Cerebrospinal Fluid Amyloid-beta (A beta) as an Effect Biomarker for Brain A beta Lowering Verified by Quantitative Preclinical Analyses

MS#220-4546, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 05/2012; 342(2):366-75. DOI: 10.1124/jpet.112.192625
Source: PubMed

ABSTRACT Reducing the generation of amyloid-β (Aβ) in the brain via inhibition of β-secretase or inhibition/modulation of γ-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of β-secretase inhibitors (BACEi), γ-secretase inhibitors (GSI), and γ-secretase modulators (GSM), Aβ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for Aβ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF Aβ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF Aβ lowering is related to that for brain Aβ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF Aβ as an effect biomarker for brain Aβ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of Aβ lowering in the brain.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurological and psychiatric disorders are frequently associated with disruption of various cognitive functions, but development of effective drug treatments for these conditions has proven challenging. One of the main obstacles is the poor predictive validity of our preclinical animal models. In the present study the effects of the γ-secretase inhibitor semagacestat was evaluated in preclinical in vivo electrophysiological models. Recently disclosed Phase III findings on semagacestat indicated that Alzheimer's disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo. Since previous studies have shown that drugs impairing cognitive function (including scopolamine, NMDA (N-methyl-D-aspartate) receptor antagonists, and nociceptin receptor agonists) disrupt or decrease power of elicited theta oscillation in the hippocampus, we tested the effects of acute and sub-chronic administration of semagacestat in this assay. Field potentials were recorded across the hippocampal formation with NeuroNexus multi-site silicon probes in urethane anesthetized male C57BL/6 mice; hippocampal CA1 theta oscillation was elicited by electrical stimulation of the brainstem nucleus pontis oralis. Sub-chronic administration of semagacestat twice daily over 12 days at a dose known to reduce beta-amyloid peptide (Aβ) level [100 mg/kg, p.o. (per oral)] diminished power of elicited hippocampal theta oscillation. Acute, subcutaneous administration of semagacestat (100 mg/kg) produced a similar effect on hippocampal activity. We propose that the disruptive effect of semagacestat on hippocampal function could be one of the contributing mechanisms to its worsening of cognition in patients with AD. As it has been expected, both acute and sub-chronic administrations of semagacestat significantly decreased Aβ40 and Aβ42 levels but the current findings do not reveal the mode of action of semagacestat in disrupting hippocampal oscillignificantly reduced braination.
    Frontiers in Pharmacology 06/2013; 4:72. DOI:10.3389/fphar.2013.00072
  • [Show abstract] [Hide abstract]
    ABSTRACT: Using therapeutic antibodies that need to cross the blood-brain barrier (BBB) to treat neurological disease is a difficult challenge. We have shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1) can cross the BBB and reduce brain amyloid-β (Aβ) in mice. Can TfR enhance antibody uptake in the primate brain? We describe two humanized TfR/BACE1 bispecific antibody variants. Using a human TfR knock-in mouse, we observed that anti-TfR/BACE1 antibodies could cross the BBB and reduce brain Aβ in a TfR affinity-dependent fashion. Intravenous dosing of monkeys with anti-TfR/BACE1 antibodies also reduced Aβ both in cerebral spinal fluid and in brain tissue, and the degree of reduction correlated with the brain concentration of anti-TfR/BACE1 antibody. These results demonstrate that the TfR bispecific antibody platform can robustly and safely deliver therapeutic antibody across the BBB in the primate brain.
    Science translational medicine 11/2014; 6(261):261ra154. DOI:10.1126/scitranslmed.3009835 · 14.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The failure of several potential Alzheimer’s disease therapeutics in mid- to late-stage clinical development has provoked significant discussion regarding the validity of the amyloid hypothesis. In this review, we propose a minimum criterion of 25% for amyloid-β (Aβ) lowering to achieve clinically meaningful slowing of disease progression. This criterion is based on genetic, risk factor, clinical and preclinical studies. We then compare this minimum criterion with the degree of Aβ lowering produced by the potential therapies that have failed in clinical trials. If the proposed minimum Aβ lowering criterion is used, then the amyloid hypothesis has yet to be adequately tested in the clinic. Therefore, we believe that the amyloid hypothesis remains valid and remains to be confirmed or refuted in future clinical trials.
    Alzheimer's Research and Therapy 03/2014; 6(14). DOI:10.1186/alzrt244 · 3.50 Impact Factor


Available from
May 27, 2014