Background

LY2886721 was the first BACE inhibitor to reach Phase 2 clinical research. Prior compounds by Lilly and many other pharmaceutical companies had lacked sufficient brain penetrance, exposure, or other key pharmacological characteristics. Inhibiting the β-secretase enzyme responsible for APP processing with a small molecule drug has been a goal in Alzheimer's drug development since the identification of BACE1 in 1999. The rationale is that this approach blocks the amyloid cascade at its inception, regardless of which species of the Aβ peptide is most toxic to the brain.

At research conferences, Lilly scientists reported that LY2886721 was selective for BACE, i.e., it did not inhibit other aspartyl proteases such as cathepsin D, pepsin, and renin, and reduced Aβ in a dose-dependent manner in HEK293Swe cells and in primary neurons from PDAPP transgenic mice. In mice, the compound’s half-life was short, but a 3–30 mg/kg dose lowered brain Aβ by 20–65 percent relative to vehicle-treated groups; the effect lasted up to nine hours after dosing. In beagles, the compound’s half-life was longer and a 0.5 mg/kg dose halved CSF Aβ in nine hours; plasma Aβ levels were reduced for 24 hours (see Jul 2012 conference story). No peer-reviewed research articles on this compound have been published thus far.

Findings

Lilly completed six Phase 1 studies of LY2886721’s safety, tolerability, and pharmacology in a total of 150 healthy volunteers and people with Alzheimer’s disease at doses of 1–70 mg. Single and multiple ascending oral dosing was accompanied by repeat CSF sampling in the hours and days thereafter. This was done to assess CSF penetration and target engagement by way of measuring levels of the drug, BACE1 substrate, and BACE1 cleavage products. The compound lowered CSF Aβ40, Aβ42, and sAPPβ concentrations while increasing sAPPα, consistent with expectations for BACE1 inhibition. Fourteen days of daily dosing reduced BACE1 activity by 50–75 percent, and CSF Aβ42 by 72 percent. No safety concerns were apparent in dosing up to six weeks (see Jul 2012 news story).

In March 2012, Lilly started an international Phase 2 study to compare the tolerability, efficacy, and pharmacodynamics of 15mg and 35mg doses of LY2886721 in 128 patients with MCI due to Alzheimer's disease (AD) or with mild AD and biomarker evidence of brain amyloid deposition. Patient selection was based on revised diagnostic criteria. The trial was to measure CSF Aβ40 and 42 levels at weeks 12 and 26. In June 2013, however, the company ended dosing in this trial after routine monitoring flagged four cases of abnormal liver biochemistry values. Patients continued to be monitored, but clinical development of LY2886721 was halted (see Lilly press release). Its toxicity was generally considered to be an off-target effect of the compound unrelated to BACE inhibition (see Jun 2013 news story).

This compound had been chosen based on Phase 1 and preclinical data to be evaluated in the first Dominantly Inherited Alzheimer's Network (DIAN) therapeutic trial (see Oct 2012 news story).For Lilly, this was the second BACE inhibitor to fail early in the clinic. A previous compound, LY2811376, had been discontinued in late Phase 1 when simultaneous rat toxicology studies showed damage to the pigment epithelium of the eye (see Jul 2013 conference story).