Validating Prodrug PRX-P4-003 approach in humans by phase 0 microdose study

通过 0 期微剂量研究在人体中验证前药 PRX-P4-003 方法

• 批准号: 9797677
• 负责人: Sandeep Patil
• 金额: $ 66.23万
• 依托单位: PRAXIS BIORESEARCH, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-03 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797677
• 关键词: Adult; Affect; Alzheimer' s Disease; Attention deficit hyperactivity disorder; Authorization documentation; Binge eating disorder; Biological Assay; Biological Sciences; Chemicals; Chemistry; Clinical; Data; Development; Diagnostic and Statistical Manual of Mental Disorders; Disease; Dose; Drug Kinetics; Drug toxicity; Eating; Eating Disorders; Ethics; Florida; Formulation; Fund Raising; Goals; Human; Human Volunteers; Hyperphagia; In Vitro; Intravenous; Investigational Drugs; Italy; Lipase; Measures; Metabolism; Monkeys; Narcolepsy; Oral; Outcome Measure; Pancreas; Pancreatic duct; Parents; Pathology; Patients; Pharmaceutical Preparations; Phase; Plasma; Prevalence; Primates; Prodrugs; Property; Rattus; Recovery; Risk; Route; Safety; Small Business Innovation Research Grant; Small Intestines; Structure; Suspensions; Therapeutic; Toxicology; Validation; Water; absorption; base; clinical efficacy; cost effective; design; drug candidate; first-in-human; good laboratory practice; human data; human study; in vivo; intravenous administration; medical complication; meetings; novel; novel therapeutics; preclinical safety; programs; safety study; scale up; success

Binge Eating Disorder (BED) is the most common eating disorder and carries an elevated risk of medical complications due to uncontrolled overeating. It can be treated effectively with stimulants, but their known abuse and diversion risk is a persistent concern. Our strategic approach is to build on the proven efficacy of stimulants in BED while reducing abuse potential. The goal of this Fast-Track SBIR project is to develop PRX-P4-003 as a safer “first-in-class” therapy for BED. PRX-P4-003, is a novel prodrug that shows an unprecedented ability to reduce the risk of oral and parenteral abuse based on a well-tolerated dopaminergic stimulant, fencamfamine [(-)-FCF]. The unique structure of PRX-P4-003 has resulted in a prodrug with dual protection properties; firstly, this water insoluble prodrug is inactive in vivo following intravenous administration and secondly minimizes the potential for oral abuse due to delayed absorption properties. These protection properties were accomplished by chemically formulating the prodrug as a substrate specifically for pancreatic lipase, which is overwhelmingly (>99%) located in the pancreatic duct and small intestine. Praxis has compiled a substantial body of evidence in vitro; in vivo and preliminary toxicology studies have demonstrated the feasibility of this Prodrug stimulant for further development. Since the key clinical efficacy and safety parameters are generally well understood for parent and this class of drugs, the next critical determinant of success for the program is to confirm the exposure and other key pharmacokinetic (PK) parameters of (-)-FCF after oral dosing of the PRX-P4-003 in humans. After a pre-IND meeting with the FDA we obtained authorization to pursue a microdose pharmacokinetic (PK) study under the Exploratory IND Path. In Phase I the aims are to: (1) Scale-up synthesis of (-)-FCF and Prodrug PRX-P4-003. (2) Optimize analytical assay for (-)-FCF. (3) Demonstrate linear PK of Parent (-)-FCF in a primate study. In Phase II the aims are to: (4) Demonstrate safety of (-)-FCF and PRX-P4-003 in Pre-IND toxicity study in rats. (5) Validate PRX-P4-003 as an orally viable prodrug in a clinical Phase 0 microdose PK study. Successful completion of this Fast-Track SBIR project will provide key validation data in humans required for further non-clinical and clinical advancement of PRX-P4-003.

暴饮暴食症（BED）是最常见的饮食失调症，并且具有较高的医疗风险。 不受控制的暴饮暴食引起的并发症。它可以有效地治疗兴奋剂，但其已知的 滥用和转移风险是一个持续的关切。我们的战略方针是， 在床上使用兴奋剂，同时减少滥用的可能性。这个快速通道SBIR项目的目标是开发 PRX-P4-003是一种更安全的“一流”BED疗法。PRX-P4-003是一种新型前药， 基于耐受性良好的多巴胺能药物， 兴奋剂，芬坎法明[（-）-FCF]。PRX-P4-003的独特结构导致了具有双重结构的前药。 保护性质：首先，该水不溶性前药在静脉内给药后在体内无活性 其次由于延迟吸收特性而使口服滥用的可能性最小化。这些保护 通过化学配制前药作为胰腺癌特异性的底物， 脂肪酶，其绝大多数（>99%）位于胰管和小肠中。普拉西斯汇编了 大量体外证据;体内和初步毒理学研究表明， 这种前药兴奋剂的进一步发展的可行性。由于关键的临床疗效和安全性 对于母体和这类药物，参数通常是很好理解的，这是下一个关键的决定因素。 该项目的成功之处在于确认了（-）-FCF的暴露量和其他关键药代动力学（PK）参数 PRX-P4-003口服给药后，在与FDA进行IND前会议后，我们获得了 批准在探索性IND途径下进行微剂量药代动力学（PK）研究。 目的是：（1）（-）-FCF和前药PRX-P4-003的放大合成。(2)优化分析测定， （-）-FCF。(3)在灵长类动物研究中证明母体（-）-FCF的线性PK。第二阶段的目标是：（4） 证明（-）-FCF和PRX-P4-003在大鼠IND前毒性研究中的安全性。(5)PRX-P4-003作为 在临床0期微剂量PK研究中的口服活性前药。成功完成此快速通道 SBIR项目将提供进一步非临床和临床研究所需的人体关键验证数据。 PRX-P4-003的进展。