Macfarlane Stephen, Grimmer Timo, Teo Ken, O'Brien Terence J, Woodward Michael, Grunfeld Jennifer, Mander Alastair, Brodtmann Amy, Brew Bruce J, Morris Philip, Short Cathy, Kurrle Susan, Lai Rosalyn, Bharadwaj Sneha, Drysdale Peter, Sturm Jonathan, Lewis Simon J G, Barton David, Kalafatis Chris, Sharif Saif, Perry Richard, Mannering Nicholas, MacSweeney J Emer, Pearson Stephen, Evans Craig, Krishna Vivek, Thompson Alex, Munisamy Malathy, Bhatt Neel, Asher Aliya, Connell Sandra, Lynch Jennifer, Rutgers Sterre Malou, Dautzenberg Paul Lj, Prins Niels, Oschmann Patrick, Frölich Lutz, Tacik Pawel, Peters Oliver, Wiltfang Jens, Henri-Bhargava Alexandre, Smith Eric, Pasternak Stephen, Frank Andrew, Chertkow Howard, Ingram Jennifer, Hsiung Ging-Yuek Robin, Brittain Rodney, Tartaglia Carmela, Cohen Sharon, Villa Luca M, Gordon Elizabeth, Jubault Thomas, Guizard Nicolas, Tucker Amanda, Kaufmann Walter E, Jin Kun, Chezem William R, Missling Christopher U, Sabbagh Marwan N
The Dementia Centre, HammondCare, Melbourne, Victoria, Australia.
Technical University of Munich, School of Medicine and Health, Klinikum rechts der Isar, Munich, Germany.
J Prev Alzheimers Dis. 2025 Jan;12(1):100016. doi: 10.1016/j.tjpad.2024.100016. Epub 2025 Jan 1.
There are no approved oral disease-modifying treatments for Alzheimer's disease (AD).
The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement.
ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial.
Multicenter - 52 medical research centers/hospitals in 5 countries.
508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934.
The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model.
Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related.
Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs.
目前尚无获批用于治疗阿尔茨海默病（AD）的口服疾病修饰疗法。
本研究旨在评估口服小分子σ-1受体（SIGMAR1）激动剂巴卡美新（ANAVEX®2-73）通过恢复包括增强自噬在内的细胞稳态，在早期AD中的疗效和安全性。
ANAVEX2-73-AD-004是一项随机、双盲、安慰剂对照的48周IIb/III期试验。
多中心——5个国家的52个医学研究中心/医院。
508名早期AD（3期）参与者被随机分配，接受中等剂量组30mg或高剂量组50mg的巴卡美新（n = 338）或安慰剂（n = 170）口服胶囊，每日一次，共48周。这些组的参与者被邀请参加开放标签扩展研究ATTENTION-AD，该研究于2024年6月完成，ClinicalTrials.gov标识符为NCT04314934。
共同主要认知和功能结局评估为从基线到48周的阿尔茨海默病协作研究认知量表13项（ADAS-Cog13）和阿尔茨海默病协作研究日常生活能力量表（ADCS-ADL）的变化。结局包括次要结局临床痴呆评定量表总和（CDR-SB）以及A/T/N谱中的生物标志物、血浆淀粉样蛋白β42/40比值和通过磁共振成像（MRI）测量的全脑体积变化。所有临床终点均使用重复测量混合模型（MMRM）进行分析，血浆生物标志物测量通过韦尔奇t检验进行分析，体积MRI扫描通过一般线性模型进行分析。
在意向性治疗人群的462名随机参与者中（平均年龄73.7岁；225名[48.7%]为女性），338名（73.2%）完成了试验。根据多重性控制规则，共同主要结局得到满足，因为在预先指定的巴卡美新组和安慰剂组之间，从基线到48周的最小二乘均值（LSM）变化在ADAS-Cog13方面差异在P < 0.025水平显著，在CDR-SB方面差异在P < 0.025水平显著，而ADCS-ADL在第48周未达到显著差异（ADAS-Cog13差异为-2.027[95%置信区间-3.522至-0.533]；P = 0.008；CDR-SB差异为-0.483[95%置信区间-0.853至-(-0.114)]；P = 0.010；ADCS-ADL差异为0.775[95%置信区间-0.874至2.423]；P = 0.357）。与安慰剂相比，巴卡美新组血浆Aβ42/40比值显著升高（P = 0.048），全脑体积损失显著减少（P = 0.002）。在全安全人群中，≥1次严重治疗中出现的不良事件（TEAE）在巴卡美新组的56名参与者（16.7%）和安慰剂组的17名参与者（10.1%）中发生。常见的TEAE包括头晕，头晕是短暂的，严重程度大多为轻度至中度。巴卡美新组和安慰剂组各有1例死亡，均不被认为与治疗相关。
巴卡美新在无相关神经影像学不良事件的安全性方面表现良好，在预先指定的主要认知终点ADAS-Cog13上，与安慰剂相比，巴卡美新组以及巴卡美新30mg（减缓34.6%）和50mg（减缓38.5%）个体组在48周时显著减缓临床进展36.3%。预先指定的次要终点CDR-SB，在最近成功的AD药物申报中用作唯一主要终点，在第48周时，与安慰剂相比，巴卡美新显著改善。这些发现得到了A/T/N谱生物标志物的支持，包括血浆Aβ42/40比值和全脑萎缩的减轻。此外，预先指定的SIGMAR1基因变异亚组分析证实了巴卡美新组通过上游SIGMAR1激活产生的有益临床效果——具有常见SIGMAR1野生型基因（不包括突变的SIGMAR1 rs1800866变异携带者）的受试者在预先指定的主要认知终点ADAS-Cog13上在48周时临床进展减缓49.8%，获得了更大的显著临床益处。每日一次口服巴卡美新可能代表早期AD的一种新型治疗方法，可作为抗β淀粉样蛋白药物的补充或替代药物。
