CNP520 Phase III dose selection support: Identifying the doses producing a desired reduction in CSF Aß-40
Olivier J David (1), Mita M Thapar (2), Colm B Farrell (2), Etienne Pigeolet (1)
(1) Pharmacometrics, Novartis, Basel, Switzerland, (2) PK/PD Modelling & Simulation, ICON, Marlow, UK
Objectives: One important pathological feature of Alzheimer disease (AD) is the presence of deposits forming amyloid plaques in the brain cortex of affected individuals. These plaques are constituted of aggregated fibrils of Aβ peptides that derive from the amyloid precursor protein (APP) [1]. There is a growing body of evidence that beta-amyloid peptides are involved in the pathophysiology of AD [2]. CNP520 is an orally-available, centrally active and potent inhibitor of BACE-1, an enzyme involved in the processing of APP. CNP520 by reducing Aβ generation and restoring Aβ equilibrium offers the promise of disease modification in AD. The goal of this population pharmacokinetic/pharmacodynamic (PK/PD) analysis was to characterize the dose-exposure and the exposure-response (CSF concentration of Aβ-40 peptide) of CNP520. This work was used to support the selection of doses providing the desired level of CSF Aβ-40 inhibition for a long term disease prevention study.
Methods:The popPK/PD modeling was performed on clinical data from a first-in-human, single and multiple ascending oral dose study in healthy adult and elderly subjects (n>200). The model was then validated on data from a 3-month study in healthy elderly subjects (n>120). The CNP520 and CSF concentration of the Aβ-40 peptide were fitted to a PK/PD model using non-linear mixed-effects modelling implemented in NONMEM (version 7.3.0) and Monolix 2016R1. The validation on the second study and further simulations were performed with mlxR version 3.1.0.
Results: CNP520 PK is best described with a linear two-compartment model with an absorption lag time, sequential zero and first-order absorption processes and first order elimination. Weight and age were statistically significant predictors of CNP520 PK.
The drug effect was modeled by linking plasma CNP520 concentrations to CSF Aβ-40 concentrations via an indirect response population PK/PD model, in which CNP520 inhibited the Aβ-40 synthesis. This model estimated a maximal CSF Aβ-40 inhibition of approximately 95% with an IC50 of 28.4 ng/mL. Simulations on the external dataset were accurate with an estimation of approximately 60% CSF Aβ-40 inhibition at steady-state for a dose of 10 mg/day.
Conclusions: The PK of CNP520 and its PD effect were modeled and validated. The model was further used to derive CSF Aβ-40 inhibition for many different doses supporting the selection of doses for a long term prevention study of the disease.
References:
[1] Masters CL, Beyreuther K (2006) Pathways to the discovery of the Aβ-amyloid of Alzheimer’s disease. J. Alzheimer’s Disease; 9 (Suppl. 3): 155-61.
[2] Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science; 297: 353-56.