Joao A. Abrantes, Switzerland
F. Hoffmann-La Roche Ltd Alzhiemer's DiseaseAuthor Of 1 Presentation
TRANSLATION OF RG6102, AN AMYLOID-TARGETING THERAPY WITH SUPERIOR BRAIN PENETRATION PROPERTIES, TO THE CLINIC
Abstract
Aims
Here we describe the development of RG6102, a bispecific monoclonal antibody (mAb) construct combining the anti-beta amyloid antibody gantenerumab with a “Brain Shuttle” module that specifically binds to transferrin receptor-1 (TfR1). Active TfR1-mediated transcytosis across the blood–brain barrier may allow superior target engagement and beta amyloid clearance through faster and more widespread brain penetration.
Methods
RG6102 was characterized in vitro and in vivo including a single-dose pharmacokinetics (PK) study in non-human primates (NHP). A translational PK/pharmacodynamics (PK/PD) model was developed combining data from this PK study with beta amyloid plaque removal information from the clinically established PK/PD profile of gantenerumab, and used to inform dose selection for the first-in-human, single-ascending dose (SAD) study of RG6102 (NCT04023994).
Results
Upon intravenous administration of RG6102 in NHP, a 6- to 17-fold increase in the steady-state brain area under the curve or >30-fold Cmax (peak concentration), compared with gantenerumab, was observed across different brain tissues. Preliminary SAD data incorporated in the translational PK/PD model predicted faster systemic clearance than the allometric projection. A human cerebrospinal fluid (CSF)/plasma ratio of ~0.8% was measured.
Conclusions
In preclinical NHP studies, the brain shuttle-gantenerumab construct RG6102 showed improved exposure and widespread distribution in the brain, compared with gantenerumab. Preliminary first-in-human data revealed a markedly increased CSF/plasma ratio for RG6102 compared with typical mAbs (~0.8% vs. 0.1–0.2%). Studies are underway in individuals with Alzheimer’s disease to test whether these findings translate into an enhanced pharmacodynamic effect (amyloid PET reduction) with the ultimate goal to improve clinical outcomes.