Development of the Novel Antifungal VT-1129 for Cryptococcal Meningitis

隐球菌性脑膜炎（CM）是由包囊酵母新型隐球菌和格特隐球菌感染引起的，几乎只在免疫功能低下的个体中观察到。撒哈拉以南非洲艾滋病毒感染者人数众多（估计超过2 000万），无法充分获得抗逆转录病毒疗法，因此极易感染这种疾病。在这类患者中，最常见的CM药物治疗是大剂量氟康唑单药治疗，但治疗10周后仅获得40%的生存率。一种更有效的抗真菌药物，可以每天口服一次，可能会为这个被忽视的人群提供显着的生存改善。该项目包括临床前研究性新药（IND）使能研究，这些研究将评估VT-1129作为治疗CM的新型口服独立候选药物。 TRND研究人员对先导化合物VT-1129进行了验证研究，包括啮齿动物和非啮齿动物的药代动力学、疗效和毒理学研究，从而能够选择最佳给药方案来平衡疗效和安全性。TRND团队优化了一种合成工艺，以低成本扩大药物生产，这将支持发展中国家患者的治疗。与疾病控制和预防中心（CDC）完成了额外的合作研究，以测试该分子对来自非洲的400种真菌菌株的体外功效。这项TRND支持使Viamet成功筹集风险资本资金，以继续开发风险降低的候选人。

Cryptococcal meningitis (CM) results from infection by the encapsulated yeasts Cryptococcus neoformans and Cryptococcus gattii and is observed almost exclusively in immune-compromised individuals. The enormous population of HIV-infected people in sub-Saharan Africa (estimated to be more than 20 million), with inadequate access to antiretroviral therapy, is highly susceptible to this disease. The most common drug treatment for CM in this patient population is high-dose fluconazole monotherapy, but it achieves only a 40 percent survival rate after 10 weeks of treatment. A more potent anti-fungal drug that can be given orally once a day would likely provide a significant improvement in survival for this neglected population. This project includes pre-clinical Investigational New Drug (IND)-enabling studies that will evaluate VT-1129 as a novel, oral, stand-alone drug candidate for the treatment of CM. TRND researchers conducted validation studies for the lead compound, VT-1129, including pharmacokinetic, efficacy and toxicology studies in rodents and non-rodents, enabling selection of an optimal dosing regimen to balance efficacy and safety. The TRND team optimized a synthetic process for scaled-up production of drug at a low cost that will support treatment of patients in the developing world. Additional collaborative studies were completed with the Centers for Disease Control and Prevention (CDC) to test the in vitro efficacy of the molecule against 400 fungal strains from Africa. This TRND support enabled Viamet to successfully raise venture capital funding to continue development of the de-risked candidate.