Paper Alert: First BACE Trial Published—New Inhibitor On Deck

On 16 November 2011, news dispensed at recent international meetings reached the pages of the Journal of Neuroscience with a paper reporting that Eli Lilly’s oral BACE1 inhibitor, LY2811376, reduces cerebrospinal fluid (CSF) Aβ in healthy volunteers.

The Alzforum closely followed the storied development of this compound, which looked good in mice, dogs, and people, when a rat toxicology study gave it the axe just before Phase 2 (see ARF 2011 AD/PD story; ARF related news story). Further experiments in BACE knockout mice determined that the adverse eye effects in the rats stemmed from some feature of the compound unrelated to BACE1 inhibition, and the company is developing another BACE1 inhibitor that “replicates and extends the pharmacodynamic responses” of LY2811376, first author Patrick May told ARF (see comment below). ClinicalTrials.gov lists three Phase 1 trials for LY2886721, an unidentified compound.

In the company scientists’ view, the research offers a broader message of hope to the AD field. “This first description of an orally available CNS-active β-secretase inhibitor after more than a decade of research clearly demonstrates that BACE1 is a tractable target, and that profound central Aβ lowering can be achieved by BACE1 inhibition in humans,” the authors write.—Esther Landhuis

Comments

  1. LY2811376 represents a breakthrough in targeting BACE1, the protease that initiates the amyloid cascade. After 10 years of research, many in the field were beginning to question whether this critical protease could be targeted with a small-molecule inhibitor. While previously presented at international meetings, the data in this article represent the first disclosure in a peer-reviewed journal of an orally available small-molecule inhibitor of BACE, and a critical first step in the development of a BACE inhibitor to test the amyloid hypothesis. While development of LY2811376 has been terminated, Lilly has in clinical development another β-secretase inhibitor which replicates and extends the pharmacodynamic responses observed in humans with LY2811376.

    View all comments by Patrick May

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References

News Citations

  1. Barcelona: Out of Left Field—Hit to The Eye Kills BACE Inhibitor
  2. Getting to First BACE: BACE1 Inhibition Takes a Step Forward

External Citations

  1. LY2886721

Further Reading

Primary Papers

  1. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, Stout SL, Timm DE, Smith Labell E, Gonzales CR, Nakano M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO, Cocke PJ, Greg Hall D, Friedrich S, Citron M, Audia JE. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16. PubMed.

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