Cline Erika N, Antwi-Berko Daniel, Sundell Karen, Johnson Elizabeth, Hyland Maddelyn, Zhang Hao, Vanderstichele Hugo, Kaplow June, Dean Robert A, Stoops Erik, Vanmechelen Eugeen, Koel-Simmelink Marleen J A, Teunissen Charlotte E, Sethuraman Gopalan, Feaster Todd, Siemers Eric, Jerecic Jasna
Acumen Pharmaceuticals, Inc, 1210-1220 Washington St., Suite 210, Newton, MA 02465, USA.
Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam, the Netherlands.
J Prev Alzheimers Dis. 2025 Apr;12(4):100082. doi: 10.1016/j.tjpad.2025.100082. Epub 2025 Feb 17.
Sabirnetug (ACU193) is a humanized monoclonal antibody selective for soluble amyloid beta oligomers (AβOs), synaptotoxins that are early and persistent triggers of Alzheimer's disease (AD). Sabirnetug pharmacodynamics were examined in the INTERCEPT-AD phase 1 study in mild cognitive impairment and mild dementia due to AD (NCT04931459) using biofluid biomarkers associated with Aβ and tau pathology, synaptic dysfunction, neuroinflammation, and neurodegeneration.
INTERCEPT-AD was a randomized, first-in-human study of sabirnetug versus placebo administered as a single (SAD; 2, 10, 25, 60 mg/kg) or multiple (MAD; three doses of 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) ascending doses. Biomarkers were measured pre-/post-dose in CSF and EDTA-plasma. Correlations of biomarker changes versus dose, exposure duration, and target engagement were determined.
In MAD cohorts, CSF pTau181 decreased significantly (60 mg/kg Q4W, p = 0.049). VAMP2 decreased significantly at all doses (p ≤ 0.041); neurogranin decreased significantly at 60 mg/kg Q4W (p = 0.037). Aβ/Aβ trended upward with sabirnetug dose. Aβ/Aβ and neurogranin changes correlated with sabirnetug-AβO target engagement (p ≤ 0.01). Decreases in tTau, VAMP2, and neurogranin correlated with exposure duration (p ≤ 0.007). Plasma pTau181, pTau217, GFAP, and NfL trended lower.
Following three sabirnetug doses, changes in CSF and plasma biomarkers were observed. The CSF biomarker response increased with increasing dose and exposure duration, consistent with previous reports that sabirnetug reaches the central compartment and engages its AβO target. The ongoing phase 2 ALTITUDE-AD study (NCT06335173) will test whether sabirnetug's pharmacodynamic effects can be substantiated with a larger sample size and longer treatment duration.
Sabirnetug（ACU193）是一种人源化单克隆抗体，对可溶性淀粉样β寡聚体（AβOs）具有选择性，AβOs是阿尔茨海默病（AD）早期且持续的突触毒素触发因素。在INTERCEPT-AD 1期研究中，使用与Aβ和tau病理学、突触功能障碍、神经炎症和神经退行性变相关的生物流体生物标志物，对轻度认知障碍和AD所致轻度痴呆患者（NCT04931459）进行了Sabirnetug的药效学研究。
INTERCEPT-AD是一项随机、首次人体研究，比较Sabirnetug与安慰剂，以单次（SAD；2、10、25、60mg/kg）或多次（MAD；每4周[Q4W]给予三剂10或60mg/kg或每2周给予25mg/kg）递增剂量给药。在脑脊液和乙二胺四乙酸血浆中给药前/后测量生物标志物。确定生物标志物变化与剂量、暴露持续时间和靶点结合的相关性。
在MAD队列中，脑脊液pTau181显著降低（60mg/kg Q4W，p=0.049）。所有剂量下VAMP2均显著降低（p≤0.041）；60mg/kg Q4W时神经颗粒蛋白显著降低（p=0.037）。Aβ/Aβ随Sabirnetug剂量呈上升趋势。Aβ/Aβ和神经颗粒蛋白的变化与Sabirnetug-AβO靶点结合相关（p≤0.01）。tTau、VAMP2和神经颗粒蛋白的降低与暴露持续时间相关（p≤0.007）。血浆pTau181、pTau217、GFAP和NfL呈下降趋势。
给予三剂Sabirnetug后，观察到脑脊液和血浆生物标志物的变化。脑脊液生物标志物反应随剂量和暴露持续时间的增加而增加，这与之前关于Sabirnetug到达中枢腔室并与其AβO靶点结合的报道一致。正在进行的2期ALTITUDE-AD研究（NCT06335173）将测试是否可以通过更大的样本量和更长的治疗持续时间来证实Sabirnetug的药效学作用。
