Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

The beta-site APP cleaving enzyme
1, known as BACE1, has been a
widely pursued Alzheimer’s disease drug target owing to its
critical role in the production of amyloid-beta. We have previously
reported the clinical development of LY2811376 and LY2886721. LY2811376
advanced to Phase I before development was terminated due to nonclinical
retinal toxicity. LY2886721 advanced to Phase II, but development
was halted due to abnormally elevated liver enzymes. Herein, we report
the discovery and clinical development of LY3202626, a highly potent,
CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed
these key development challenges.