Reactions 1473, p2 - 12 Oct 2013

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Disappointing results for phase III semagacestat trial A multinational phase III trial of semagacestat in patients with mild to moderate Alzheimer’s disease was terminated prematurely on the basis of a lack of efficacy and poor tolerability. At a pre-planned interim analysis, performed by an independent data and safety monitoring board, semagacestat recipients showed a dose-related clinical worsening on several primary and secondary measures of cognition and functioning. Compared with placebo recipients, semagacestat recipients had significantly (p < 0.001) higher incidences of weight loss, skin cancer, infections, treatment discontinuation because of adverse events, and serious adverse events. A futility analysis indicated that a benefit in terms of the primary outcomes could not be demonstrated. Semagacestat was being developed by Eli Lilly as a potential disease-modifying therapy. The compound is an inhibitor of γ-secretase, an enzyme involved in the production of amyloid precursor protein (APP), which is responsible for the formation of cortical amyloid-β (Aβ) protein plaques. According to the authors of this trial, the tolerability issues could be attributed to the drug’s inhibition of Notch (a substrate for γ-secretase), and the lack of efficacy could be attributed to the drug’s effect on APP metabolism. The authors conclude that "the question of whether this worsening represents an on-target effect of central γ-secretase inhibition and central Aβ reduction or an unintended effect related to the known engagement of other inhibitory substrates remains unanswered." Doody RS, et al. A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease. New England Journal of Medicine 369: 341-350, No. 4, 25 Jul 2013. 803094091 Available from: URL: http://dx.doi.org/10.1056/NEJMoa1210951

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Reactions 12 Oct 2013 No. 1473