Oral Therapeutics for Viral Malignancies

病毒性恶性肿瘤的口服治疗

• 批准号: 6662622
• 负责人: Douglas V Faller
• 金额: $ 37.36万
• 依托单位: GENE REGULATION LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-07 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6662622
• 关键词: Epstein Barr virus; amidohydrolases; antiviral agents; arginine; butyrates; combination chemotherapy; drug screening /evaluation; ganciclovir; gene induction /repression; neoplastic cell; oral administration; pharmacokinetics; thymidine kinase; viral carcinogenesis

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is associated with a number of human lymphoid malignancies and carcinomas for which there are presently few effective treatments. Each year in the U.S., there are approximately 27,000 people afflicted with diseases caused by the Epstein-Barr virus, and an additional 107,000 people afflicted with malignancies associated with the Epstein-Barr virus. Worldwide, EBV-associated diseases are even more common, and current treatments are typically unsuccessful. Under FDA IND #47,529, we are currently testing Arginine Butyrate in combination with ganciclovir for treatment of these malignancies. Arginine Butyrate induces the latent EBV-enzyme thymidine kinase (TK), which, in turn, renders the EBV-positive malignant cells susceptible to killing by the anti-viral agent ganciclovir. This therapeutic strategy has been successful in early trials. Arginine butyrate, however, has drawbacks as a therapeutic, requiring constant, IV infusion to achieve detectable plasma levels. The development of new, oral agents will allow this therapy to be extended to a larger population of patients and a wider group of diseases. We already have proof-of principal that such orally-active agents can be developed. Our aims from the Phase I STTR were to identify new, long-lived, orally-bioavailable derivatives of our first, prototype drug, Arginine Butyrate, as therapeutics for the therapy of Epstein Barr virus (EBV)-associated malignancies. In this Phase II application, we propose to conduct formal preclinical development studies of a lead new compound, as required by the FDA, to obtain Investigational New Drug Status to begin Phase I clinical trials in humans. The aims of this proposal are: To prepare a medicinal formulation of the sodium salt of ST101, a synthetic SCFAD which ates EBV TK expression, to refine oral dosing-regimens for ST101, to prepare an Investigational New Drug (IND) Application for sodium ST101, and to evaluate additional SCFADs for activity in induction of EBV TK.

描述（由申请人提供）：EB病毒（EBV）与许多人类淋巴恶性肿瘤和癌症有关，目前对此几乎没有有效的治疗方法。在美国，每年约有 27,000 人患有 Epstein-Barr 病毒引起的疾病，另有 107,000 人患有与 Epstein-Barr 病毒相关的恶性肿瘤。在世界范围内，EB 病毒相关疾病更为常见，目前的治疗通常不成功。根据 FDA IND #47,529，我们目前正在测试精氨酸丁酸盐与更昔洛韦联合治疗这些恶性肿瘤。精氨酸丁酸盐诱导潜在的 EBV 酶胸苷激酶 (TK)，进而使 EBV 阳性恶性细胞易于被抗病毒剂更昔洛韦杀死。这种治疗策略在早期试验中取得了成功。然而，精氨酸丁酸盐作为治疗剂有缺点，需要持续静脉输注才能达到可检测的血浆水平。新的口服药物的开发将使这种疗法能够扩展到更多的患者群体和更广泛的疾病群体。我们已经有了可以开发此类口服活性药物的原理证明。我们第一阶段 STTR 的目标是确定我们的第一个原型药物精氨酸丁酸盐的新的、长效的、口服生物可利用的衍生物，作为治疗 Epstein Barr 病毒 (EBV) 相关恶性肿瘤的疗法。在此 II 期申请中，我们建议按照 FDA 的要求对先导新化合物进行正式的临床前开发研究，以获得研究性新药状态，以开始人体 I 期临床试验。该提案的目的是： 制备 ST101 钠盐（一种可吸收 EBV TK 表达的合成 SCFAD）的药物制剂，完善 ST101 的口服给药方案，准备 ST101 钠盐的研究性新药 (IND) 申请，并评估其他 SCFAD 的 EBV TK 诱导活性。