The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans

Pharmacologic effects in vivo of oral administration of LY2886721. Young PDAPP mice (n = 6–8 per group) were treated with increasing doses of LY2886721 or vehicle, and hippocampal Aβ_1-x (A), cortical Aβ_1-x (B), cortical C99 (C), or cortical sAPPβ (D) levels were determined from brain extracts obtained 3 h after dosing. LY2886721 produced dose-dependent decreases in all APP-related PD markers of BACE1 inhibition in PDAPP mice, p < 0.01 versus vehicle control, ANOVA/Dunnett's post hoc analysis.

Peripheral and central PD effects of LY2886721 in beagle dogs after a single 1.5 mg/kg dose. Baseline plasma and CSF samples were collected from cannulated beagle dogs (n = 6) before dosing with 1.5 mg/kg LY2886721. After dosing, plasma and CSF samples were collected at various times and stored for analysis; Aβ_1-x levels are measured in plasma and CSF and averaged across all 6 animals. Baseline plasma Aβ_1-x was 234 ± 17 pg/ml (mean ± SEM; n = 6) and baseline CSF Aβ_1-x was 4.85 ± 0.64 ng/ml (mean ± SEM; n = 6). LY2886721 produced robust and time-dependent decreases in Aβ_1-x in both plasma and CSF of dog relative to baseline. **p < 0.01 compared with baseline. p-values derived from ANOVA: Dunnett's post hoc analysis.

Plasma Aβ species by time course in humans after administration of a single dose of 5, 7, 10, 15, 25, 35, and 70 mg of LY2886721 in healthy subjects. Subjects received a single dose of 5, 7, 10, 15, 25, 35, or 70 mg of LY2886721 (n = at least 6/dose) or placebo. Samples were drawn for PD biomarkers at baseline and at times up to 168 h after dosing. The time at which the mean nadir occurred across LY2886721 doses was 6–12 h and appeared to be independent of dose. The reduction from baseline in levels of Aβ species, as measured by either the nadir or the average reduction over the first 24 h, tended to increase with increasing doses of LY2886721. At the highest dose, 70 mg, the reduction from baseline was 83.3% for plasma concentrations of Aβ_1–40 (A) and 74.0% for Aβ_1–42 (B). Plasma levels of Aβ_1–40 and Aβ_1–42 slowly approached baseline levels by 168 h.

CSF levels of amyloid β species after a single dose of 35 mg of LY2886721 in healthy subjects (n = 4). CSF concentrations of Aβ_1–40 and Aβ_1–42 closely paralleled one another after a single 35 mg dose of LY2886721. The mean nadir for both species occurred at 18 h, ∼6–12 h after the plasma nadir occurred. At nadir, the mean reduction from baseline was 40.0% for Aβ_1–40 and 36.3% for Aβ_1–42, approximately half the reduction seen in plasma at the same dose. After concentrations reached nadir, they slowly returned to their predose baseline values over 32–36 h.

Steady-state plasma Aβ species time course in humans after once daily administration of 5, 15, 35, or 70 mg of LY2886721 for 14 d in healthy human subjects. Healthy subjects (n = 6–10 per dose group) received daily doses of 5, 15, 35, or 70 mg of LY2886721 for 14 d. After the last dose, plasma samples were collected for up to 216 h and analyzed for Aβ_1–40 and Aβ_1–42. Values are expressed as the percentage change from baseline levels. Both Aβ species were reduced compared with placebo, reached a nadir, and slowly approached baseline by the end of the sampling period (216 h). A, Aβ_1–40 concentrations were reduced and reached a nadir at 8 h for the 3 lower doses and 9 h for the highest dose of 70 mg. Whether measured as change from baseline or time-averaged change from day 1 baseline from 0–24 h, the percentage reduction from baseline increased with dose (reduction from baseline at nadir: 66.3%, 73.5%, 83.5%, and 86.4% for 5, 15, 35, and 70 mg, respectively). B, Concentrations of Aβ_1–42 were reduced in a similar manner_. Steady-state Aβ_1–42 concentrations reached a mean nadir at between 8 and 10 h and reductions from baseline concentrations after 14 d of a steady dose ranged from 47.1% to 80.1%.