Semagacestat doesn't improve cognitive status in Alzheimer's

(HealthDay)—For patients with Alzheimer's disease, treatment with the small-molecule γ-secretase inhibitor semagacestat does not improve cognitive status and is associated with worsening of cognitive function, according to a study published in the July 25 issue of the New England Journal of Medicine.

Rachelle S. Doody, M.D., Ph.D., from the Baylor College of Medicine in Houston, and colleagues randomized 1,537 patients with probable Alzheimer's disease to receive 100 mg semagacestat, 140 mg semagacestat, or placebo daily in a double-blind trial. Changes in cognition were assessed from baseline to week 76 using the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), and changes in functioning were measured using the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale.

Based on the recommendation of the data and safety monitoring board, the trial was terminated before completion, when there were 189 patients in the placebo group and 153 and 121 in the 100 mg and 140 mg semagacestat groups, respectively. The researchers found that the ADAS-cog scores worsened in all groups, with no significant differences noted between the study drug and placebo arms. In all groups, the ADCS-ADL scores worsened (P = 0.14 for placebo versus 100 mg semagacestat; P < 0.001 for placebo versus 140 mg semagacestat). Treatment with semagacestat correlated with significantly more weight loss, skin cancers and infections, adverse event related treatment discontinuation, and serious adverse events.

"As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability," the authors write. "Semagacestat was associated with more adverse events, including skin cancers and infections."

The study was funded by Eli Lilly.

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