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Target engagement in an alzheimer trial: Crenezumab lowers amyloid ? oligomers in cerebrospinal fluid.

ABSTRACT: OBJECTIVE:Oligomeric forms of amyloid ? protein (oA?) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), but it is not known whether anti-A? antibodies are capable of lowering oA? levels in humans. METHODS:We developed an ultrasensitive immunoassay and used it to measure oA? in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-A? antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oA? levels, and these were compared to levels at week 69 in placebo (n = 28), SC (n = 35), and IV (n = 35) treated patients. RESULTS:Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oA? at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p =?0.0035 for SC and p = 0.01 for IV crenezumab versus placebo. The median percentage change was -48% in the SC arm and -43% in the IV arm. No systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change. INTERPRETATION:Crenezumab lowered CSF oA? levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oA? as a novel pharmacodynamic biomarker for use in trials of anti-A? agents. ANN NEUROL 2019;86:215-224.

SUBMITTER: Yang T

PROVIDER: S-EPMC6771589 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid.

Yang Ting T Dang Yifan Y Ostaszewski Beth B Mengel David D Steffen Verena V Rabe Christina C Bittner Tobias T Walsh Dominic M DM Selkoe Dennis J DJ

Annals of neurology 20190622 2

<h4>Objective</h4>Oligomeric forms of amyloid β protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), but it is not known whether anti-Aβ antibodies are capable of lowering oAβ levels in humans.<h4>Methods</h4>We developed an ultrasensitive immunoassay and used it to measure oAβ in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-Aβ antibody crenezumab. Patients received subcutaneous (SC) ...[more]

PMID: 31168802

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Project description:BACKGROUND:Crenezumab, a fully humanized anti-beta-amyloid (A?) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of A?. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric A?(1-40) and A?(1-42) peptides in serum/plasma and cerebrospinal fluid (CSF) samples from the phase II ABBY and BLAZE studies and the phase Ib GN29632 study. METHODS:In ABBY, BLAZE, and GN29632 studies, patients with mild-to-moderate AD were treated with either placebo or crenezumab (300?mg subcutaneously every 2?weeks [q2w], or 15?mg/kg, 30?mg/kg, 45?mg/kg, 60?mg/kg, or 120?mg/kg intravenously q4w). Serum/plasma PK/PD analyses included samples from 131 patients who received crenezumab in all three studies. CSF PK/PD analyses included samples from 76 patients who received crenezumab in ABBY or BLAZE. The impact of baseline patient factors on A? profiles was also evaluated. RESULTS:The serum concentration of crenezumab increased in a dose-proportional manner between 15 and 120?mg/kg q4w. Total monomeric plasma A?(1-40) and A?(1-42) levels significantly increased after crenezumab administration. The mean crenezumab CSF to serum ratio was ~?0.3% and was similar across dosing cohorts/routes of administration. No clear correlation was observed between crenezumab concentration and A?(1-42) increase in CSF at week 69. The target-mediated drug disposition (TMDD) model described the observed plasma concentration-time profiles of crenezumab and A? well. Elimination clearance (CLel) and central volume of distribution (Vcent) of crenezumab were estimated at 0.159?L/day and 2.89?L, respectively, corresponding to a half-life of ~?20?days. Subcutaneous bioavailability was estimated at 66.2%. CONCLUSIONS:Crenezumab PK was dose proportional up to 120?mg/kg, with a half-life consistent with IgG monoclonal antibodies. Our findings provide evidence for peripheral target engagement in patients with mild-to-moderate AD. The study also showed that a model-based approach is useful in making inference on PK/PD relationship with unmeasured species such as free plasma A? levels. TRIAL REGISTRATIONS:ABBY: ClinicalTrials.gov, NCT01343966. Registered April 28, 2011. BLAZE:ClinicalTrials.gov, NCT01397578. Registered July 19, 2011. GN29632: ClinicalTrials.gov, NCT02353598. Registered February 3, 2015.

Project description:To improve the ability to develop treatments that prevent incipient Alzheimer disease (AD) from progressing to overt AD, it is important to understand the molecular basis of the earliest pathophysiological abnormalities and to determine how amyloid-? (A?) is involved very early in its pathogenesis.To investigate 2 specific A? oligomers, A? trimers and A?*56, in human cerebrospinal fluid (CSF); evaluate the effects of aging and AD; and obtain support for the hypothesis that they may be pathogenic by determining their relationships to CSF tau.A CSF sampling study.The University of Minnesota Medical School in Minneapolis, Minnesota, and the Salhgrenska University Hospital, Sweden.Forty-eight older adults with mild cognitive impairment or AD (impaired group); 49 age-matched cognitively intact control subjects (unimpaired group); and 10 younger, normal control subjects.Measurements of CSF A? trimers, A?*56, the 42-amino acid A? isoform (A?1-42), total tau (T-tau), and phospho-tau 181 (p-tau(181)). The hypothesis being tested was formulated after data collection. RESULTS We observed that A? trimers and A?*56 levels increased with age; within the unimpaired group, they were elevated in subjects with T-tau/A?1-42 ratios greater than a cutoff that distinguished the unimpaired group from subjects with AD. In the unimpaired group, T-tau and p-tau(181) were found to correlate strongly with A? trimers and A?*56 (r > 0.63), but not with A?1-42 (-0.10 < r < -0.01). The strong correlations were found to be attenuated in the impaired group.In cognitively intact older adults, CSF A? trimers and A?*56 were elevated in individuals at risk for AD, and they showed stronger relationships with tau than did A?1-42, a surrogate for A? fibril deposition. These findings suggest that prior to overt symptoms, 1 or both of the A? oligomers, but not fibrillar A?, is coupled to tau; however, this coupling is weakened or broken when AD advances to symptomatic stages. The uncoupling is interesting in light of the failure of experimental A? therapies to improve mild cognitive impairment/AD, which has prompted a shift in the timing of A? therapies to asymptomatic subjects. Knowing which A? species to target in asymptomatic subjects may enhance the success of future treatments for AD.

Project description:BackgroundAltered proteome profiles have been reported in both postmortem brain tissues and body fluids of subjects with Alzheimer disease (AD), but their broad relationships with AD pathology, amyloid pathology, and tau-related neurodegeneration have not yet been fully explored. Using a robust automated MS-based proteomic biomarker discovery workflow, we measured cerebrospinal fluid (CSF) proteomes to explore their association with well-established markers of core AD pathology.MethodsCross-sectional analysis was performed on CSF collected from 120 older community-dwelling adults with normal (n?=?48) or impaired cognition (n?=?72). LC-MS quantified hundreds of proteins in the CSF. CSF concentrations of ?-amyloid 1-42 (A?1-42), tau, and tau phosphorylated at threonine 181 (P-tau181) were determined with immunoassays. First, we explored proteins relevant to biomarker-defined AD. Then, correlation analysis of CSF proteins with CSF markers of amyloid pathology, neuronal injury, and tau hyperphosphorylation (i.e., A?1-42, tau, P-tau181) was performed using Pearson's correlation coefficient and Bonferroni correction for multiple comparisons.ResultsWe quantified 790 proteins in CSF samples with MS. Four CSF proteins showed an association with CSF A?1-42 levels (p value ??0.05 with correlation coefficient (R)???0.38). We identified 50 additional CSF proteins associated with CSF tau and 46 proteins associated with CSF P-tau181 (p value ??0.05 with R???0.37). The majority of those proteins that showed such associations were brain-enriched proteins. Gene Ontology annotation revealed an enrichment for synaptic proteins and proteins originating from reelin-producing cells and the myelin sheath.ConclusionsWe used an MS-based proteomic workflow to profile the CSF proteome in relation to cerebral AD pathology. We report strong evidence of previously reported CSF proteins and several novel CSF proteins specifically associated with amyloid pathology or neuronal injury and tau hyperphosphorylation.

Project description:BACKGROUND:We investigated the effect of crenezumab, a humanized anti-amyloid-beta (A?) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer's disease (AD). METHODS:This double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18-26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment. RESULTS:From August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n?=?26) or placebo (n?=?13); high-dose IV cohort: crenezumab (n?=?36) or placebo (n?=?16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF A?(1-42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20-26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed. CONCLUSION:The primary endpoint was not met. Exploratory findings suggest potential A? target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

Project description:ImportanceCerebrospinal fluid (CSF) and positron emission tomographic (PET) amyloid biomarkers have been proposed for the detection of Alzheimer disease (AD) pathology in living patients and for the tracking of longitudinal changes, but the relation between biomarkers needs further study.ObjectiveTo determine the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures.Design, setting, and participantsLongitudinal clinical cohort study from 2005 to 2014 including 820 participants with at least 1 florbetapir F-18 (hereafter referred to as simply florbetapir)-PET scan and at least 1 CSF β-amyloid 1-42 (Aβ1-42) sample obtained within 30 days of each other (501 participants had a second PET scan after 2 years, including 150 participants with CSF Aβ1-42 measurements). Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database.Main outcomes and measuresFour different PET scans processing pipelines from 2 different laboratories were compared. The PET cutoff values were established using a mixture-modeling approach, and different mathematical models were applied to define the association between CSF and PET amyloid measures.ResultsThe values of the CSF Aβ1-42 samples and florbetapir-PET scans showed a nonlinear association (R2 = 0.48-0.66), with the strongest association for values in the middle range. The presence of a larger dynamic range of florbetapir-PET scan values in the higher range compared with the CSF Aβ1-42 plateau explained the differences in correlation with cognition (R2 = 0.36 and R2 = 0.25, respectively). The APOE genotype significantly modified the association between both biomarkers. The PET cutoff values derived from an unsupervised classifier converged with previous PET cutoff values and the established CSF Aβ1-42 cutoff levels. There was no association between longitudinal Aβ1-42 levels and standardized uptake value ratios during follow-up.Conclusions and relevanceThe association between both biomarkers is limited to a middle range of values, is modified by the APOE genotype, and is absent for longitudinal changes; 4 different approaches in 2 different platforms converge on similar pathological Aβ cutoff levels; and different pipelines to process PET scans showed correlated but not identical results. Our findings suggest that both biomarkers measure different aspects of AD Aβ pathology.

Dataset Information

Target engagement in an alzheimer trial: Crenezumab lowers amyloid ? oligomers in cerebrospinal fluid.

Publications

Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid.

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