Background

This is a monoclonal antibody directed primarily against soluble protofibrillar and fibrillar species of Aβ. It is relatively inactive against Aβ monomers and small oligomeric aggregates. This humanized antibody was engineered on an IgG4 backbone. Its parent murine mAb, SAR255952, is reported to have low effector function, which is thought to reduce the risk of amyloid-related imaging abnormalities (ARIA). SAR228810 reportedly has low binding affinity for activating FcγRs on human microglia and no binding to complement C1q, a pro-inflammatory component of the innate immune system. The rationale is that these features confer less risk of a proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. In APPSL transgenic mice, the antibody prevented amyloid accumulation, microglia activation, and synaptic dysfunction, without causing vascular changes (Pradier et al., 2018).

Findings

From 2012-2015, a multicenter Phase 1 trial tested six ascending doses of intravenous infusion and two doses of subcutaneous injection on safety, pharmacokinetics, and pharmacodynamic endpoints in 48 patients at sites in Sweden and other countries.

Sanofi stopped development of SAR228810 in late 2018, citing pipeline prioritization as the reason (see slide 29 of 2018 year-end results presentation).

For trial details, see clinicaltrials.gov