Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Alzheimer's Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA.
J Alzheimers Dis. 2024;101(s1):S79-S93. doi: 10.3233/JAD-231126.
Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer's disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD.
Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ.
Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment.
Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD.
Varoglutamstat 是一种首创的小分子，正在被研究用于治疗早期阿尔茨海默病（AD）。它是谷氨酰胺环化酶（QC）的抑制剂，该酶将淀粉样蛋白-β（Aβ）肽翻译后修饰成毒性形式的焦谷氨酸 Aβ（pGlu-Aβ）和同工型 QC，将细胞因子单核细胞趋化蛋白-1（CCL2）翻译后修饰成神经炎症性 pGlu-CCL2。早期临床试验确定了 varoglutamstat 的安全性和耐受性剂量范围，并提供了支持其在早期 AD 中临床疗效的生物标志物数据。
介绍 varoglutamstat 在治疗早期 AD 中的科学原理和 VIVA-MIND（NCT03919162）试验的方法学，该试验采用无缝 2A-2B 设计。我们的综述还包括其他针对 pGlu-Aβ 的药物治疗方法。
VIVA-MIND 试验的 2A 期将确定 varoglutamstat 的最高安全剂量，该剂量具有足够的血浆暴露量和计算出的目标占有率，并且耐受性良好。使用预定义的安全停止边界进行连续安全性评估将有助于确定可进入 2B 期的最高耐受剂量。对认知功能和脑电图变化的中期无效性分析将为是否继续进行 2B 期提供信息。2B 期将通过 72 周的治疗评估最佳选择的 2A 期剂量的疗效和长期安全性。
Varoglutamstat 提供了一种独特的双重作用机制，针对疾病级联反应的多个致病因素。VIVA-MIND 提供了一种新颖有效的试验设计，以确定其在早期 AD 中的最佳剂量、安全性、耐受性和疗效。
