AL002 in Early Alzheimer’s Disease Misses Phase 2 Endpoint

Key Takeaways

• AL002 did not meet the primary endpoint versus placebo at week 96 in early Alzheimer’s disease.
• Sustained central nervous system target engagement with cerebrospinal fluid biomarker changes was reported during treatment.
• MRI changes resembling amyloid-related imaging abnormalities were the most frequent treatment-emergent adverse events.

In the phase 2 AL002 trial in early Alzheimer’s disease, 381 participants were included, and AL002 did not meet the primary clinical endpoint versus placebo at week 96. Sustained central nervous system target engagement and pharmacodynamic activity were also observed during treatment. Those biomarker findings were separate from the clinical result and were not presented as evidence of benefit. The study paired a missed efficacy endpoint with measurable biomarker activity.

This phase 2 randomized, double-blind, placebo-controlled trial evaluated AL002, a humanized TREM2 agonistic monoclonal antibody. Participants were assigned 1:1:1:1 to AL002 15 mg/kg, 40 mg/kg, 60 mg/kg, or placebo. Treatment was given intravenously every 4 weeks for 48 to 96 weeks. The primary endpoint was change from baseline in Clinical Dementia Rating-Sum of Boxes score versus placebo.

The trial did not meet the primary endpoint at week 96. Least-squares mean differences versus placebo were −0.31 with a 95% confidence interval of −1.61 to 0.98 for 15 mg/kg. Corresponding estimates were 0.13 with a 95% confidence interval of −1.18 to 1.43 for 40 mg/kg and −0.17 with a 95% confidence interval of −1.49 to 1.15 for 60 mg/kg. In the mixed-effects model for repeated measures, P was > 0.05.

Pharmacodynamic findings indicated sustained target engagement in the central nervous system. Cerebrospinal fluid soluble TREM2 decreased, while osteopontin increased during treatment. MRI changes resembling amyloid-related imaging abnormalities were the most frequent treatment-emergent adverse events. The authors characterized the study as negative but informative for further study of TREM2 therapeutics and ARIA.