While the cause of neuronal loss in Alzheimer's disease (AD) remains unknown, the amyloid hypothesis continues to be a leading possibility. Although Phase III trials of tramiprosate and tarenflurbil, compounds that target amyloid-beta (abeta), did not show evidence of a treatment effect on cognition or functional measures, whether the drug concentrations achieved in the brain in those trials were sufficient to have an effect on the AD pathologic process is unclear. Semagacestat is a gamma secretase inhibitor that has been in clinical development for over 10 years. Phase I and II trials provided biomarker data demonstrating inhibition of gamma secretase and reduction in the rate of abeta synthesis in the brain at the doses subsequently administered in Phase III studies. Two multi-national Phase III studies to test the clinical efficacy and safety of semagacestat were initiated - IDENTITY (Interrupting Alzheimer's Dementia by Evaluating Treatment of amyloid pathology) and IDENTITY-2. The results of the IDENTITY study will be reported. IDENTITY was a 3-arm, randomized, double-blind, placebo-controlled trial utilizing active treatment doses of 140 mg or 100 mg, and a placebo arm. The initial placebo-controlled period was 76 weeks in duration. A delayed start design was incorporated such that for subjects initially randomized to placebo, active treatment with semagacestat was started at week 76 and continued until week 88, with the dose titrated to 140 mg. Dose reductions (from 140 mg to 100 mg or from 100 mg to 60 mg) were allowed between weeks 4-64 if needed based on adverse events. Inclusion/exclusion criteria included a diagnosis of probable AD based on NINDS/ADRDA criteria and a Mini-Mental State Examination (MMSE) score of 16-26. Premenopausal women were excluded. Clinical measures included the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL), the Clinical Dementia Rating scale (CDR), the Neuropsychiatric Inventory (NPI), and the Resource Utilization in Dementia - Lite questionnaire (RUD-Lite). Subjects were invited to participate in 4 sub-studies of biomarkers - volumetric magnetic resonance imaging (vMRI), fluoro-deoxy-glucose positron emission tomography (FDG PET), PET using the amyloid imaging agent florbetapir, and cerebrospinal fluid (CSF) tau and abeta. For each optional sub-study, procedures were performed at baseline and end of the placebo-controlled period of the trial. An unblinded Data Monitoring Committee (DMC) met on a quarterly basis to review safety data. The protocol specified that an interim evaluation of cognitive data would be performed by the DMC after 50% of subjects had completed 12 months of treatment. The initially planned final analyses included 2 co-primary outcomes, the 11 question version of the ADAS-cog and the ADCS-ADL. A mixed-model repeated measures (MMRM) assessment was used to evaluate the difference in change from baseline to the end of the placebo-controlled period. An assessment of the delayed-start period was planned as a secondary outcome; this analysis was the change from baseline until Week 88 at the end of the study. For the biomarker sub-studies, vMRI measures included hippocampal volume and total brain volume; CSF measures included abeta1-40, abeta1-42, total tau and phospho-tau181 (p-tau181). Between March 2008 and August 2009, 1,536 subjects in 19 countries were enrolled in the IDENTITY trial. Preliminary baseline data at the time of submission of this abstract include the following. The mean (SD) MMSE score at screening was 20.8 (3.1) and the mean time since onset of symptoms was reported to be 4.7 (2.6) years. The mean age was 73.8 (8.2) years, and 53.4% of the subjects were female. Of 1,359 subjects who underwent apolipoprotein E genotyping, 59.9% carried at least one ApoE epilson 4 allele. At baseline, the mean ADAS-cog11, ADCS-ADL and CDR sum of boxes scores were 22.9 (8.9), 60.8 (12.6) and 5.5 (2.7) respectively. At baseline, 53.8% of subjects were taking a cholinesterase inhibitor, 29.9% of subjects were taking a cholinesterase inhibitor with memantine, and 3.9% were taking memantine alone. In August 2010, after the DMC's protocol-specified interim review of the cognitive and functional data, the DMC recommended that the IDENTITY trial should be stopped due to dose-dependent worsening of cognition for semagacestat-treated subjects. After an additional unblinded review of the data by an Internal Review Committee (IRC) consisting of 9 members of Eli Lilly management, the sites were informed on August 17, 2010 that dosing of all subjects in all semagacestat studies should be stopped immediately. Other than the DMC and the Lilly IRC, blinding was maintained for all members of the study team. The protocol was extensively modified to collect additional blinded follow-up data for subjects who had not completed the trial on August 17, 2010. An endpoint visit approximately one month after discontinuing study drug was used to collect the endpoint data specified in the original protocol. Three additional visits were scheduled at 4 weeks, 12 weeks and 28 weeks after the endpoint visit to collect safety data and ADAS-cog11 and ADCS-ADL scores. The last patient visit is expected to occur by May 2011. Efficacy and safety data from the original study and follow-up period will be presented. The Phase I and Phase II development of semagacestat was based on safety assessments and evidence of gamma secretase inhibition in the brain based on biomarkers during up to 14 weeks of treatment with semagacestat. The first opportunity to adequately assess the effect of semagacestat on cognitive functioning occurred during the first planned interim analysis of the IDENTITY trial. The possible reasons for the unexpected worsening in cognition with semagacestat will be better understood following analyses of data obtained during the follow-up period after dosing was discontinued. These analyses will include a determination of whether the cognitive worsening was reversible. The possible causes of the cognitive worsening associated with semagaestat will be discussed.
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Siemers et al. (2011) studied this question.