Background

This compound is an inhibitor targeted to the catalytic site of the enzymes BACE1 and BACE2. It was discovered by the biotechnology company Vitae Pharmaceuticals using Contour®, its structure-based drug design platform, and is being clinically developed with the pharmaceutical firm Boehringer Ingelheim. As with other β-secretase inhibitors, the rationale is to reduce generation of the Aβ peptide and in this way test the amyloid hypothesis of Alzheimer's disease in the clinic. According to the companies, the compound lowers brain Aβ levels in animal models and can be given by mouth; however, no preclinical studies of BI 1181181 have been published in the peer-reviewed literature. 

Findings

In 2014, this compound was studied in Phase 1. A first trial evaluated CSF Aβ reduction, as well as safety and pharmacology parameters, of a single tablet in 36 healthy young men in Belgium. A second trial assessed similar parameters of single but rising oral doses in 65 healthy men in Germany. This second study also measured bioavailability of a tablet and powder formulation and the effect of food on the pharmacokinetics of BI 1181181. In October 2014, Vitae Pharmaceuticals declared both trials a success (Oct 2014 news). At AAIC 2015, Boehringer scientists reported the data, showing that BI 1181181 in Phase 1 had dose-dependently reduced plasma and CSF Aβ40 and Aβ42, and had a sufficiently long half-life to support once-daily dosing (see AAIC posters on BI website). 

A third Phase 1 study started in November 2014 to study the safety, pharmacokinetics, and pharmacodynamics of a 10-day course of multiple ascending doses in 48 healthy young and old men and women in Germany. In February 2015, Boehringer placed BI 1181181 on hold while investigating skin reactions in some study participants (see Feb 2015 news). A fourth Phase 1 trial was withdrawn before it began enrolling. BI 1181181 was discontinued in favor of a second-generation compound (personal communication, AAIC 2015).

For all clinical trials of this compound, see clinicaltrials.gov.