Viamet Pharmaceuticals, Durham, NC.
Viamet Pharmaceuticals, Durham, NC.
Am J Obstet Gynecol. 2018 Jun;218(6):624.e1-624.e9. doi: 10.1016/j.ajog.2018.03.001. Epub 2018 Mar 11.
Lanosterol demethylase is an enzyme that is essential for fungal growth and catalyzes an early step in the biosynthetic pathway of ergosterol, which is a sterol that is required for fungal cell membrane formation and integrity. Lanosterol demethylase is the molecular target of the class of drugs referred to as "azole antifungals." VT-1161 is a novel, oral, selective inhibitor of fungal lanosterol demethylase and is being developed for the treatment of recurrent vulvovaginal candidiasis.
We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared with placebo in women with recurrent vulvovaginal candidiasis, which was defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period.
Two hundred fifteen women with a documented history of recurrent vulvovaginal candidiasis and who, at screening, were experiencing an episode of acute vulvovaginal candidiasis (acute vulvovaginal candidiasis; composite vulvovaginal signs and symptoms score of ≥3 and a positive potassium hydroxide test for yeast) were enrolled. After treatment of the acute infection with fluconazole, subjects were assigned randomly to 1 of 5 treatment regimens: (1) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (2) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (3) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 23 weeks; (4) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 23 weeks; or (5) a matching placebo regimen for 24 weeks. The primary efficacy outcome was the proportion of subjects with ≥1 culture-verified acute vulvovaginal candidiasis episodes through week 48.
In the intent-to-treat population, the proportion of subjects with ≥1 acute vulvovaginal candidiasis episodes ranged from 0-7% across the 4 VT-1161 arms vs 52% in the placebo arm, with all arms achieving statistical significance vs placebo. VT-1161 was well-tolerated with a favorable safety profile, and the incidence of adverse events was lower in all VT-1161 arms compared with placebo. In addition, no patient in any VT-1161 arm discontinued the study early because of an adverse event or laboratory abnormality. There was also no evidence of an adverse effect of VT-1161 on liver function or electrocardiogram recordings.
In this study, VT-1161 was shown to be efficacious and safe in the treatment of patients with recurrent vulvovaginal candidiasis. These data strongly support further clinical investigation of VT-1161 for the treatment of recurrent vulvovaginal candidiasis.
羊毛甾醇脱甲基酶是一种对真菌生长至关重要的酶，它催化麦角甾醇生物合成途径中的早期步骤，麦角甾醇是真菌细胞膜形成和完整性所必需的甾醇。羊毛甾醇脱甲基酶是被称为“唑类抗真菌药”的一类药物的分子靶标。VT-1161 是一种新型、口服、选择性真菌羊毛甾醇脱甲基酶抑制剂，正在开发用于治疗复发性外阴阴道念珠菌病。
我们评估了与安慰剂相比，4 种口服 VT-1161 方案治疗复发性外阴阴道念珠菌病（定义为在 12 个月内至少有 3 次急性外阴阴道念珠菌病症状发作）的疗效和安全性。
215 名有复发性外阴阴道念珠菌病病史的女性，在筛选时正在经历急性外阴阴道念珠菌病（急性外阴阴道念珠菌病；复合外阴阴道体征和症状评分≥3，氢氧化钾试验阳性）。在使用氟康唑治疗急性感染后，受试者被随机分配至以下 5 种治疗方案之一：（1）VT-1161 150mg 每日 1 次，连用 7 天，然后每周 1 次，连用 11 周，随后每周 1 次给予安慰剂，连用 12 周；（2）VT-1161 300mg 每日 1 次，连用 7 天，然后每周 1 次，连用 11 周，随后每周 1 次给予安慰剂，连用 12 周；（3）VT-1161 150mg 每日 1 次，连用 7 天，然后每周 1 次，连用 23 周；（4）VT-1161 300mg 每日 1 次，连用 7 天，然后每周 1 次，连用 23 周；（5）匹配的安慰剂方案，连用 24 周。主要疗效终点是在第 48 周时通过培养证实至少有 1 例急性外阴阴道念珠菌病发作的受试者比例。
在意向治疗人群中，4 种 VT-1161 方案中≥1 例急性外阴阴道念珠菌病发作的受试者比例为 0-7%，而安慰剂组为 52%，所有方案均与安慰剂相比具有统计学意义。VT-1161 耐受性良好，安全性良好，与安慰剂组相比，所有 VT-1161 组的不良事件发生率均较低。此外，没有患者因不良事件或实验室异常而提前退出研究。VT-1161 也没有证据显示对肝功能或心电图记录有不良影响。
在这项研究中，VT-1161 治疗复发性外阴阴道念珠菌病有效且安全。这些数据强烈支持进一步研究 VT-1161 治疗复发性外阴阴道念珠菌病。
