MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients

Abstract

Introduction: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides.

Methods: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ₄₂, the pathogenic self-aggregating species of Aβ.

Results: MEDI1814 reduces free Aβ₄₂ without impacting Aβ₄₀ in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n = 57) in single or repeat doses up to 1800 mg intravenously or 200 mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ₄₂, increases in total (bound and free) Aβ₄₂, but no change in total Aβ₄₀ in CSF across doses.

Discussion: MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ₄₂.

Keywords: amyloid beta 42; drug development; pharmacodynamics; pharmacokinetics; preclinical; safety; tolerability.

FIGURE 1

Aβ peptide selectivity of MEDI1814. Aβ peptide competition of MEDI1814 to biotinylated Aβ_1‐42 using homogeneous time‐resolved fluorescence, with europium cryptate labelled anti‐human Fc immunoglobulin and XL665‐labelled streptavidin from CisBio. Peptide sequences and half‐maximal inhibitory concentration values are depicted. MEDI1814 has high selectivity for full length Aβ_1‐42 and Aβ_1‐43 (versus Aβ_1‐40) and high affinity for both full and N‐terminal‐only truncated forms of Aβ_1‐42. Aβ, amyloid beta.

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.

FIGURE 3

Pharmacodynamics of MEDI1814 in cynomolgus monkeys. Intravenous weekly administration of MEDI1814 over 13 weeks in cynomolgus monkey: (A), free CSF Aβ₄₂; (B) total plasma Aβ₄₂; (C) total CSF Aβ₄₂; (D) total CSF Aβ₄₀. A dose‐dependent increase in total Aβ₄₂ in both plasma and CSF was observed at the end of the treatment phase in the 10 mg/kg IV, 100 mg/kg IV, and 75 mg/kg SC groups. The majority of free Aβ₄₂ (> 95%) was suppressed in CSF at all dose levels at the end of the treatment phase (A). At the end of a 9‐week treatment‐free period, total Aβ₄₂ levels in plasma increased in the 100 mg/kg IV dose group compared to the vehicle group (B); compared to the vehicle group, total CSF Aβ₄₂ was higher, though not significant (C), and free CSF Aβ₄₂ was suppressed. The specificity of MEDI1814 binding to Aβ₄₂ over Aβ₄₀ was confirmed by lack of effect on total CSF Aβ₄₀ at all tested doses (D). Washout denotes a period of 9 weeks after dosing had stopped. Aβ, amyloid beta; CSF, cerebrospinal fluid; ELISA, enzyme‐linked immunosorbent assay; IV, intravenous; LOQ, limit of quantification; SC, subcutaneous.

FIGURE 4

Comparison of observed and predicted pharmacodynamic responses to MEDI1814 after administration to patients with AD. Data show median % change from baseline in CSF free Aβ₄₂ after administration of placebo and MEDI1814 single doses (25, 100, 300, 900, and 1800 mg IV or 100 mg SC in the single ascending dose study [A]) or repeat doses (300, 900, and 1800 mg IV or 200 mg SC, administered monthly in the multiple ascending dose study [B]). Relative to baseline, a dose‐dependent reduction of free Aβ₄₂ in CSF and increase in total (bound and free) Aβ₄₂ was observed at day 29 after single MEDI1814 doses (A). Near maximal levels of suppression were observed after the 900 and 1800 mg IV repeat doses (B). Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; assay; IV, intravenous; SC, subcutaneous.

FIGURE 5

Effect of MEDI1814 on CSF Aβ biomarkers after single and multiple dose administration to patients with AD. Data show percentage change from baseline to follow‐up day 29 in CSF levels of (A), free Aβ₄₂, (B) total Aβ₄₂, and (C) total Aβ₄₀ after single doses of placebo or MEDI1814 (25, 100, 300, 900, and 1800 mg IV or 100 mg SC). Median and individual data points are shown for % change from baseline. Free Aβ₄₂ in CSF was greatly reduced in the highest dose cohorts (300–1800 mg IV), but lower levels of suppression were observed for the lower doses (100 mg IV, 100 mg SC, and 25 mg IV), compared to placebo. All individual data with median values shown where baseline and post‐dose sample available. Data are pooled for the placebo group after single dosing across the dose range. Data are pooled for the placebo groups after multiple dosing according to administration (IV or SC). Green symbol – Aβ42 free data at LLOQ (single ascending dose = 32 pg/mL; multiple ascending dose = 12 pg/mL). Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; IV, intravenous; LLOQ, lower limit of quantification; MAD, multiple ascending dose; SC, subcutaneous.

FIGURE 6

Effect of MEDI1814 on CSF (A), plasma NfL (B), and p‐tau217 (C) levels after administration of three monthly IV doses to patients with AD. Compared to baseline, CSF NfL levels were reduced after three monthly IV doses of MEDI1814 1800 mg compared to a median increase in placebo‐treated patients (A). Similarly, plasma NfL levels were reduced after three monthly IV doses of MEDI1814 1800 mg compared to a median increase in placebo‐treated patients (B). Data are mean ± standard error. Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; IV, intravenous; NfL, neurofilament light chain; p‐tau, phosphorylated tau.

FIGURE 7

Serum concentration profiles of MEDI1814 in patients with AD. (A) Single ascending dose. (B) Multiple ascending dose. Pharmacokinetic properties of MEDI1814 were consistent across single‐ and multiple‐dosing paradigms. Serum exposures were dose‐proportional, and concentrations declined in a biphasic manner with similar rates of elimination (effective mean serum half‐life ≈ 14–20 days). AD, Alzheimer's disease; IV, intravenous; MAD, multiple ascending dose; SAD, single ascending dose; SC, subcutaneous.