and Buphenyl¿ metabolites. ¿ preliminary evidence of efficacy (as assessed by venous ammonia levels and urinary excretion of phenylacetylglutamine [PAGN]). ¿ amino acid levels. ¿ convenience and comfort associated with drug treatment as assessed by the patient or caregiver. ¿ compliance with study drug treatment as assessed by diary data. BACKGROUND AND SIGNIFICANCE The urea cycle is required for excretion of excess nitrogen compounds generated by dietary intake and protein catabolism. Human genetic deficiencies of urea cycle enzymes are well known and usually present in the neonatal period or early infancy with metabolic crises and subsequent neurological impairment. Each disease has significant variability in severity based on the heterogeneity of mutations and other factors. Urea cycle disorders can result from decreased or absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). Treatment of urea cycle disorders relies on two strategies. The first is reduction of nitrogen load through the use of a protein-restricted diet. The second approach uses "alternative" or latent enzymatic pathways of the liver to conjugate glutamine or glycine to carrier molecules and arginine supplementation to increase urinary excretion of nitrogenous products. Nitrogen-scavenging drugs for UCDs include sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate (Buphenyl¿). Sodium phenylacetate, together with sodium benzoate (10%/10%) are marketed as AMMUNOL¿ Injection, which is administered intravenously as an acute treatment for hyperammonemia in patients with UCDs. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of sodium phenylbutyrate with citrulline or arginine. Patient with UCDs who are treated with sodium phenylbutyrate may still experience episodes of hyperammonemic encephalopathy requiring hospitalization and immediate aggressive metabolic intervention. Orthotopic liver transplantation may also be considered for patients with severe disease. Buphenyl¿ (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS. It is also indicated in all patients with neonatal-onset deficiency (enzyme deficiency presenting in the first 28 days of life) and in patients with late-onset disease who have a history of hyperammonemic encephalopathy.1 Buphenyl¿ is orally administered in these patients to increase the excretion of nitrogen through conjugation with glutamine, providing an alternative waste elimination pathway that circumvents the urea cycle. Following oral administration, phenylbutyrate is converted to phenylacetate, which is then conjugated with glutamine in the liver and kidneys and excreted as phenylacetylglutamine (PAGN).2 Phenylacetylglutamine is excreted by both renal glomerular filtration and tubular secretion. The nitrogen content of PAGN per mole is identical to that of urea (both contain 2 moles of nitrogen). Although an effective treatment, Buphenyl¿ has some disadvantages. It has a high pill burden (approximately 40 tablets [20 g] per day for an adult or 4 tsp of powder for a 20-kg child), unpleasant taste and high sodium content. Buphenyl¿ also has a short half-life and therefore must be administered 3 to 6 times per day. Glyceryl tri (4-phenylbutyrate) (GT4P), a prodrug of phenylbutyrate (PBA) (Buphenyl¿) and a pre-prodrug of the active compound phenylacetate (PAA), is under development as an alternative therapy to Buphenyl¿ in patients with UCDs. In the gastrointestinal tract or following absorption, GT4P is very rapidly enzymatically hydrolyzed to glycerol and PBA. So like Buphenyl¿, GT4P is expected to provide a means of waste nitrogen disposal that circumvents the urea cycle. In distinct contrast to Buphenyl¿, GT4P is odorless, colorless, tasteless oil. Additionally, there is no sodium burden on the patients with GT4P and a substantially reduced pill burden due to the concentrated nature of the drug. Results from the one previous clinical study conducted with GT4P suggest that GT4P will be safe and well tolerated and may be preferred by patients and their caregivers.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 尿素循环障碍 (UCD) 是先天性代谢错误，可能由以下任何酶的活性降低或缺失引起：氨甲酰磷酸合成酶 (CPS)、鸟氨酸转氨甲酰酶 (OTC)、精氨琥珀酸合成酶 (ASS)、精氨琥珀酸裂解酶 (ASL)或精氨酸酶 (ARG) 这些疾病会阻止废氮转化为尿素，并导致有毒水平的积累。受影响患者的血液和大脑中存在氨。 大多数 UCD 患者通过单独饮食或通过饮食氮限制加口服丁苯剂量进行长期治疗。 （苯丁酸钠）与瓜氨酸或精氨酸虽然是一种有效的治疗方法，但丁苯¿有一些缺点，例如药片负担高（成人每天约 40 片 [20 克]，或 20 公斤儿童每天约 4 茶匙粉末）、味道不愉快以及钠含量高。临床试验有一些证据。 PBA 的其他迹象表明高药丸负担可能会降低遵守治疗方案的可能性。 三(4-苯基丁酸)甘油酯 (GT4P) 是苯基丁酸酯 (PBA) (丁苯) 的前药，也是活性化合物苯乙酸 (PAA) 的前体药物，正在开发中作为丁苯的替代疗法。 GT4P 有望在 UCD 患者中提供类似的氮清除能力，同时消除目前的不良味道、气味、钠含量和药物负担问题。 这是一项 2 期、开放标签、转换、剂量递增研究，对象是正在服用丁苯的 UCD 患者。作为维持治疗，GT4P 将作为丁苯的替代品引入。在长达 9 周的剂量递增阶段逐渐进行，其中可能包括最多 10 次住院就诊。 GT4P 将成为丁苯的安全、耐受性良好的替代品¿适用于尿素循环障碍患者。 具体目标 本研究的主要目的是评估 GT4P 与丁苯相比的安全性和耐受性。尿素循环障碍 (UCD) 患者。 次要目标是评估： ¿ GT4P 和丁苯的血浆和尿液药代动力学 (PK) 特征¿代谢物。 ¿ 疗效的初步证据（通过静脉氨水平和苯乙酰谷氨酰胺 [PAGN] 的尿液排泄进行评估）。 ¿ 氨基酸水平。 ¿ 由患者或护理人员评估与药物治疗相关的便利性和舒适度。 ¿ 通过日记数据评估对研究药物治疗的依从性。 一、背景及意义 尿素循环是排出饮食摄入和蛋白质分解代谢产生的过量氮化合物所必需的。众所周知，人类遗传性尿素循环酶缺陷，通常存在于新生儿期或婴儿早期，伴有代谢危机和随后的神经功能障碍。根据突变的异质性和其他因素，尿素循环障碍的严重程度存在显着差异，可能是由于以下任何酶的活性降低或缺失所致：氨甲酰磷酸合成酶 (CPS)、鸟氨酸。转氨甲酰酶 (OTC)、精氨基琥珀酸合成酶 (ASS)、精氨基琥珀酸裂解酶 (ASL) 或精氨酸酶 (ARG)。 尿素循环障碍的治疗依赖于两种策略，第一种是通过限制蛋白质饮食来减少氮负荷，第二种方法是利用肝脏的“替代”或潜在酶途径将谷氨酰胺或甘氨酸与载体分子结合。补充精氨酸以增加尿中含氮产物的排泄用于 UCD 的氮清除药物包括苯甲酸钠、苯乙酸钠和钠。苯丁酸钠（Buryl¿）与苯甲酸钠（10%/10%）一起作为 AMMUNOL¿注射剂，静脉注射，作为 UCD 患者高氨血症的急性治疗方法。 大多数 UCD 患者通过单独饮食或饮食氮限制加口服剂量的苯丁酸钠与瓜氨酸或精氨酸进行长期治疗。接受苯丁酸钠治疗的 UCD 患者可能仍会出现高氨血症性脑病，需要住院治疗并立即进行积极的代谢干预。对于病情严重的患者也可以考虑进行原位肝移植。 丁苯¿ （苯丁酸钠）片剂和粉剂自 1996 年起在美国获准上市，作为涉及 CPS、OTC 或 ASS 缺陷的 UCD 患者长期治疗的辅助治疗。新生儿发病的缺乏症（出生后 28 天出现酶缺乏症）和有高氨血症病史的晚发性疾病患者脑病.1 丁苯¿在这些患者中口服给药，通过与谷氨酰胺结合来增加氮的排泄，提供另一种废物消除途径，绕过尿素循环。口服后，苯丁酸转化为苯乙酸，然后在肝脏和肾脏中与谷氨酰胺结合。并以苯乙酰谷氨酰胺 (PAGN) 形式排泄。2 苯乙酰谷氨酰胺由两个肾小球排泄每摩尔 PAGN 的氮含量与尿素相同（均含有 2 摩尔氮）。 虽然丁苯是一种有效的治疗方法，它有一些缺点。它的药片负担较高（成人每天约 40 片 [20 克]，20 公斤儿童约 4 茶匙粉末）、味道不愉快且钠含量较高。半衰期也很短，因此每天必须给药 3 至 6 次。 三(4-苯基丁酸)甘油酯 (GT4P) 是苯基丁酸酯 (PBA) (丁苯) 的前药，也是活性化合物苯乙酸 (PAA) 的前体药物，正在开发中作为丁苯的替代疗法。在 UCD 患者中，GT4P 在胃肠道中或吸收后会很快被酶水解为甘油和 PBA，就像丁苯一样。 ，GT4P有望提供一种绕过尿素循环的废氮处理手段。 与丁苯形成鲜明对比?? , GT4P 是无臭、无色、无味的油。此外，GT4P 患者没有钠负担，并且由于该药物的浓缩性质，GT4P 的药物负担显着减少。安全且耐受性良好，可能会受到患者及其护理人员的青睐。