Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease

Objective: Sabirnetug (ACU193) is a humanized monoclonal antibody selective for soluble amyloid beta oligomers (A/3Os), 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 to AD (NCT04931459) using biofluid biomarkers associated with A /3 and tau pathology, synaptic dysfunction, neuroinflammation, and neurodegeneration. Methods: INTERCEPT-AD was a randomized, first-in-human study of sabirnetug versus placebo administered a single (SAD; 2, 10, 25, 60 mg/kg) or multiple (MAD; three doses of 10 or 60 mg/kg every 4 weeks [Q4W] 25 mg/kg Q2W) ascending doses. Biomarkers were measured pre-/post-dose in CSF and EDTA-plasma. tions of biomarker changes versus dose, exposure duration, and target engagement were determined. Results: 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 = A /31-42 /A /31-40 trended upward with sabirnetug dose. A/31-42/A/31-40 and neurogranin changes correlated sabirnetug-A/3O target engagement ( p <= 0.01). Decreases in tTau, VAMP2, and neurogranin correlated posure duration ( p <= 0.007). Plasma pTau181, pTau217, GFAP, and NfL trended lower. Discussion: Following three sabirnetug doses, changes in CSF and plasma biomarkers were observed. biomarker response increased with increasing dose and exposure duration, consistent with previous reports sabirnetug reaches the central compartment and engages its A/3O target. The ongoing phase 2 ALTITUDE study (NCT06335173) will test whether sabirnetug's pharmacodynamic effects can be substantiated with sample size and longer treatment duration.