Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks

Heather Guthrie, Lawrence S Honig, Helen Lin, Kaycee M Sink, Kathleen Blondeau, Angelica Quartino, Michael Dolton, Montserrat Carrasco-Triguero, Qinshu Lian, Tobias Bittner, David Clayton, Jillian Smith, Susanne Ostrowitzki, Heather Guthrie, Lawrence S Honig, Helen Lin, Kaycee M Sink, Kathleen Blondeau, Angelica Quartino, Michael Dolton, Montserrat Carrasco-Triguero, Qinshu Lian, Tobias Bittner, David Clayton, Jillian Smith, Susanne Ostrowitzki

Abstract

Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody.

Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated.

Methods: In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported.

Results: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level.

Conclusion: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

Keywords: Alzheimer’s disease; amyloid positron emission tomography; amyloid-β peptide; crenezumab; humanized monoclonal antibody; infusion site adverse event; magnetic resonance imaging; safety.

Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-0134r1).

Figures

Fig. 1
Fig. 1
Study design. Participants were enrolled sequentially. The next ascending dose cohort (60 or 120 mg/kg) was initiated if all previous dosing cohorts were supported by adequate safety and tolerability and provided that no previous dosing cohort was closed to enrollment due to safety concerns by the time the last participant enrolled in the study had completed the Week 5 MRI scan and the second study drug administration. Participation in the OLE phase was optional. The OLE dose was equivalent to the dose assigned during the double-blind randomization phase for all participants, except for those in the 120 mg/kg cohort who received 60 mg/kg IV every 4 weeks upon starting the OLE period. Additionally, at or after Week 133, participants in the 30 or 45 mg/kg dosing cohort were given the option to increase the dose of active drug to 60 mg/kg IV every 4 weeks. D, Day; IV, intravenously; MRI, magnetic resonance imaging; OLE, open-label extension; SMC, safety monitoring committee; W, week.
Fig. 2
Fig. 2
Mean (SD) serum crenezumab concentrations. Data shown are from the Phase II ABBY study (SRI cohort) for the 15 mg/kg dose and from the Phase Ib (GN29632) study reported here for the 30–120 mg/kg doses during the 13-week, randomized, placebo-controlled period. SD, standard deviation; SRI, safety run-in.
Fig. 3
Fig. 3
Plasma Aβ1–40(A) and Aβ1–42 (B) concentrations following administration of crenezumab during the 13-week, double-blind, randomized treatment phase. Aβ, amyloid-β.

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