重新利用双羟萘酸吡维铵治疗家族性腺瘤性息肉病 (FAP)-猫眼课题宝

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

项目类别：

财政年份：

2018

资助国家：

美国

项目状态：

已结题

起止时间：

2018-03-15 至 2021-08-31

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

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中文摘要

翻译

摘要罕见的遗传性疾病家族性腺瘤性息肉病(FAP)患者会发生数千例癌症前期息肉发生在早期，并最终发展为结直肠癌(CRC)。现行的标准是对FAP的治疗是结肠切除术。然而，结肠切除术不可避免的副作用使人虚弱。此外，结肠切除术不能防止结肠外肠道肿瘤的后续发展，这是导致死亡的主要原因结肠切除术后。目前，FDA还没有批准用于治疗或化学预防FAP的药物病人。我们已经证明，吡喃可以被重新用作WNT信号和WNT信号的有效抑制剂在FAP动物模型上是有效的。口服帕莫酸吡啶可忽略不计的全身性并限制对肠道的接触，从而降低中毒的可能性。将这些数据提交给在FDA，我们被授予了一项孤儿药物指定，专门为FAP患者销售吡喃。为了澄清将吡喃作为FAP患者的改良剂带回临床所需的步骤，使用 505(B)(2)监管机制，我们最近与FDA举行了IND前会议。本阶段I/II快速通道申请是由FDA对成功的研究新药(IND)申请的建议推动的吡喃在治疗FAP中的应用。如果成功的话，对FAP患者重新使用丙戊酸将会代表1)治疗和生活质量的重大改善，以及2)成功的床边替补合理选择靶向治疗的应用。

英文摘要

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.

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