Background

Semagacestat is a γ-secretase inhibitor that reduces Aβ40 and 42 production and secretion by the γ-secretase enzyme complex. The rationale is that reducing the formation of Aβ from its substrate APP targets an upstream event in the amyloid cascade and represents a direct test of the amyloid hypothesis. In preclinical animal studies, semagacestat reduced both soluble Aβ and amyloid plaque burden.

Findings

Semagacestat is the first γ-secretase inhibitor to have been taken into Phase 3 clinical trials. Phase 1 evaluated, in 27 healthy volunteers, three doses of semagacestat for its ability to lower the rate of Aβ synthesis in the CSF. It reported dose-dependent reduction (Bateman et al., 2009). This trial used a new radiolabeling technique to measure production and turnover rates of newly generated proteins in the CSF. Called SILT, it has since become more widely used in CNS drug development (Bateman et al., 2007).

In Phase 2, an initial trial in 70 people with mild to moderate Alzheimer's disease tested 30 mg for one week followed by 40 mg for five weeks (Siemers et al., 2006). A second trial gave 60 mg of semagacestat for two weeks, then 100  mg for another 12 weeks to  51 Alzheimer's patients. On the primary outcome of safety and tolerability, this trial showed a greater number of skin-related side effects in the treatment group, for example rash and lightening hair color. It also showed a significant reduction of plasma Aβ levels, but not in CSF Aβ levels. On secondary efficacy endpoints of cognition and function, this study showed no difference between semagacestat and placebo. A time course showed a biphasic response to semagacestat called "overshoot." Following the inhibitory phase, plasma Aβ exceeded baseline levels and remained elevated at all doses throughout most of a 24-hour post-dose period (Fleisher et al., 2008; Siemers et al., 2007).

Lilly started two pivotal Phase 3 trials, IDENTITY-1 and IDENTITY-2, intending to assess a total of 3,036 patients on up to 21 months of treatment. IDENTITY-1 compared 100 and 140 mg/day of semagacestat to placebo for their ability to improve cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and function as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) in patients with Alzheimer's disease in 24 countries around the world. IDENTITY-2 tested 60 mg/day against the same outcome measures but contained more secondary endpoints and substudy assessments. Both trials were to run until 2012, but were halted in April 2011 because of both an increased risk of skin cancer and infections and lack of efficacy. Notably, both cognition and function not only did not improve but worsened in all three treatment groups  (Doody et al., 2013). Lilly terminated development of semagacestat.

Possible explanations for semagacestat's failure center around the compound's broad-based inhibition of all γ-secretase's 40-plus substrates, particularly Notch. This is is thought to have been detrimental to both safety and pharmacology (see conference story). In addition, a toxic function for an intermediate product of APP processing called b-CTF, whose concentration rises with semagacestat treatment, has been proposed  (see conference story). At a systems level, disruption of hippocampal network function has been reported (Hajos et al., 2013).

Insight gained from semagacestat development has stimulated the search for APP-versus-Notch selective inhibitors and for γ-secretase modulators.  Semagacestat continues to be used in research. For clinical trials of semagacestat, see clinicaltrials.gov.