Vanutide Cridificar and the QS-21 Adjuvant in Japanese Subjects with Mild to Moderate Alzheimer's Disease: Results from Two Phase 2 Studies
Vanutide Cridificar and the QS-21 Adjuvant in Japanese Subjects with Mild to Moderate Alzheimer's Disease: Results from Two Phase 2 Studies
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DOI：
10.2174/1567205012666150302154121
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发表时间：
2015-01-01
影响因子：
2.1
通讯作者：
Yoshiyama, Tamotsu
中科院分区：
文献类型：
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作者：
Arai, Heii;Suzuki, Hideo;Yoshiyama, Tamotsu
目的：多种证据表明，淀粉样蛋白β（A β）肽在脑中的病理性积累与阿尔茨海默病（AD）的病理生理学有关。通过与抗A β特异性抗体结合从大脑中去除A β正在积极研究中。用全长A β（42）肽（AN1792）接种成功地在患有AD的人类受试者中引发抗A β抗体，但与脑膜脑炎相关。为了避免这种安全性问题，设计了氨基末端A β（1 - 7）肽缀合物vanutide cridificar（ACC-001），目前正在临床开发中。本报告描述了在日本轻度至中度AD受试者中进行的两项II期多次剂量递增研究。安全性和免疫原性评价分别为主要和次要目的。研究方法：ACC-001以3、10或30 μ g的剂量给予三组受试者，在研究1中有或没有QS-21佐剂，在研究2中有QS-21佐剂;对照组由单独的QS-21（两项研究）和磷酸盐缓冲盐水（仅研究1）组成。结果如下：研究期间，大多数受试者报告了各种治疗后出现的不良事件（TEAE）;其中大多数事件的严重程度为轻度或中度。3例受试者因不良事件退出研究（研究2）。最常见的治疗相关TEAE为注射部位反应。两项研究均未观察到死亡。所有剂量的ACC-001 + QS-21均引起高、持续的抗A β抗体滴度; QS-21是该效应所必需的。结论：本研究为进一步研究抗A β疫苗治疗AD提供了有价值的信息。
Objective: Multiple lines of evidence indicate that pathological accumulation of amyloid beta (A beta) peptide in the brain is linked to the pathophysiology of Alzheimer's disease (AD). Removal of A beta from the brain by binding to anti-A beta specific antibodies is under active investigation. Vaccination with a full-length A beta(42) peptide (AN1792) successfully elicited anti-A beta antibodies in human subjects with AD, but was associated with meningoencephalitis. To avoid this safety issue, an aminoterminal A beta(1-7) peptide conjugate, vanutide cridificar (ACC-001), was designed and is currently in clinical development. This report describes two phase 2 multiple ascending-dose studies in Japanese subjects with mild to moderate AD. Safety and immunogenicity evaluation were the primary and secondary objectives, respectively. Methods: ACC-001 was administered to three cohorts of subjects at doses of 3, 10, or 30 mu g, with or without a QS-21 adjuvant in Study 1, and with a QS-21 adjuvant in Study 2; control groups consisted of QS-21 alone (both studies) and phosphate-buffered saline (Study 1 only). Results: A variety of treatment-emergent adverse events (TEAEs) were reported from most subjects during the studies; most of these were mild or moderate in intensity. Three subjects withdrew from the study because of an adverse event (in Study 2). The most common treatment-associated TEAE was injection site reactions. No deaths were observed in either study. All doses of ACC-001 + QS-21 elicited high, sustained anti-A beta antibody titers; QS-21 was necessary for this effect. Conclusion: These data will provide valuable information on further investigation of anti-A beta vaccine therapy for AD.