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Clinical Trials |

Phase 2 Safety Trial Targeting Amyloid β Production With a γ-Secretase Inhibitor in Alzheimer Disease FREE

Adam S. Fleisher, MD; Rema Raman, PhD; Eric R. Siemers, MD; Lida Becerra, MS; Christopher M. Clark, MD; Robert A. Dean, MD; Martin R. Farlow, MD; James E. Galvin, MD, MPH; Elaine R. Peskind, MD; Joseph F. Quinn, MD; Abdullah Sherzai, MD; B. Brooke Sowell, MS; Paul S. Aisen, MD; Leon J. Thal, MD
[+] Author Affiliations

Author Affiliations:University of California, San Diego, La Jolla (Drs Fleisher, Raman, Sherzai, and Thal and Mss Becerra and Sowell); Eli Lilly & Co, Indianapolis, Indiana (Drs Siemers and Dean); Departments of Neurology, University of Pennsylvania, Philadelphia (Dr Clark), Indiana University School of Medicine, Indianapolis (Dr Farlow), and Oregon Health Science University, Portland (Dr Quinn); Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri (Dr Galvin); University of Washington, Seattle (Dr Peskind); and Georgetown University, Washington, DC (Dr Aisen). Dr Aisen is now with the University of California, San Diego.†Deceased.


Section Editor: Ira Shoulson, MD

More Author Information
Arch Neurol. 2008;65(8):1031-1038. doi:10.1001/archneur.65.8.1031.
Text Size: A A A
Published online

Objective  To evaluate the safety, tolerability, and amyloid β (Aβ) response to the γ-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 Aβ 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 Aβ40concentration 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 Aβ 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 Aβ concentrations were consistent with inhibition of γ-secretase.

Trial Registration  clinicaltrials.gov Identifier: NCT00244322

Figures in this Article

LY450139 is a functional γ-secretase inhibitor that is currently under development as a disease-modifying therapy for Alzheimer disease (AD). As reported previously, LY450139 rapidly reduces amyloid β (Aβ) concentrations in the brain, cerebrospinal fluid (CSF), and plasma of transgenic V717F human amyloid precursor protein mice (PDAPP mice)1,2and in the plasma of humans.3In addition, the administration of LY450139 at doses of 30 mg/kg once daily for 5 months to PDAPP mice results in reduced accumulation of Aβ in the hippocampus and cortex, as measured by means of enzyme-linked immunosorbent assay.4Previous clinical studies using LY450139 with either healthy volunteers5or patients with AD6have shown short-term reductions in plasma Aβ40levels up to approximately 40% using single daily doses up to 50 mg. A single-dose escalation study3using 60, 100, or 140 mg in healthy volunteers demonstrated a dose-proportional increase in drug levels in plasma and CSF and a dose-dependent reduction in plasma Aβ levels.

The tolerability of LY450139 treatment in clinical studies of up to 50 mg for 2 weeks5or 40 mg for 6 weeks6was generally good. However, concern exists about cumulative toxic effects that may not be revealed in short low-dose trials or higher single-dose biomarker studies. A potential cause of clinical toxic effects for γ-secretase inhibitors is the inhibition of Notch cleavage by these compounds.7Notch cleavage is integral to cell differentiation pathways in many organ systems, including the gastrointestinal tract and lymphoid cell lines. To our knowledge, the effect of multiple-dose administration of 100 and 140 mg of LY450139 in patients with AD has not been reported previously.

In this study, we aim to demonstrate the safety and tolerability of LY450139 over 14 weeks using single daily doses of 100 and 140 mg. We sought to determine whether extended exposure to these higher doses of LY450139 would be tolerated and would result in expected changes in plasma and CSF Aβ levels.

ENROLLMENT

Fifty-one patients were enrolled at 6 academic research centers between October 1, 2005, and December 31, 2006. The protocol was reviewed and approved by the institutional review board at each participating site. All research participants and caregivers gave written informed consent. The Alzheimer's Disease Cooperative Study's Data Safety Monitoring Board, which is advisory to the National Institute of Aging, provided oversight on an ongoing basis.

PATIENTS

Participants were 50 years or older and diagnosed as having probable AD, as defined by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria.8Individuals receiving stable doses of cholinesterase inhibitor drugs or memantine were included. Patients were excluded if they had a history of irritable bowel syndrome, chronic diarrhea, peptic ulcer, or gastroesophageal reflux disease; a history of cardiac disease; significant electrocardiographic (ECG) abnormalities; hematologic disorders; hepatic or renal disease; active malignancy within 5 years; or clinically important depressive, neuropsychiatric, cerebrovascular, or respiratory disease.

STUDY DESIGN

This is a multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial (Figure 1). Participants were randomized to receive LY450139 or placebo using a 2:1 randomization scheme via a telephone-based interactive voice-response system. Patients randomized to the LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for the next 6 weeks. At 8 weeks, the treatment arm was randomized again to receive 6 additional weeks of treatment at either 100 or 140 mg/d. Dose reductions were allowed for dose-limiting adverse events (AEs) during the treatment phase.

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Figure 1.

Protocol schema.

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SAFETY ASSESSMENTS AND LABORATORY MEASURES

All AEs occurring during the study were characterized. Safety data, such as vital signs, ECG data, and laboratory test results, were collected throughout the trial. Vital signs were recorded at each study visit, with ECGs performed at baseline and at weeks 2, 4, 8, 10, 14, and 16.

Routine hematology and clinical chemistry laboratory tests were performed at screening; at weeks 2, 4, 8, 10, and 14 (treatment); and at a 26-week follow-up visit. Measurements of CD4, CD8, CD19, IgG, IgA, and IgM cells were obtained at baseline, treatment end, and the 26-week follow-up visit. T-cell function was assessed by means of flow cytometry.3Urinalysis was tested at screening and at weeks 8 and 14. Stool samples were tested for occult blood at each study visit after baseline. Optional DNA testing for apolipoprotein E subtype was performed.

PLASMA AND CSF Aβ AND LY450139 LEVELS

Plasma samples for measurement of biomarkers and drug levels were collected at baseline and at weeks 14 and 16. At week 14, multiple samples were collected in 6 hours for pharmacodynamic modeling (30 minutes before and 0.5, 1, 2, 4, and 6 hours after receiving the drug). The CSF samples were collected into polypropylene tubes by means of a lumbar puncture at baseline and approximately 6 hours after the administration of the last dose of LY450139 at week 14.3Plasma and CSF concentrations of Aβ were measured from all the samples,3and concentrations of LY450139 were measured from all the samples after baseline.5

CLINICAL MEASURES

At baseline and at weeks 8 and 14, assessments were made of cognition and daily functioning using the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog 11)9and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL).10

STATISTICAL ANALYSIS

Adverse event data are reported using intention-to-treat analyses (n=51) across 26 weeks, with a completers analysis for all comparisons of laboratory and clinical measures through week 14 (n=43). To maximize the sensitivity of the safety measures, no adjustments were made for multiple comparisons. All statistical tests were 2-sided. P<.05 was considered statistically significant for biomarker and clinical measures, and P<.10 was used for safety variables to indicate potential clinical significance. All analyses were performed using the R statistical package, version 2.3.1.11

SAFETY

Data from all randomized participants for 26 weeks were included in the safety analyses. The Fisher exact test was performed to assess group differences in proportions of participants reporting specific types of AEs and serious AEs.

CLINICAL AND BIOMARKER ANALYSES

Analysis of covariance (ANCOVA) was used to assess 14-week change scores in all efficacy and biomarker outcomes of interest, with treatment group as a factor. Significance was based on the overall Fstatistic for interactions among all 3 treatment arms. Baseline values of outcome measures were entered as covariates into each model to account for any baseline group differences. In addition, any variable found to have significant between-group differences at baseline and to correlate with the outcome measure being tested was entered as a confounder into a post hoc ANCOVA model. Outcome variables included vital signs, laboratory measures, Fridericia-corrected QT intervals, log mean CSF Aβ40and Aβ42measures, and ADAS-Cog 11 and ADCS-ADL scores. A 2-way ANCOVA was used to investigate whether the treatment effect on the change in ADAS-Cog 11 scores was modified by donepezil hydrochloride therapy. Post hoc Bayesian estimates were used to determine pharmacokinetic variables.5At week 14, mean change in LY450139 and absolute mean plasma Aβ levels were compared for each time point over 6 hours using Kruskal-Wallis nonparametric tests of means.

PARTICIPANTS

Of 71 participants who were screened for the trial, 51 were eligible and randomized. Forty-three participants completed the treatment phase of the trial (Figure 2). No differences existed in dropout rates (84%) or medication compliance (96%-99%) among the 3 groups.

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Figure 2.

Data flowchart for the 26-week trial. The intention-to-treat analyses included all 51 patients originally randomized, including all subsequent dropouts. The completers analyses included the 43 patients who completed the week 14 visit.

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The 3 groups were balanced at baseline regarding all demographics, clinical measures (except Mini-Mental State Examination [MMSE] scores), apolipoprotein E ε4 distribution, and acetylcholine esterase inhibitor and memantine use (Table 1). Differences in baseline laboratory values are given in Table 1.

Table Graphic Jump LocationTable 1. Participant Characteristics at Baseline
SAFETY AND TOLERABILITY

All AEs that occurred in 2 or more participants are given in Table 2. Only the category of skin and subcutaneous tissue disorders reached significance for differences between groups (P=.05). In this category, there were 3 possible “drug-related” rashes and 3 reports of hair color change (lightening) in the treatment groups, with none in the placebo group. Although not reaching statistical significance, the percentage of patients reporting nausea, vomiting, or diarrhea was 27% in the treatment groups and only 13% in the placebo group (P=.41). In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted 1 or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P=.18). There were 4 serious AEs (Table 3). A small-bowel obstruction was considered to be possibly related to the study drug; no medical intervention was required, the study drug was discontinued, and the obstruction resolved spontaneously.

Table Graphic Jump LocationTable 2. Adverse Events by Treatment Arm During the Studya
Table Graphic Jump LocationTable 3. Serious Adverse Events by Treatment Arm

Eight participants dropped out of the trial during the treatment phase because of AEs (n=3), personal conflict (n=3), physician decision due to difficulty in managing increasing agitation and paranoia (n=1), and a protocol violation consisting of a patient reporting a history of gastroesophageal reflux disease after randomization (n=1). The AEs included diarrhea, heme-positive stool (required dropout per protocol), and the previously described bowel obstruction. There were 3 site-initiated dose reductions for rash, abdominal discomfort, and nausea.

Between-group differences were seen in some safety laboratory value changes during the therapy phase (Table 4). None of these changes were considered clinically important based on the degree of change and the lack of associated adverse events. No statistically significant group differences existed in mean change in the ECG Fridericia-corrected QT interval over 14 weeks. The 140-mg group showed the greatest numeric change, with a prolongation of 19.3 milliseconds (4.80%) compared with an increase of 2.8 milliseconds (0.69%) in the placebo group (P=.18).

Table Graphic Jump LocationTable 4. Changes in Laboratory Values During 14 Weeks of Treatment: 3-Group Completers' Analysis
PHARMACOKINETICS

At week 14, a rapid increase in plasma drug levels was seen after drug administration (Figure 3). Peak plasma levels occurred at 1.26 hours (t½=2.23 hours) for the 100-mg group and at 1.68 hours (t½=2.59 hours) for the 140-mg group. A CSF sample could not be obtained for 1 participant in the 140-mg group. Six hours after drug administration at week 14, the 100- and 140-mg groups had mean (SD) CSF drug concentrations of 77.4 (34.3) ng/mL and 102.1 (30.3) ng/mL, respectively (Wilcoxon rank sum P=.02).

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Figure 3.

Changes in arithmetic mean plasma LY450139 concentrations over 6 hours at week 14. Error bars represent SD.

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PHARMACODYNAMICS OF PLASMA AND CSF CONCENTRATIONS OF Aβ40AND Aβ42
Plasma Aβ

At week 14, just before drug administration, absolute mean plasma Aβ40levels were increased by a mean (SD) of 32.0% (34.6%) in the 100-mg group and 35.2% (60.6%) in the 140-mg group compared with study baseline (Kruskal-Wallis P=.009) (Figure 4). No statistically significant elevations were seen in Aβ42levels.

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Figure 4.

Change in absolute mean plasma amyloid β 40 (Aβ40) concentrations after administration of LY450139 at week 14. Error bars represent SD.

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After drug administration at week 14, mean plasma Aβ40levels declined rapidly in both treatment groups (Figure 4). Concentrations decreased significantly below baseline by hour 2 for both treatment groups (P=.02), and they continued to decline up to 6 hours after administration (P<.001). The maximum reduction in Aβ40concentration was 58.2% for the 100-mg group and 64.6% for the 140-mg group (Figure 4). No statistically significant difference in Aβ40reduction existed between the 100- and 140-mg groups. During this 6-hour period, 14 of 36 treated participants had 1 or more plasma Aβ42measures decline below the lower limit of quantification measured by means of enzyme-linked immunosorbent assay (28.0 pg/mL), making these data statistically noninterpretable.

CSF Aβ

No significant reductions were seen in mean log CSF Aβ40(F=2.025, P=.15) or Aβ42(F=0.73, P=.49) levels in the full ANCOVA model. Percentage changes from baseline in absolute means are presented in Figure 5. Spearman rank correlations showed a trend association between CSF drug levels and percentage change in CSF Aβ concentration in the 140-mg group (Aβ40: r=–0.51, P=.09; Aβ42: r=–0.51, P=.09) but not in the 100-mg group (Aβ40: r=–0.35, P=.17; Aβ42: r=–0.20, P=.44). Change in absolute CSF Aβ levels showed trend associations with drug levels for the 140-mg group (Aβ40: r=–0.43, P=.17; Aβ42: r=–0.55, P=.07) and the 100-mg group (Aβ40: r=–0.47, P=.06; Aβ42: r=–0.21, P=.42).

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Figure 5.

Change in absolute mean cerebrospinal fluid (CSF) amyloid β 40 (Aβ40) and Aβ42levels between baseline and week 14. MMSE indicates Mini-Mental State Examination.

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CLINICAL MEASURES

No significant differences were seen in ADAS-Cog 11 (P=.36) and ADCS-ADL (P=.63) scores after 14 weeks of treatment among any of the 3 groups (Table 5). This lack of treatment effect was not modified by the inclusion of donepezil use in the ANCOVA model.

Table Graphic Jump LocationTable 5. Changes in ADAS-Cog 11 and ADCS-ADL Scores During 14 Weeks of Treatment: 3-Group Completers' Analysis
POST HOC ANALYSES

The MMSE score was the only variable found to be a confounding measure. The 3 treatment groups differed at baseline on MMSE scores, with a possible relationship found between baseline MMSE scores and change in CSF Aβ40concentrations (Spearman ρ=0.30, P=.06). An ANCOVA model including MMSE score as a covariate revealed a trend toward significant reductions in CSF Aβ40levels at week 14 compared with study baseline in the treatment groups compared with the placebo group (F=2.90, P=.07) (Figure 5).

This longitudinal study in elderly patients with AD was necessary for assessing safety and possible Notch-related toxic effects, which would not likely be revealed by single-dose studies.12Notch toxicity encompasses many of the drug-related tolerability concerns for γ-secretase inhibitors.13Notch is a transmembrane protein that plays a role in nuclear signaling, and, similar to the amyloid precursor protein, it seems to be cleaved by a presenilin-dependent γ-secretase complex.7It plays an important role in programmed cellular death. Organ systems with rapid cellular turnover have, therefore, been the primary concern for Notch-related toxic effects. Both gastrointestinal and immune cell functions have been altered in preclinical studies with LY450139 (data on file, Eli Lilly & Co). To our knowledge, no previous human study of LY450139 has demonstrated clinically significant toxic effects on the immune system.3,5,6Diffuse macular rash on the extremities and torso and hair color changes in some participants were likely the result of treatment with LY450139. However, no evidence existed of other toxic effects associated with these. The rash and the hypopigmentation were reversible. Gastrointestinal symptoms, somnolence and asthenia, and ECG changes were not statistically significantly different between groups, yet they should still be considered potentially important drug-related AEs given the known mechanism of action of this drug and the limited statistical power of this study.

As shown in Figure 4, the plasma level of Aβ40is higher than the study baseline level before drug administration at visit 14. In a previous single-dose study,3a biphasic response of plasma Aβ to LY450139 was observed at 60, 100, and 140 mg, with an initial reduction in plasma Aβ concentration followed by an elevation higher than baseline levels 8 to 10 hours after administration. Doses of 100 mg or greater prolonged plasma reductions and reduced plasma elevations over 24 hours compared with 60 mg.3Similar patterns of peripheral changes in Aβ levels have been seen in preclinical studies14of guinea pigs with LY450139 and in studies of other γ-secretase inhibitors.15However, similar increases in CSF and brain Aβ levels have not been demonstrated in previous preclinical studies of LY450139 at multiple intervals after drug administration up to 24 hours (data on file). In addition, studies using very low doses of LY450139 showed increased plasma Aβ levels without a period of reduction.5,14Thus, 1 possible explanation for a transient increase in plasma Aβ concentration is that in peripheral, but not in central, tissue(s) γ-secretase inhibitors have a stimulatory effect on the enzyme at low concentrations that is overcome by the inhibitory effects at higher concentrations. Although steady-state Aβ reductions would be desirable, twice-daily dosing is not possible owing to observed Notch-related toxic effects in multiple organ systems in preclinical studies of Fischer 344 rats and dogs (data on file, Eli Lilly & Co). The clinical implications of this are unclear.

The expected clear changes in CSF Aβ levels were not demonstrated in this study despite robust reductions in plasma Aβ40and dose-related LY450139 concentrations in the CSF. Correlation analyses between CSF drug levels and Aβ levels suggest a pharmacodynamic response but perhaps lack statistical power. In preclinical studies, CSF Aβ-lowering effects have been seen in PDAPP mice1and dogs (data on file, Eli Lilly & Co). Lack of CSF changes in the setting of clear serum changes may reflect rapid transport of Aβ from CSF into plasma and a lengthened period for Aβ to reach equilibrium in the CSF. In a trial15of a similar γ-secretase inhibitor, changes in CSF Aβ concentration lagged behind changes in plasma Aβ concentration, with significant decreases seen at 12 hours. One study16demonstrated that carbon 13‐labeled Aβ levels did not reach equilibrium in lumbar CSF until approximately 13 hours after the beginning of the infusion. In the present study, Aβ levels were measured approximately 6 hours after morning drug administration. Longer periods may be required to identify CSF changes. Furthermore, transgenic PDAPP mice,1wild-type mice,1and guinea pigs14show a clear association between the reduction in plasma and brain Aβ levels after the administration of LY450139. Whether CSF changes in Aβ concentration can be detected in people with AD after oral administration of LY450139 requires additional studies.

The long-term efficacy of this drug is not known. Given the slow rate of clinical progression in AD, we did not expect to see drug effects on measures of cognition or ADLs in this 14-week trial. Without this, a full risk-benefit assessment cannot be made. This trial sufficiently demonstrates that LY450139 can be tolerated, although not without risk. Given the potential for disease-modifying effects of this Aβ-lowering agent, and the arguably acceptable tolerance and safety profile of LY450139 demonstrated in this study, further large-scale efficacy trials are justified. Based, in part, on the results of this phase 2 study, Eli Lilly & Co launched a multinational phase 3 trial in the second quarter of 2008, with an enrollment goal of 1500 patients with AD.

Correspondence:Adam S. Fleisher, MD, University of California, San Diego, 8950 Villa La Jolla Dr, Ste C227, La Jolla, CA 92037 (afleisher@ucsd.edu).

Accepted for Publication: April 11, 2008.

Author Contributions:All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fleisher, Siemers, Dean, and Thal. Acquisition of data: Fleisher, Siemers, Clark, Dean, Farlow, Galvin, Peskind, Quinn, Sherzai, and Thal. Analysis and interpretation of data: Fleisher, Raman, Siemers, Becerra, Dean, Farlow, Sowell, Aisen, and Thal. Drafting of the manuscript: Fleisher, Raman, Siemers, Dean, Sowell, and Thal. Critical revision of the manuscript for important intellectual content: Fleisher, Raman, Siemers, Becerra, Clark, Dean, Farlow, Galvin, Peskind, Quinn, Sherzai, Sowell, and Aisen. Statistical analysis: Raman, Siemers, Becerra, and Sowell. Obtained funding: Thal. Administrative, technical, and material support: Fleisher, Siemers, Dean, Farlow, Sherzai, Aisen, and Thal. Study supervision: Fleisher, Raman, Siemers, Clark, Farlow, P eskind, Aisen, and Thal.

Financial Disclosure:Drs Siemers and Dean are employees of Eli Lilly & Co, the manufacturer of the study drug. All the study sites were subcontracted through the ADCS at the University of California, San Diego, which held the primary contract with Eli Lilly & Co. Dr Farlow has received research grant funding support from Eli Lilly & Co that was independent of and unrelated to this trial.

Funding/Support:This study was fully funded by Eli Lilly & Co. The ADCS infrastructure is supported by cooperative grant UO1AG10483 from the National Institute on Aging.

Role of the Sponsor:The study design was developed by Eli Lilly & Co in consultation with the ADCS. The study was conducted by the ADCS, with data collection, management, analysis, and interpretation by the ADCS. Manuscript preparation was completed by the ADCS in consultation with Eli Lilly & Co.

Additional Information:The ADCS had access to all the data, with full, unrestricted publication rights.

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Boggs  LNFuson  KSBaez  M  et al.  Clusterin (Apo J) protects against in vitro amyloid-β (1-40) neurotoxicity. J Neurochem 1996;67 (3) 1324- 1327
PubMed
Siemers  ERDean  RAFriedrich  S  et al.  Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin Neuropharmacol 2007;30 (6) 317- 325
PubMed
Ness  DKBoggs  LNHepburn  DL  et al.  P2-053 reduced β-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 [abstract]. Neurobiol Aging 2004;25 ((suppl 2)) S238- S239
Siemers  ESkinner  MDean  RA  et al.  Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28 (3) 126- 132
PubMed
Siemers  ERQuinn  JFKaye  J  et al.  Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006;66 (4) 602- 604
PubMed
Hartmann  DTournoy  JSaftig  PAnnaert  WDe Strooper  B Implication of APP secretases in notch signaling. J Mol Neurosci 2001;17 (2) 171- 181
PubMed
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34 (7) 939- 944
PubMed
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PubMed
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Figures

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Figure 1.

Protocol schema.

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Place holder to copy figure label and caption
Figure 2.

Data flowchart for the 26-week trial. The intention-to-treat analyses included all 51 patients originally randomized, including all subsequent dropouts. The completers analyses included the 43 patients who completed the week 14 visit.

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Place holder to copy figure label and caption
Figure 3.

Changes in arithmetic mean plasma LY450139 concentrations over 6 hours at week 14. Error bars represent SD.

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Figure 4.

Change in absolute mean plasma amyloid β 40 (Aβ40) concentrations after administration of LY450139 at week 14. Error bars represent SD.

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Figure 5.

Change in absolute mean cerebrospinal fluid (CSF) amyloid β 40 (Aβ40) and Aβ42levels between baseline and week 14. MMSE indicates Mini-Mental State Examination.

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Tables

Table Graphic Jump LocationTable 1. Participant Characteristics at Baseline
Table Graphic Jump LocationTable 2. Adverse Events by Treatment Arm During the Studya
Table Graphic Jump LocationTable 3. Serious Adverse Events by Treatment Arm
Table Graphic Jump LocationTable 4. Changes in Laboratory Values During 14 Weeks of Treatment: 3-Group Completers' Analysis
Table Graphic Jump LocationTable 5. Changes in ADAS-Cog 11 and ADCS-ADL Scores During 14 Weeks of Treatment: 3-Group Completers' Analysis

References

May  PCYang  ZLi  W-YHyslop  PASiemers  EBoggs  LN Multi-compartmental pharmacodynamic assessment of the functional γ-secretase inhibitor LY450139 in PDAPP transgenic mice and non-transgenic mice [abstract]. Neurobiol Aging 2004;25 ((suppl 2)) S65
Boggs  LNFuson  KSBaez  M  et al.  Clusterin (Apo J) protects against in vitro amyloid-β (1-40) neurotoxicity. J Neurochem 1996;67 (3) 1324- 1327
PubMed
Siemers  ERDean  RAFriedrich  S  et al.  Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin Neuropharmacol 2007;30 (6) 317- 325
PubMed
Ness  DKBoggs  LNHepburn  DL  et al.  P2-053 reduced β-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 [abstract]. Neurobiol Aging 2004;25 ((suppl 2)) S238- S239
Siemers  ESkinner  MDean  RA  et al.  Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28 (3) 126- 132
PubMed
Siemers  ERQuinn  JFKaye  J  et al.  Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006;66 (4) 602- 604
PubMed
Hartmann  DTournoy  JSaftig  PAnnaert  WDe Strooper  B Implication of APP secretases in notch signaling. J Mol Neurosci 2001;17 (2) 171- 181
PubMed
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34 (7) 939- 944
PubMed
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