Name:	LY450139 Dihydrate
Other Names:	hydroxylvaleryl monobenzocaprolactam , Semagacestat
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Orally available, small-molecule γ-secretase inhibitor
Mechanisms:	γ-secretase inhibitor
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Reduction of Aβ40 and 42 production and secretion by γ-secretase enzyme; reduction of soluble Aβ and amyloid plaque burden.
Role in Alzheimer's Disease:	Eli Lilly has halted development and further testing of Semagacestat (LY450139), announced on Aug 17 2010. Preliminary analysis of from two Phase III trials (NCT00762411 and NCT00594568) have shown that 'patients treated with semagacestat worsened to a statistically significantly greater degree than those treated with placebo' and furthermore, 'semagacestat is associated with an increased risk of skin cancer compared with those who received placebo'. See related Alzforum News Lilly Halts IDENTITY Trials as Patients Worsen on Secretase Inhibitor and Lilly press release Lilly Halts Development of Semagacestat for Alzheimer's Disease Based on Preliminary Results of Phase III Clinical Trials. γ-secretase inhibitor LY450139 completed Phase 2 clinical testing in June 2007. This was a collaborative effort of the Alzheimer’s Disease Cooperative Study (ADCS) group and sponsor company. In a multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial, biomarker analysis of the treatment group showed that plasma Aβ40 decreased by 58.2 percent in the 100 mg/day group, and by 64.6 percent in the 140 mg/day group; the decrease in CSF Aβ40 was smaller and not statistically significant. See ARF related news story. Using a novel radiolabeling technique to identify newly synthesized protein in the CSF, LY450139 has been shown to decrease synthesis of Aβ without affecting clearance (see ARF related news story and Bateman et al., 2009)
Pharmacological Role:	The compound LY450139 is a potent inhibitor of γ-secretase, the enzyme that is involved in producing Aβ peptide from APP, and has been shown to reduce Aβ production and secretion in vivo in humans. (see ARF related news story and Siemers et al., 2006) Human pharmacokinetics have been reported from two clinical tests of LY450139 (Siemers et al., 2005; Siemers et al., 2006). Plasma Aβ production was lowered dose-dependently in both studies, with maximal inhibition correlating with Tmax of 1 hour. Cell IC50 reported as 15 nM (data not shown) and terminal half-life in human subjects was approximately 2.5 hours with Cmax occurring at 1 hour (Siemers et al., 2005). A time course showed a biphasic response to LY450139 such that following the inhibitory phase, plasma Aβ measured exceeded baseline levels at all doses tested, and remained elevated at all doses throughout most of a 24-hour post-dose period. CSF Aβ remained unchanged. Phase 1 trial results of LY450139 single dosing (60, 100, and 140 mg) in healthy adult (age 49-53) volunteers demonstrated a biphasic response of Aβ (reduction followed by elevation above baseline) and no statistically significant change in CSF Aβ (Siemers et al., 2007).
Contraindications:	γ-secretase inhibitors are closely watched for adverse effects, particularly in the skin, gastrointestinal, and immune systems. There are 40+ endogenous substrates for γ-secretase whose cleavage may play important roles in the adult human, most notably Notch (De Strooper et al., 1999). In vivo, Notch function is essential for differentiation of T and B lymphocytes (reviewed in Allman et al., 2002). γ-secretase inhibitors reduce thymocyte number and block thymocyte differentiation at an early stage in fetal thymic organ cultures (Hadland et al., 2001; Doerfler et al., 2001).
Side Effects:	Safety and tolerability endpoints were a major focus of the recently completed Phase 2 trial of LY450139. Three treatment discontinuations included a small bowel obstruction, hemoglobin-positive stool, and diarrhea. Drug- and dose-related QT prolongation occurred in the 140 mg/day treatment group. Other adverse effects included skin rashes and hair color change in treated patients. Somnolence, fatigue, and asthenia occurred in 10 LY450139-treated patients vs. two placebo patients. In a previous study of LY450139 two subjects were withdrawn from treatment in a 2-week tolerability study (Siemers et al., 2005). One subject withdrew from increased serum amylase and lipase concentrations, and exacerbation of previous gall bladder and biliary disease. The second patient experienced nausea, vomiting, weakness, and diarrhea accompanied by elevation in white blood cell count. In a second previous clinical test of LY450139 the incidence of gastrointestinal side effects in treated patients included six cases of diarrhea vs. zero in placebo group (n = 33-35 in each study group, p = 0.025), and esophageal failure that eventually led to death of a treated subject (Siemers et al., 2006). Elevated eosinophil counts were noted in LY450139-treated patients. The side effect profile of LY450139 in patients is consistent with a mechanistic cause, i.e., inhibition of γ-secretase substrate Notch.
Evidence pro its efficacy:	LY450139 is a potent inhibitor of γ-secretase, and reduces Aβ production and secretion in vivo in humans. (See ARF related news story and Siemers et al., 2006. Also see ARF related news story and Bateman et al., 2009)
Evidence con its efficacy:	Properties of concern: 1. The biphasic response to drug as shown in plasma Aβ time course suggests that a transient period of reduced Aβ may be followed by a period of elevated Aβ. 2. Gastrointestinal adverse effects have been observed in all clinical tests of LY450139, with accompanied increases in white blood cells (eosinophils). One 76-year-old subject withdrew from clinical testing of LY450139 and died shortly after treatment discontinuation. This patient had gastrointestinal bleeding due to a Barrett esophagus during the treatment period, subsequently developed endocarditis, and then died approximately 5 months after discontinuing LY450139.
Companies:	Eli Lilly and Company
Notes:	Eli Lilly has halted two Phase 3 clinical studies in mild to moderate AD, instructing patients to 'immediately stop taking the study drug they have received'. Studies affected include IDENTITY-2 and IDENTITY. Last updated: September 3, 2010

References

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