Graduation study design: Evaluation of once‐weekly subcutaneous administration of gantenerumab on brain amyloid load

Background Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Aβ), is a potential disease‐modifying treatment for early Alzheimer’s disease (AD). Exposure‐dependent signals of clinical efficacy were observed with low‐dose gantenerumab in post‐hoc analyses of the SCarlet RoAD study (NCT01224106) in participants with prodromal AD.1 Open‐label extension studies with uptitration to a target dose of up to 1200 mg confirmed significant Aβ removal without new or unexpected safety findings.2 Two Phase III studies are ongoing to assess efficacy and safety of gantenerumab in early AD, using a 1020 mg/month regimen at target dose (GRADUATE I/GRADUATE II [NCT03444870/NCT03443973]). These studies maximise exposure with a single titration scheme and target dose regardless of APOE genotype over more than two years of treatment. The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once‐weekly (Q1W) administration of gantenerumab (255 mg) in participants with early (prodromal‐to‐mild) AD. Subcutaneous Q1W administration of gantenerumab may simplify home dosing to meet the individual needs and preferences of people with AD and their caregivers, and to improve their experience by providing additional flexibility and convenience. Methods In this open‐label, single arm, Phase II study, participants will receive gantenerumab by subcutaneous injection over a 2‐year period, starting with 120 mg every 4 weeks (Q4W), followed by 255 mg Q4W and Q2W for 12 weeks each, and a target dose of 255 mg Q1W. This target dose is equivalent to the 1020 mg/month studied in the GRADUATE trials. The primary objective is to evaluate the PD effect of a Q1W dosing regimen of gantenerumab on brain amyloid load measured by positron emission tomography (PET). Secondary objectives include the assessment of gantenerumab administration by a caregiver at home, safety, and PK/PD relationships. Exploratory objectives will include additional imaging and plasma biomarkers, cognitive and functional assessments. Result Results to come. Conclusion The GRADUATION study will determine the effect of once‐weekly administration of gantenerumab on brain amyloid load, safety, PK/PD and biomarker endpoints, and assess the feasibility of administration by caregivers at home. References: (1) Ostrowitzki et al., 2017; Alzheimers Res Ther. 9:95. (2) Klein et al., 2019; Alzheimers Res Ther. 11:101.