Cyclic Orynotides for Systemic MDR Candidiasis

环状 Orynotides 治疗系统性耐多药念珠菌病

• 批准号: 10395976
• 负责人: Dat Quang Tran
• 金额: $ 98.33万
• 依托单位: ORYN THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-07 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395976
• 关键词: ADME Study; AIDS/HIV problem; Achievement; Address; Animals; Antifungal Agents; Applications Grants; Azoles; Biological; Body Weight; Candida; Candida albicans; Candida auris; Candidiasis; Canis familiaris; Caspofungin; Cercopithecidae; Chemotherapy-Oncologic Procedure; Clinical; Complication; Cyclic GMP; Data; Development; Disease; Disseminated candidiasis; Dose; Dose Fractionation; Drug Kinetics; Evaluation; Formulation; Goals; Health; Host Defense; Human; Immunization; Immunocompetent; Immunocompromised Host; Inbred BALB C Mice; Incidence; Individual; Industrial fungicide; Infection; Injectable; Kidney; Lead; Libraries; Maintenance; Mediating; Modeling; Multi-Drug Resistance; Multiple Fungal Drug Resistance; Mus; Mycoses; Pathogenicity; Patients; Peptide Hydrolases; Peptides; Performance; Periodicity; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Plasma; Polyenes; Positioning Attribute; Preparation; Protocols documentation; Rattus; Research; Resistance; Resistant candida; Safety; Small Business Innovation Research Grant; Systemic infection; Therapeutic; Toxicology; Treatment Efficacy; Virulent; analog; base; comparative efficacy; design; drug candidate; emerging pathogen; immunogenicity; immunosuppressed; in vivo; lead series; mortality; mouse model; multi-drug resistant pathogen; novel; novel strategies; novel therapeutics; organ transplant recipient; pathogenic fungus; peptide drug; pharmacokinetics and pharmacodynamics; phase 2 study; preclinical development; resistant strain; response; safety study; theta-defensin; weight maintenance

This Fast Track SBIR grant proposal seeks to develop a new class of macrocylic peptide drugs for treatment of systemic candidiasis, an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp. Currently, there are but three classes of antifungal drugs available for treatment of invasive fungal diseases (polyenes, azoles, and echinocandins), and it has been nearly two decades since the last new class of antifungals (echinocandins) was approved. MDR isolates of Candida spp. that are resistant to all azoles and echinocandins are increasingly common, highlighting the urgent need for new antifungal therapeutics. This project seeks to develop a new class of proprietary antifungal peptides, OrynotidesTM, the design of which was bioinspired by θ-defensins, cyclic host- defense peptides expressed in Old World monkeys but not humans. A lead series of 35 Orynotides, down- selected from a larger proprietary library, is composed of macrocyclic peptides that are potently fungicidal against clinical isolates of MDR C. albicans and other pathogenic Candida spp., including C. auris a highly virulent globally emerging pathogen. Each of the Orynotide candidates has been prequalified as being fungicidal, highly stable in biological matrices, stable to proteases in fungal lysates, non-toxic to mice, and readily manufacturable. Among the prequalified Orynotides are compounds that markedly enhance survival in two models of systemic candidiasis including infections caused by caspofungin resistant C. albicans and MDR C. auris. Based on these findings, we propose in Phase 1 of the project to identify at least three peptides (from the prequalified panel of 35 Orynotides) that are equal or superior to a reference Orynotide that is effective in murine C. albicans candidiasis. Comparative efficacy metrics will include enhanced survival, reduction of fungal burden, and maintenance of body weight. Achievement of this Phase 1 milestone would trigger Phase 2 studies. The first of two Phase 2 Aims will identify a lead Orynotide, from 3-5 lead finalists, for preclinical development based on therapeutic efficacy, safety, and exposure-response analyses in immunocompetent and neutropenic mice. Phase 2 studies will then focus on IND enabling GLP toxicology studies of the lead Orynotide, with the goal being to file an IND by the end of the third year of Phase 2. Completion of this objective will position the applicant and its partners to introduce a new class of antifungal drugs for treatment of systemic candidiasis. This would represent the first new antifungal class to be introduced for human mycoses in nearly two decades.

该快速通道 SBIR 拨款提案旨在开发一类新型大环肽药物，用于治疗 念珠菌病是住院和住院期间严重且往往是全身性致命感染的越来越常见的原因 由于这些感染，免疫抑制患者的死亡率急剧上升。 白色念珠菌和其他念珠菌属的多重耐药（MDR）菌株的出现 可用于治疗侵袭性真菌病的三类抗真菌药物（多烯、唑类和 自从上一类新的抗真菌药物（棘白菌素）问世以来已经近二十年了。 对所有唑类和棘白菌素具有耐药性的念珠菌属菌株越来越多地获得批准。 常见，凸显了对新抗真菌疗法的迫切需求。该项目旨在开发一种新的抗真菌药物。 专有的抗真菌肽 OrynotidesTM，其设计受到 θ-防御素、环状宿主-的生物启发 防御肽在旧世界猴子中表达，但在人类中不表达。 35 种 Orynotides 的先导系列，下调。 选自更大的专有库，由大环肽组成，具有潜在的杀菌作用 耐多药白色念珠菌和其他致病性念珠菌属的临床分离株，包括高毒力的耳念珠菌 全球新兴病原体。每种 Orynotide 候选物均已通过资格预审，具有很强的杀菌作用。 在生物基质中稳定，对真菌裂解物中的蛋白酶稳定，对小鼠无毒，并且易于制造。 在经过预审的 Orynotides 中，有一些化合物能够显着提高两种系统性癌症模型的生存率。 念珠菌病，包括由卡泊芬净耐药的白色念珠菌和耐多药念珠菌引起的感染。 研究结果表明，我们建议在该项目的第一阶段鉴定至少三种肽（来自资格预审小组 35 Orynotides）等于或优于对鼠白色念珠菌有效的参考 Orynotide 念珠菌病的比较疗效指标包括提高生存率、减少真菌负担和 达到第一阶段的里程碑将触发第二阶段的研究。 两个第 2 阶段目标将从 3-5 个先导决赛入围者中确定一个先导 Orynotide，用于基于 对免疫功能正常和中性粒细胞减少小鼠的治疗效果、安全性和暴露反应分析。 第 2 期研究将重点关注 IND，以便对先导 Orynotide 进行 GLP 毒理学研究，目标是 在第二阶段的第三年年底之前提交 IND。完成这一目标将使申请人能够 其合作伙伴推出一类新型抗真菌药物来治疗系统性念珠菌病。 代表了近二十年来针对人类真菌病推出的第一个新的抗真菌药物。