Acumen presents sabirnetug fluid biomarker, target engagement analyses

Acumen Pharmaceuticals presented cerebrospinal fluid biomarker data from the sabirnetug Phase 1 INTERCEPT-AD trial in an oral presentation at the International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders in Lisbon, Portugal, and online. Acumen also presented a poster showcasing the method used to develop a first-of-its-kind assay to measure target engagement of an AbetaO-selective antibody. Acumen’s sabirnetug is the first humanized monoclonal antibody to clinically demonstrate selective target engagement of AbetaOs, a soluble and highly toxic form of Abeta that accumulates early in AD and triggers synaptic dysfunction and neurodegeneration. Positive topline results from 62 participants dosed in the Phase 1 INTERCEPT-AD trial were reported in July 2023, and additional insights from exploratory analyses have further confirmed sabirnetug’s proof-of-mechanism and broad therapeutic potential as a next-generation treatment for early AD. Sabirnetug Lowers CSF Neurogranin & pTau181 Levels in INTERCEPT-AD Study in Early AD: Several key CSF biomarkers are associated with the pathological changes that occur in AD, and evidence suggests these biomarkers may better reflect the underlying pathology of AD than imaging alone. Results from CSF samples collected before and after drug exposure in the INTERCEPT-AD study were presented and assessed for biomarkers indicative of amyloid pathology, tau pathology, neuronal injury and synaptic injury. Sabirnetug had an observed dose-dependent trend in the multiple ascending dose cohorts on CSF levels of pTau181, pTau217 total tau, neurogranin and the Abeta42/Abeta40 ratio, consistent with the downstream pharmacologic effects after just three administrations of the drug. Key findings include: Improvements in biomarkers associated with AD pathology, including significantly lowered CSF levels of neurogranin and pTau181 and trending toward an increasing Abeta42/40 ratio using 60 mg/kg Q4W as compared to the placebo group; A nominally significant correlation between target engagement of AbetaOs and change in neurogranin across all doses, supportive of drug effect; and A trend in correlation between target engagement of AbetaOs and change in p-tau181 across all doses, also supportive of drug effect. These findings support a biological link between sabirnetug and neurogranin and pTau181 and are consistent with sabirnetug’s proposed mechanism of action and intended target engagement of AbetaOs, as sabirnetug’s effects on these two biomarkers are more closely related to binding of AbetaOs than plaque reduction. Target Engagement in INTERCEPT-AD: Development of a Novel Assay Measuring Sabirnetug-Amyloid Beta Oligomer Complexes in Human CSF Additionally, Acumen presented a poster detailing its method to develop the first assay to directly measure target engagement of AbetaOs by an immunotherapy in the INTERCEPT-AD trial. The novel assay configuration was tailored to selectively detect sabirnetug-AbetaO complex in CSF as a direct measure of target engagement, showing clear dose-related increases in target engagement across all cohorts. This data also informed development of a pharmacokinetic-pharmacodynamic model, which ultimately demonstrated that the highest doses used in INTERCEPT-AD approached maximal target engagement, as was presented in October 2023. Acumen is on track to initiate a Phase 2 trial evaluating sabirnetug in the first half of 2024 and a Phase 1 subcutaneous study in mid-2024.