Repurposing of Pyrvinium Pamoate for Familial Adenomatous Polyposis (FAP)

重新利用双羟萘酸吡维铵治疗家族性腺瘤性息肉病 (FAP)

• 批准号: 9930731
• 负责人: Darren Orton
• 金额: $ 137.6万
• 依托单位: STEMSYNERGY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9930731
• 关键词: Adenomatous Polyposis Coli; Age; Animal Model; Animals; Anthelmintics; Award; Back; Canis familiaris; Cardiovascular system; Cause of Death; Chemistry; Chemoprevention; Clinic; Clinical; Clinical Research; Colectomy; Colon; Colorectal Cancer; DNA Sequence Alteration; Data; Defecation; Development; Discrimination; Disease; Documentation; Dose; Drug Kinetics; Enterobiasis; Excision; Exhibits; Exposure to; FDA approved; Feces; Flatulence; Frequencies; Future; Goals; Guidelines; Hereditary Disease; In Vitro; Incontinence; Individual; International; Intestinal Neoplasms; Intestines; Investigational Drugs; Investigational New Drug Application; Legal patent; Literature; Malignant Neoplasms; Medical; Methods; Mutation; Neuraxis; Non-Rodent Model; Oral; Orphan Drugs; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase I Clinical Trials; Polyps; Precancerous Polyp; Prevalence; Process; Protocols documentation; Pyrvinium pamoate; Quality of life; Rare Diseases; Recommendation; Regulatory Affairs; Regulatory Pathway; Respiratory System; Rodent; Safety; Small Business Innovation Research Grant; Teenagers; Toxic effect; Validation; WNT Signaling Pathway; acute toxicity; base; bench to bedside; cancer cell; drug synthesis; effective therapy; financial incentive; inhibitor/antagonist; meetings; mouse model; multidisciplinary; new therapeutic target; off-patent; pre-clinical; prevent; programs; research clinical testing; scale up; side effect; stability testing; standard of care; symposium; targeted treatment

ABSTRACT Individuals with the rare, inherited disorder Familial Adenomatous Polyposis (FAP) develop thousands of precancerous polyps at an early age and ultimately develop colorectal cancer (CRC). The current standard of care for FAP is colectomy. However, unavoidable side-effects of colectomy are debilitating. Furthermore, colectomy does not prevent subsequent development of extra-colonic intestinal tumors, the main cause of death post-colectomy. There are currently no drugs FDA approved for the treatment or chemoprevention of FAP patients. We have demonstrated that pyrvinium can be repurposed as a potent inhibitor of WNT signaling and is efficacious in an animal model of FAP. Oral dosing of pyrvinium pamoate produces negligible systemic exposure and limits the exposure to the gut which reduces the likelihood of toxicity. Submitting these data to the FDA, we were awarded an Orphan Drug Designation to market pyrvinium exclusively for FAP patients. To clarify the steps required to take pyrvinium back into the clinic as a repurposed agent for FAP patients, using a 505(b)(2) regulatory mechanism, we recently had a pre-IND meeting with the FDA. This Phase I/II Fast-Track application is driven by the FDA’s recommendations for a successful Investigational New Drug (IND) application for pyrvinium in the treatment of FAP. The repurposing of pyrvinium for FAP patients, if successful, would represent 1) A major improvement in therapy and in the quality of life, and 2) The successful bench to bedside application of a rationally selected targeted therapy.

抽象的 患有罕见的，遗传性疾病家族性腺瘤性息肉病（FAP）的个体发展了数千个 癌前的息肉在很小的时候，最终发展为结直肠癌（CRC）。当前标准 护理FAP是收集的。然而，不可避免的收集术副作用使人衰弱。此外， 收集术并不能阻止随后发展外侧肠肿瘤，这是死亡的主要原因 后切除术。目前尚无药物FDA批准用于治疗或化学预防FAP 患者。我们已经证明，可以将吡氏植物重新定义为Wnt信号传导的潜在抑制剂和 在FAP动物模型中有效。 pamoate的口服剂量会产生可忽略的全身性 暴露并限制了肠道的暴露，从而降低了毒性的可能性。将这些数据提交给 FDA，我们被授予专门针对FAP患者的室里的孤儿药物名称。要澄清 将p楼作为FAP患者重新利用的药物带回诊所所需的步骤，使用A 505（b）（2）调节机制，我们最近与FDA进行了预先会议。此阶段I/II快速轨道 申请是由FDA对成功调查新药（IND）申请的建议驱动的 用于FAP治疗的吡内属。 FAP患者的吡内维体的重新利用，如果成功的话，将 代表1）治疗和生活质量的重大改进，以及2）成功的长凳 采用合理选择的靶向治疗。