FIGURE 2.

Pharmacodynamics of MEDI1814 in Sprague–Dawley rats. Intravenous administration of MEDI1814 and m266 twice over 14 days with samples collected 7 days post second dose (A–D). Maximal suppression of free Aβ₄₂ was observed at 5 and 10 mg/kg, with significant effects being observed at 0.5–10 mg/kg relative to isotype control. Dose‐dependent increase of total (bound and free) Aβ₄₂ is observed both CSF and brain. Total Aβ₄₀ in the brain was unaffected by either isotype control or MEDI1814, showing selectivity of MEDI1814 for Aβ₄₂ in the brain. MEDI1814 dosed 14 times over 13 weeks, with samples collected 8 weeks after the final dose (E and F). Free Aβ₄₂ in CSF decreased in all the MEDI1814 treatment groups after 14 weekly doses (E). Total CSF Aβ₄₂ increased dose‐dependently in the 10 mg/kg and 100 mg/kg IV and 75 mg/kg SC groups compared to the appropriate vehicle group after 14 doses (F). At the end of the treatment‐free period, 8‐ and 3.5‐fold higher total Aβ₄₂ levels in the CSF were observed in the 100 mg/kg IV and 75 mg/kg SC groups, respectively. Concentrations shown are absolute in pg/mL as determined by ELISA. One‐way analysis of variance and Tukey multiple comparison: ^ns p ≥ 0.05, *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. Aβ, amyloid beta; CSF, cerebrospinal fluid; ELISA, enzyme‐linked immunosorbent assay; IV, intravenous; SC, subcutaneous.