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Clinical Trial
. 2008 Aug;65(8):1031-8.
doi: 10.1001/archneur.65.8.1031.

Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease

Adam S Fleisher  1 , Rema Raman, Eric R Siemers, Lida Becerra, Christopher M Clark, Robert A Dean, Martin R Farlow, James E Galvin, Elaine R Peskind, Joseph F Quinn, Abdullah Sherzai, B Brooke Sowell, Paul S Aisen, Leon J Thal
Affiliations
Clinical Trial

Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease

Adam S Fleisher et al. Arch Neurol. 2008 Aug.

Abstract

Objective: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease.

Design: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial.

Setting: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks.

Main outcome measures: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale.

Results: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures.

Conclusions: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

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Conflict of interest statement

Disclosure: Dr. Siemers and Dr. Dean are employees of Eli Lilly, the manufacturer of the study drug. Eli Lilly and company provided all funding for this study. All study sites were subcontracted through the Alzheimer's Disease Cooperative Study at the University of California, San Diego, which held the primary contract with Eli Lilly. Dr. Farlow has received research grant funding support from Eli Lilly which was independent and unrelated to this trial. For all other authors there are no disclosures to be made of any personal financial support from, or equity positions in, manufacturers of drugs or products mentioned in the manuscript. All authors have agreed to conditions noted on the Author Disclosure Form. All of the authors have been instrumental in the interpretation of the data and its presentation in this paper. This manuscript has not been simultaneously submitted for publication to any other journal. There is no patient identifiable data presented in this manuscript. Written permission for publication has been obtained from all authors.

Figures

Figure 1
Figure 1
Protocol schema:
Figure 2
Figure 2
Data flow chart Data flow chart for the 26 week trial. The intention to treat analyses included all 51 subjects originally randomized, including all subsequent drop-outs. The completer's analyses included those 43 subjects who completed the week 14 visit.
Figure 3
Figure 3
Change in Plasma LY450139 concentrations over 6 hours at week fourteen Arithmetic mean (+-SD) LY450139 plasma concentrations following final dose of LY450139.
Figure 4
Figure 4
Change in Plasma Aβ40 concentrations following LY450139 Week fourteen absolute mean plasma Aβ40 change over 6 hours post drug dosing.
Figure 5
Figure 5
Change in absolute mean CSF Aβ40 and Aβ42 between baseline and week fourteen.
See this image and copyright information in PMC

References

    1. May PC, Yang Z, Li WY, Hyslop PA, Siemers E, Boggs LN. Multi-compartmental pharmacodynamic assessment of the functional gamma-secretase inhibitor LY450139 in PDAPP transgenic mice and non-transgenic mice. Neurobiology of Aging. 2004;25(Supplement 2):S65.
    1. Boggs LN, Fuson KS, Baez M, et al. Clusterin (Apo J) protects against in vitro amyloid-beta (1-40) neurotoxicity. J Neurochem. 1996;67(3):1324–1327. - PubMed
    1. Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol. 2007 Nov-Dec;30(6):317–325. - PubMed
    1. Ness DK, Boggs LN, Hepburn DL, et al. P2-053 Reduced [beta]-amyloid burden, increased C-99 concentrations and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate daily by gavage for 5 months. Neurobiology of Aging. 2004;25(Supplement 2):S238–S239.
    1. Siemers E, Skinner M, Dean RA, et al. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol. 2005;28(3):126–132. - PubMed

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