. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology. 2006 Feb 28;66(4):602-4. PubMed.

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  1. Finally, LY450139 progressed into phase Ib/IIa human trials despite the red flag associated with it due to the inhibition of Notch cleavage. Several other companies abandoned their compounds that displayed reduction in Notch cleavage.

    The dosage was 30-40 mg/d over 6 weeks. One serious event of gastrointestinal bleeding occurred, but this was assigned to Barrett's oesophagus, a condition that develops in some people with chronic gastroesophagal reflux.

    The histological changes do not indicate impairment of Notch cleavage. However, the impact of LY450139 on cell growth in the oesophagus and on the acid-resistant cells lining the stomach needs to be addressed further. More importantly for AD: Abeta levels in the CSF were not related to the concentrations of LY450139; plasma Abeta levels were reduced by 38 percent. Unfortunately, there are no data on cognitive function. Obviously the trial size and duration were just too short.