Sandra Visser(1), Joanna Parkinson(2), Fredrik Olsson(3), Erno van Schaick(4), Johan Lundquist(3), Camilla Dahlqvist(3)
1) Global DMPK Centre of Excellence, 2) Modeling & Simulation, 3) Neuroscience, Innovative Medicines CNSP AstraZeneca Södertälje, Sweden 4) Exprimo, Mechelen, Belgium
Objectives: A growing body of pathological, biomarker, genetic and mechanistic data strongly suggests that Ab amyloidosis plays a key role in Alzheimer's disease (AD) pathogenesis. The Ab peptide is generated from amyloid precursor protein, APP, via the sequential cleavages by b-and g-secretase. g-secretase inhibitors (GSI) are being developed as putative AD therapeutics and have reached late stage clinical testing. Unfortunately, to date none of them have resulted in significant improvement for patients, which led to questions regarding the validity of the ‘amyloid hypothesis'. The aim of the current work was to perform a model based meta analysis on Ab biomarkers from published clinical trials with GSI. Literature and in house data were used to evaluate if the amyloid hypothesis has been tested and explore if this could have been predicted from preclinical data.
Methods: Clinical data on Ab levels and drug exposure over time for 5 GSI were digitized from literature references. Preclinical and in vitro data from various species were collected both in house and extracted from the literature. A descriptive model based analysis was undertaken using summary level time-concentration-effect data. A combination of a composite Emax and a turnover model was used to describe the biphasic effects. From the parameter estimates, the exposure giving 50% inhibition from baseline was derived and compared between species.
Results: All GSI demonstrate biphasic effects on Ab levels in plasma. For all GSI, the average plasma Ab effect over 24 h at therapeutic doses was an increase rather than the intended decrease. The limited information on inhibition on CNS Ab production did not exclude presence of biphasic responses in the central compartment, nor indicate a significant reduction in Ab levels at intended therapeutic doses. Preclinical species and in vitro tests did demonstrate similar behavior in plasma Ab levels and the inhibitory potencies were in similar range as for human.
Conclusions: The inhibition on CNS Ab production in recent clinical trials has been very limited both in size and duration, suggesting that more efficacious Ab production inhibitingdrugs need to be tested that lower Ab substantially over the dosing interval period prior to drawing any conclusions regarding the validity of the ‘amyloid hypothesis'. Properly designed PKPD experiments in preclinical species can assist in clinical study design and dose selection.
Reference: PAGE 21 (2012) Abstr 2495 [www.page-meeting.org/?abstract=2495]
Poster: CNS