Lily presented data from the first of two phase III trials of semagacestat, including data from a 32-week follow-up period after dosing was halted in August 2010.
Semagacestat is a gamma secretase inhibitor that had been studied as a potential treatment for Alzheimer's disease. Results provided patient outcomes from the active treatment portion of the study and from a modified portion of the study conducted after dosing with semagacestat was stopped.
The dosing in both semagacestat trials was halted in August 2010 because preliminary results from the two phase III trials showed semagacestat did not slow Alzheimer's disease progression and was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Lilly continued to gather data, including cognitive scores, for 32 weeks after dosing was stopped.
The study data confirmed preliminary results that showed during the period of dosing, patients receiving semagacestat declined at a greater rate than patients taking placebo. During the follow-up period after dosing was halted, the cognitive and functional deficits of the patients initially treated with semagacestat remained worse than the deficits of patients initially treated with placebo. However, the course of the decline over time in the two groups did not diverge further after dosing was stopped.
An external Data Monitoring Committee (DMC) was established prior to beginning the semagacestat IDENTITY studies so that they could monitor safety during the trials; unlike the patients and investigators, the DMC knew which patients were taking semagacestat and which patients were taking placebo. A planned analysis of the cognitive data by the DMC partway through the trial showed the increased rate of worsening, leading to the decision to discontinue dosing of semagacestat. The IDENTITY trials were then modified substantially in order to obtain more data for approximately seven months while the patients were no longer taking semagacestat. By studying the patients after stopping dosing, some of the factors that may have led to the increased cognitive decline could be more fully understood.
After 76 weeks of treatment with semagacestat or placebo, patients taking placebo (501 patients) worsened by 6.19 points on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog11), which is approximately the amount of change expected for placebo-treated patients over this time period. Patients taking 100mg semagacestat daily (506 patients) worsened by 7.29 points; patients taking 140mg semagacestat (527 patients) worsened by 7.68 points. Over the seven months after stopping dosing of semagacestat, the differences between placebo- and semagacestat-treated patients were largely unchanged. The adverse effects seen in the IDENTITY trial were similar to those seen during phase II studies.
As disclosed previously and communicated to investigators, patients and regulators earlier in the trials, an increased rate of skin cancer was seen in patients taking semagacestat; this adverse effect was not seen in phase II studies. The adverse events and laboratory abnormalities seen in the semagacestat-treated subjects resolved shortly after stopping dosing.