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S2‐02‐05: Biochemical biomarkers as endpoints in clinical trials: Applications in Phase 1, 2 and 3 studies
Author(s) -
Siemers Eric
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.05.292
Subject(s) - pharmacodynamics , cerebrospinal fluid , pharmacology , pharmacokinetics , chemistry , monoclonal antibody , medicine , antibody , immunology
not available Symposia S2-03: Epidemiology and Risk Factors: New Methods P95 S2-02-05 BIOCHEMICAL BIOMARKERS AS ENDPOINTS IN CLINICAL TRIALS: APPLICATIONS IN PHASE 1, 2 AND 3 STUDIES Eric Siemers, Eli Lilly and Company, Indianapolis, IN, USA. Contact e-mail: siemers_eric_r@lilly.com Background: Biochemical biomarkers can be used for various purposes and provide useful information for all phases of clinical trials in Alzheimer’s disease (AD). Methods: Various biochemical biomarkers were used in the development of a g-secretase inhibitor, semagacestat, and a monoclonal antibody that binds to the mid-domain of amyloid-b (Ab), solanezumab. These biomarkers include Ab1-40 and Ab1-42 in plasma and cerebrospinal fluid (CSF), total tau and p-tau181 in CSF, pyro-Glu 3-42 Ab (N3pGluAb) in plasma, and an N-terminal truncated form of Ab known as ‘‘fragment 2’’ in plasma and CSF. Results: Proof-of-mechanism data were readily obtained in Phase 1 and 2 trials using plasma Ab140 after treatment with semagacestat and solanezumab. After treatment with semagacestat, reductions of plasma Ab1-42 concentrations below assay sensitivity precluded the complete characterization of the pharmacodynamic effect; however, following solanezumab, plasma Ab1-42 concentrations increased as expected and were readily measured. CSF measures of Ab1-40 and Ab1-42 provided evidence of central activity for semagacestat and solanezumab in Phase 1 and 2 studies. CSF total tau or p-tau181 concentrations did not statistically significantly change in Phase 2 studies with either semagacestat or solanezumab; however, numerical decreases nearing statistical significance were present at some doses. Statistical power was sufficient to show a drug effect in larger or longer Phase 2 and 3 studies. Species of Ab thought to be found largely or entirely within amyloid plaques increased in plasma (N3pGluAb and fragment 2) and CSF (fragment 2) after treatment with solanezumab. Conclusions: Ab1-40 and Ab1-42 determinations in plasma and CSF in Phase 1 studies provide mechanistic information that can be used to determine appropriate doses for Phase 2 and Phase 3 trials. CSF tau might provide indirect evidence of downstream pharmacology in Phase 2 studies, which may increase probability of success in Phase 3, and which would show an effect of treatment on a core pathologic feature of AD. Similarly, biomarkers that provide evidence of effects on deposited amyloid plaques in Phase 2 studies (e.g., N3pGluAb and fragment 2) may increase probability of success in Phase 3 and provide supporting evidence of an effect on AD pathology.