IND-Enabling Preclinical Development of a New Radiomitigator

IND 促进新型放射缓解剂的临床前开发

• 批准号: 9280853
• 负责人: GABOR J TIGYI
• 金额: $ 43.64万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280853
• 关键词: Agonist; Benzoic Acids; Blood; Bone Marrow; Budgets; Chemistry; Cost Sharing; Data; Development; Development Plans; Devices; Dose; Drug Kinetics; Drug Targeting; Edg4 Protein; Emergency Situation; Explosion; FDA approved; Feedback; Fukushima; G-Protein-Coupled Receptors; Goals; Grant; Half-Life; Hematopoietic; Hour; In Vitro; Intellectual Property; Isomerism; Lead; Length; Ligands; Lipids; Lysophosphatidic Acid Receptors; Macaca mulatta; Methods; Molecular; Mus; Nuclear; Nuclear Accidents; Partition Coefficient; Pharmaceutical Chemistry; Pharmaceutical Preparations; Placebos; Property; Radiation; Radiation Injuries; Radiation Toxicity; Radiation exposure; Regimen; Research; Resources; Specificity; Structure; Tennessee; Terrorism; Therapeutic; Toxic effect; Toxicology; Universities; Whole-Body Irradiation; Work; analog; animal rule; base; design; drug development; efficacy study; experience; gastrointestinal; improved; in vivo; industry partner; inorganic phosphate; irradiation; lysophosphatidic acid; meetings; molecular mass; mortality; mouse model; phosphonate; preclinical development; preclinical evaluation; public health relevance; receptor; scaffold; small molecule; specific biomarkers; success; thiophosphate; treatment group

DESCRIPTION (provided by applicant): The overall objective of this project is to conduct IND-enabling drug development of a new small molecule radiomitigator based on the RP239 lead structure thru a partnership between the University of Tennessee and RxBio. Inc. This objective originates from a decade-long radiomitigator research that identified and validated the lysophosphatidic acid (LPA) G protein-coupled receptor (GPCR) subtype 2 (LPA2) as a therapeutic drug target for radiomitigation. RP239 is a specific small molecule agonist of LPA2. This proposal builds on our past experience and success developing octadecenyl thiophosphate (OTP) as a radiomitigator of the gastrointestinal acute radiation syndrome (GI-ARS). OTP licensed to RxBio Inc. was entered into the FDA regulatory pipeline under the sponsorship of BARDA in 2011. RP239 when applied +24h after LD90/8-10 (16.59 Gy) partial-body γ-irradiation with 5% bone marrow shielding reduced mortality of mice from the gastrointestinal acute radiation syndrome (ARS) by 72% (11/14 survival vs. 1/14 in placebo). RP239 and its analogs were also effective in reducing mortality due to the hematopoietic ARS. Importantly, when treatment was delayed to +48h post-total body irradiation, 50% of the mice survived in the RP239 treatment group compared to 21% in the placebo group. Its drug-like properties, combined with its specificity to the LPA2 receptor and lack of toxicity at therapeutic doses lead us to hypothesize that RP239 should be further evaluated as a potent radiomitigator of the mixed ARS elicited by high-levels of radiation. Our unique resources and experience with the development of OTP provide us with qualifications to take the RP239 lead on a development path that will qualify this new radiomitigator for fast tracking by the FDA under the animal rule.

描述（由适用提供）：该项目的总体目的是基于田纳西大学和RXBIO之间的合作伙伴关系，对新的小分子放射线剂进行辅助药物开发。 Inc.该目标源自一项长达长达十年的放射线剂研究，该研究鉴定并验证了溶血磷脂酸（LPA）G蛋白偶联受体（GPCR）亚型2（LPA2）作为放射性措施的治疗药物靶标。 RP239是LPA2的特定小分子激动剂。该提案建立在我们过去的经验和成功发展为胃肠道急性辐射综合征（GI-ARS）的放射性二磷酸（OTP）的成功基础上。根据Barda在2011年的赞助下，将获得授予RXBIO Inc.的OTP纳入了FDA监管管道。 RP239在LD90/8-10（16.59 Gy）后使用 +24H时，部分体体γ-辐射率为5％，骨髓屏蔽5％，从胃肠道急性急性辐射综合征（ARS）中降低了小鼠死亡率，将其降低72％（11/14的生存率。 RP239及其类似物也有效地降低了由于造血ARS而导致的死亡率。重要的是，当治疗延迟到 +48h后体内照射后，RP239治疗组中有50％的小鼠幸存下来，而安慰剂组为21％。它的药物样特性，结合其对LPA2受体的特异性以及治疗剂量时缺乏毒性，使我们假设应进一步评估RP239作为由高级放射线引起的混合ARS的有效放射性ARS的评估。我们在OTP开发方面的独特资源和经验为我们提供了资格，使RP239的领先优势在开发道路上，这将使FDA在动物规则下的快速跟踪中有资格进行快速跟踪。