P4‐088: Central and Peripheral Pharmacokinetic and Pharmacodynamic Effects of the β‐site APP Cleavage Enzyme (BACE1) Inhibitor LY2811376 In Humans
Ferenc Martényi, Stephen Loucian Lowe, Robert A. Dean, Scott A. Monk, Celedon Gonzales, Stuart W. Friedrich, Patrick C. May, James E. Audia, Martin Citron, Elizabeth Smith LaBell, Samira Moran, Mark Yen, Stanford S. Jhee, Jeanelle Kam, Larry Ereshefsky · Alzheimer s & Dementia · 2010
LY2811376 is a BACE1 inhibitor with marked Aβ-lowering effects in animal models. This was a translational study. Development was interrupted in humans due to preclinical toxicity findings. The safety, pharmacodynamics and pharmacokinetics of orally administered LY2811376 was investigated in one single and one multiple ascending dose (SAD, MAD) trial in healthy volunteers. As part of SAD, the effect of 2 doses of LY2811376 on concentrations of Aβs, sAPPβ and sAPPα (‘analytes') was determined in CSF serially collected via indwelling lumbar catheter. Plasma and CSF analytes were measured by immunoassay. Plasma drug concentrations were measured by LC/MS/MS. 55 and 28 subjects completed SAD and MAD studies, respectively. Administration of single and multiple doses of LY2811376 were well tolerated. Mean terminal half-life of LY2811376 exceeded 24 hours. Subjects exposed to single doses of LY2811376 experienced dose-dependent reductions in plasma Aβ, with significant 24-hour time averaged reductions in plasma Aβ1-40 and Aβ1-X, at the highest dose. Steady-state exposure to LY2811376 from multiple daily dosing of LY2811376 similarly significantly reduced 24-hour time-averaged Aβ1-40 and Aβ1-x concentrations as compared with placebo. Aβ rebound effects were not observed. Single doses of LY2811376 produced significant dose-dependent reductions in CSF Aβ1-40 and Aβ1-42, measured at nadir, as well as significant dose dependent 24-hour time-averaged reductions. CSF sAPPβ (as proximal biomarker) and sAPPα (biomarker of compensatory alpha-secretase activation) showed significant, dose-dependent decreases and increases relative to placebo, respectively. LY2811376 produced sustained and robust reductions in plasma and CSF Aβ in subjects, confirming proof of mechanism. While the clinical development of LY2811376 is on hold, development of potent, clinically well-tolerated BACE1 inhibitors for the treatment of Alzheimer's disease appears plausible.