Acumen Pharmaceuticals (ABOS) investor relations material

Company and scientific background

• Sabirnetug is a humanized monoclonal antibody with high selectivity for toxic amyloid-beta oligomers, originating from academic research and later reacquired from Merck as a wholly owned asset.

• The oligomer hypothesis posits that soluble amyloid-beta aggregates are the primary neurotoxic species in Alzheimer's, disrupting synaptic function and linking A-beta to tau pathology.

• Sabirnetug demonstrates 10,000-fold selectivity for oligomers over monomers and 90-fold over plaques, aiming to minimize target distraction and maximize efficacy.

• Decades of research support the toxicity of oligomers, and sabirnetug targets a broad spectrum of these aggregates, potentially offering a differentiated therapeutic effect.

• Monoclonal antibody specificity is crucial, and sabirnetug’s mechanism is designed to impact synaptic plasticity and cortical function by targeting oligomers.

Clinical development and trial data

• Phase 1b INTERCEPT-AD trial in early Alzheimer's patients showed sabirnetug was well tolerated, with a 10% ARIA rate across dose groups, and consistent pharmacokinetics for monthly dosing.

• PET imaging revealed a 20% reduction in amyloid plaque at the highest dose, and biomarker analysis indicated reversal of disease-related markers, supporting the drug’s mechanism.

• Target engagement was confirmed using a novel ELISA-based assay, with maximal engagement at 25 and 60 mg/kg doses.

• Lower ARIA rates compared to other antibodies may be due to IgG2 isotype and higher selectivity for oligomers over plaques.

• No direct correlation was observed between plaque reduction and ARIA, highlighting the complexity of the underlying biology.

Phase 2 ALTITUDE-AD study and trial design

• Phase 2 ALTITUDE-AD is an 18-month, well-powered study in early Alzheimer's, using 35 and 50 mg/kg IV doses every four weeks, with IDRS as the primary outcome.

• Enrollment completed with 532 subjects in 10 months across the US, Canada, Germany, and Spain, reflecting strong interest and efficient execution.

• The cohort is similar to those in other major trials, and the IDRS scale was strategically chosen for its sensitivity in early AD.

• Dose modeling supports adequate target coverage at both dose levels, with expectations for differentiated ARIA rates between cohorts.

• A two-step screening process using plasma pTau217 biomarker improved efficiency, reducing amyloid-negative screen failures and streamlining enrollment.