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LY3002813, a humanized IgG1 antibody directed at a truncated N-terminally pyro-glutamate modified amyloid-beta (Aβ) epitope specifically localized in amyloid plaques, induces microglial mediated removal of cerebral amyloid plaques. Phase 1b (NCT02624778) and Phase 2 (NCT03367403) studies are ongoing in patients with prodromal Alzheimer's disease (AD) through moderate AD dementia. The Phase 1b study I5T-MC-AACD (NCT02624778) is enrolling florbetapir F18 PET positive AD patients with MMSE 16-30 in to 6 dosing cohorts of up to 12 patients each with either single or repeated dosing of LY3002813 at 10mg/kg, 20mg/kg or 40mg/kg. Florbetapir F18 PET, as a pharmacodynamic (PD) measure of cortical amyloid plaque load and LY3002813 target engagement, is assessed at up to five time points post baseline over 72 weeks. Safety, tolerability and pharmacokinetics (PK) are being assessed, along with exploratory outcomes including volumetric MRI, flortaucipir F18 PET, clinical endpoints and serum/plasma/CSF biomarkers. Single and multiple doses of LY3002813 resulted in significant reductions in florbetapir F18 tracer uptake on PET by 3 months, with further reduction with repeat dosing over time. For the initial dosing cohorts, reductions in florbetapir F18 at 3 months were -11.8 (SD 21.1) centiloids after a single dose of 10 mg/kg IV (n=7); -39.0 (SD 18.1) centiloids after a single dose of 20mg/kg IV (n=7); and -44.5 (SD 24.3) centiloids for 10mg/kg IV administered every two weeks (n=10). In patients with up to 72 weeks of follow-up after completion of treatment, the reduced post-treatment florbetapir F18 PET SUVr levels were maintained, without returning to pre-dose baseline levels. LY3002813 demonstrates significant, rapid and sustained reduction in cortical amyloid plaque in Alzheimer's patients.
Fleisher et al. (Sun,) studied this question.