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Tobias Bittner - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics and pharmacodynamic effect of Crenezumab on plasma and cerebrospinal fluid beta amyloid in patients with mild to moderate alzheimer s disease
    Alzheimer's Research & Therapy, 2020
    Co-Authors: Kenta Yoshida, Anita Moein, Tobias Bittner, Susanne Ostrowitzki, Helen Lin, Lee Honigberg, Jin Y Jin, Angelica Quartino
    Abstract:

    Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of Crenezumab and its interaction with monomeric Aβ(1–40) and Aβ(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. 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 Aβ profiles was also evaluated. The serum concentration of Crenezumab increased in a dose-proportional manner between 15 and 120 mg/kg q4w. Total monomeric plasma Aβ(1–40) and Aβ(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 Aβ(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 Aβ 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%. 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 Aβ levels. ABBY: ClinicalTrials.gov, NCT01343966. Registered April 28, 2011. BLAZE: ClinicalTrials.gov, NCT01397578. Registered July 19, 2011. GN29632: ClinicalTrials.gov, NCT02353598. Registered February 3, 2015.

  • safety tolerability and pharmacokinetics of Crenezumab in patients with mild to moderate alzheimer s disease treated with escalating doses for up to 133 weeks
    Journal of Alzheimer's Disease, 2020
    Co-Authors: Heather Guthrie, Helen Lin, Angelica Quartino, Lawrence S Honig, Kaycee M Sink, Kathleen Blondeau, Michael J Dolton, Montserrat Carrascotriguero, Qinshu Lian, Tobias Bittner
    Abstract:

    Background Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of Crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive Crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received Crenezumab at the originally assigned dose level, except for Cohort 3 (Crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of Crenezumab were dose-proportional and maintained for each dose level. Conclusion Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

  • target engagement in an alzheimer trial Crenezumab lowers amyloid β oligomers in cerebrospinal fluid
    Annals of Neurology, 2019
    Co-Authors: Ting Yang, Tobias Bittner, Christina Rabe, Yifan Dang, Beth L Ostaszewski, David Mengel, Verena Steffen, Dominic M Walsh, Dennis J Selkoe
    Abstract:

    Objective 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. Methods 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) 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 oAβ 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 oAβ 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 oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti-Aβ agents. ANN NEUROL 2019;86:215-224.

  • amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti amyloid beta antibody double blind placebo controlled randomized phase ii study in mild to moderate alzheimer s disease blaze
    Alzheimer's Research & Therapy, 2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah L Mortensen, Tobias Bittner
    Abstract:

    We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD). 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. 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 Aβ(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. The primary endpoint was not met. Exploratory findings suggest potential Aβ 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. ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

  • safety tolerability and pharmacokinetics of Crenezumab in mild to moderate ad patients treated with escalating doses for up to 32 3 months p6 182
    Neurology, 2018
    Co-Authors: Helen Lin, Tobias Bittner, Angelica Quartino, William Cho, Andres Schneider, Jillian Smith, Susanne Ostrowitzki
    Abstract:

    Objective: To assess the long-term safety and tolerability of Crenezumab, as well as serum pharmacokinetics, in patients with mild-to-moderate Alzheimer’s disease (AD). Background: Crenezumab is a humanized anti-amyloid beta monoclonal antibody in development for the treatment of AD. This study (GN29632) was designed to evaluate the safety and tolerability of Crenezumab at doses up to 120 mg/kg IV q4w. A secondary objective was to characterize the serum pharmacokinetics of Crenezumab at the doses investigated. Exploratory objectives assessed clinical efficacy and effects on imaging and plasma biomarkers. Design/Methods: Mild-to-moderate AD patients (50–90 years-old) with an amyloid-positive PET scan were enrolled in 3 consecutive cohorts administering 4 infusions of 30 or 45 (cohort 1, n=26), 60 (cohort 2, n=26), or 120 mg/kg (cohort 3, n=23) IV q4w Crenezumab, or corresponding placebo (5:1 ratio). Following the double-blind placebo-controlled portion of the study, patients were offered to continue on active drug at the dose assigned at randomization, except for cohort 3 patients who would receive 60 mg/kg. Recently, the protocol was amended to now offer 60 mg/kg IV q4w to all patients in the active extension. All patients undergo regular brain MRI to monitor for ARIA-E and ARIA-H. Results: Safety and tolerability data collected as of 30 November 2017, and PK data will be presented: patients will have been exposed to Crenezumab for up to 32.3, 27.8 or 17.5 months in cohorts 1, 2, and 3 respectively. Conclusions: The long-term safety and tolerability of Crenezumab is evaluated in mild-to-moderate AD patients. Updated safety and Crenezumab serum concentration data will be presented. Disclosure: Dr. Lin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Schneider has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Quartino has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Bittner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Hu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Cho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Ostrowitzki has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech.

William Cho - One of the best experts on this subject based on the ideXlab platform.

  • amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti amyloid beta antibody double blind placebo controlled randomized phase ii study in mild to moderate alzheimer s disease blaze
    Alzheimer's Research & Therapy, 2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah L Mortensen, Tobias Bittner
    Abstract:

    We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD). 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. 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 Aβ(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. The primary endpoint was not met. Exploratory findings suggest potential Aβ 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. ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

  • abby a phase 2 randomized trial of Crenezumab in mild to moderate alzheimer disease
    Neurology, 2018
    Co-Authors: Jeffrey L Cummings, Sharon Cohen, Christopher H Van Dyck, Mark Brody, Craig Curtis, William Cho, Michael Ward, Michel Friesenhahn, Christina Rabe, Flavia Brunstein
    Abstract:

    Objective To evaluate the safety and efficacy of Crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (Crenezumab:placebo). Patients received low-dose subcutaneous Crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous Crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer9s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid 1-42 levels that correlated with Crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose Crenezumab. Together with the safety profile for Crenezumab, these data support the exploration of Crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, Crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because

  • safety tolerability and pharmacokinetics of Crenezumab in mild to moderate ad patients treated with escalating doses for up to 32 3 months p6 182
    Neurology, 2018
    Co-Authors: Helen Lin, Tobias Bittner, Angelica Quartino, William Cho, Andres Schneider, Jillian Smith, Susanne Ostrowitzki
    Abstract:

    Objective: To assess the long-term safety and tolerability of Crenezumab, as well as serum pharmacokinetics, in patients with mild-to-moderate Alzheimer’s disease (AD). Background: Crenezumab is a humanized anti-amyloid beta monoclonal antibody in development for the treatment of AD. This study (GN29632) was designed to evaluate the safety and tolerability of Crenezumab at doses up to 120 mg/kg IV q4w. A secondary objective was to characterize the serum pharmacokinetics of Crenezumab at the doses investigated. Exploratory objectives assessed clinical efficacy and effects on imaging and plasma biomarkers. Design/Methods: Mild-to-moderate AD patients (50–90 years-old) with an amyloid-positive PET scan were enrolled in 3 consecutive cohorts administering 4 infusions of 30 or 45 (cohort 1, n=26), 60 (cohort 2, n=26), or 120 mg/kg (cohort 3, n=23) IV q4w Crenezumab, or corresponding placebo (5:1 ratio). Following the double-blind placebo-controlled portion of the study, patients were offered to continue on active drug at the dose assigned at randomization, except for cohort 3 patients who would receive 60 mg/kg. Recently, the protocol was amended to now offer 60 mg/kg IV q4w to all patients in the active extension. All patients undergo regular brain MRI to monitor for ARIA-E and ARIA-H. Results: Safety and tolerability data collected as of 30 November 2017, and PK data will be presented: patients will have been exposed to Crenezumab for up to 32.3, 27.8 or 17.5 months in cohorts 1, 2, and 3 respectively. Conclusions: The long-term safety and tolerability of Crenezumab is evaluated in mild-to-moderate AD patients. Updated safety and Crenezumab serum concentration data will be presented. Disclosure: Dr. Lin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Schneider has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Quartino has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Bittner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Hu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Cho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Ostrowitzki has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech.

  • Additional file 6: of Amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)
    2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah Mortensen, Tobias Bittner
    Abstract:

    Figure S4. CSF Aβ(1–42) Crenezumab correlation analysis. Correlation analysis of change in CSF Aβ(1–42) from baseline and Crenezumab concentrations at week 69 in patients in the low-dose SC cohort (circles) and high-dose cohort (triangles). (PDF 98 kb

  • Amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Stephen Salloway, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah Mortensen, Lee A. Honigberg, Tobias Bittner
    Abstract:

    Abstract Background We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) 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 Aβ(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 Aβ 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

Angelica Quartino - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics and pharmacodynamic effect of Crenezumab on plasma and cerebrospinal fluid beta amyloid in patients with mild to moderate alzheimer s disease
    Alzheimer's Research & Therapy, 2020
    Co-Authors: Kenta Yoshida, Anita Moein, Tobias Bittner, Susanne Ostrowitzki, Helen Lin, Lee Honigberg, Jin Y Jin, Angelica Quartino
    Abstract:

    Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of Crenezumab and its interaction with monomeric Aβ(1–40) and Aβ(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. 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 Aβ profiles was also evaluated. The serum concentration of Crenezumab increased in a dose-proportional manner between 15 and 120 mg/kg q4w. Total monomeric plasma Aβ(1–40) and Aβ(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 Aβ(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 Aβ 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%. 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 Aβ levels. ABBY: ClinicalTrials.gov, NCT01343966. Registered April 28, 2011. BLAZE: ClinicalTrials.gov, NCT01397578. Registered July 19, 2011. GN29632: ClinicalTrials.gov, NCT02353598. Registered February 3, 2015.

  • safety tolerability and pharmacokinetics of Crenezumab in patients with mild to moderate alzheimer s disease treated with escalating doses for up to 133 weeks
    Journal of Alzheimer's Disease, 2020
    Co-Authors: Heather Guthrie, Helen Lin, Angelica Quartino, Lawrence S Honig, Kaycee M Sink, Kathleen Blondeau, Michael J Dolton, Montserrat Carrascotriguero, Qinshu Lian, Tobias Bittner
    Abstract:

    Background Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of Crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive Crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received Crenezumab at the originally assigned dose level, except for Cohort 3 (Crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of Crenezumab were dose-proportional and maintained for each dose level. Conclusion Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

  • baseline characteristics from a phase iii trial of Crenezumab in early prodromal to mild alzheimer s disease cread p4 1 002
    Neurology, 2019
    Co-Authors: Kaycee M Sink, Susanne Ostrowitzki, Helen Lin, Angelica Quartino, Reina N Fuji, Andres Schneider, Jillian Smith, Laurie Millar, Francis Warren, Howard Mackey
    Abstract:

    Objective: To describe the study design/methodology and baseline characteristics from the Phase III CREAD study (NCT02670083) in prodromal-to-mild Alzheimer’s disease (AD). Background: Crenezumab is a humanized anti-amyloid β (Aβ) monoclonal immunoglobulin G4 antibody in development for AD. Although Phase II co-primary endpoints were not met, exploratory analyses suggested Crenezumab should be tested for efficacy at a higher dose and earlier disease stage. Data from a Phase Ib study that investigated the safety/tolerability of higher doses of Crenezumab supported testing a four-fold higher dose than used in Phase II. Two global, randomized, double-blind, placebo-controlled, Phase III studies (CREAD; CREAD2, NCT03114657]) are testing the efficacy and safety of Crenezumab (60 mg/kg) in prodromal-to-mild AD. Design/Methods: Patients aged 50–85 years with prodromal-to-mild AD and evidence of cerebral amyloid pathology (cerebrospinal fluid [CSF] or amyloid by positron emission tomography [PET]) were enrolled. At screening, eligible patients had a Mini-Mental State Examination score of ≥ 22, a Clinical Dementia Rating (CDR) global score of 0.5 or 1, and a Free and Cued Selective Reminding Test immediate free recall ≤ 27. Patients were randomized 1:1 to placebo or Crenezumab (60 mg/kg intravenously every 4 weeks). Primary and secondary endpoints include change from baseline in CDR-Sum of Boxes, 13-item AD Assessment Scale-Cognitive Subscale and AD Cooperative Study-Activities of Daily Living scores over 105 weeks. Magnetic resonance imaging is used to monitor safety and measure volumetric changes. Results: The CREAD study has completed recruitment, with 813 patients enrolled. Baseline data will be presented. Conclusions: Building on learnings from the Phase II study, CREAD and CREAD2 Phase III trials are investigating the efficacy of a four-fold higher dose of Crenezumab (versus Phase II) in prodromal-to-mild AD and testing whether clinically meaningful efficacy can be achieved without the associated safety findings described with other passive anti-amyloid immunotherapies. Disclosure: Dr. Sink has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as a full time employee of Genentech, Inc. Dr. Ostrowitzki has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech, Inc. Dr. Millar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche Products Ltd. Dr. Warren has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche Products Ltd. Dr. Warren holds stock and/or stock options in Roche Products Ltd. Dr. Lin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Full time employee of Genentech, Inc. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of Roche Products Ltd. Dr. Schneider has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of F. Hoffmann-La Roche Ltd. Dr. Fuji has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Full time employee of Genentech, Inc. Dr. Quartino has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech, Inc and hold stocks in Roche. Dr. Mackey has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech and Roche. Dr. Rabbia has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche/Genentech. . Dr. Yule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffman-La Roche. Dr. Fontoura has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann La-Roche Ltd. Dr. Fontoura holds stock and/or stock options in F. Hoffmann La-Roche Ltd. which sponsored research in which Dr. Fontoura was involved as an investigator. Dr. Fontoura holds stock and/or stock options in F. Hoffmann-La Roche. Dr. Doody has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech/F. Hoffman-La Roche. Dr. Doody holds stock and/or stock options in F. Hoffman-La Roche.

  • amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti amyloid beta antibody double blind placebo controlled randomized phase ii study in mild to moderate alzheimer s disease blaze
    Alzheimer's Research & Therapy, 2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah L Mortensen, Tobias Bittner
    Abstract:

    We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD). 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. 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 Aβ(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. The primary endpoint was not met. Exploratory findings suggest potential Aβ 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. ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

  • safety tolerability and pharmacokinetics of Crenezumab in mild to moderate ad patients treated with escalating doses for up to 32 3 months p6 182
    Neurology, 2018
    Co-Authors: Helen Lin, Tobias Bittner, Angelica Quartino, William Cho, Andres Schneider, Jillian Smith, Susanne Ostrowitzki
    Abstract:

    Objective: To assess the long-term safety and tolerability of Crenezumab, as well as serum pharmacokinetics, in patients with mild-to-moderate Alzheimer’s disease (AD). Background: Crenezumab is a humanized anti-amyloid beta monoclonal antibody in development for the treatment of AD. This study (GN29632) was designed to evaluate the safety and tolerability of Crenezumab at doses up to 120 mg/kg IV q4w. A secondary objective was to characterize the serum pharmacokinetics of Crenezumab at the doses investigated. Exploratory objectives assessed clinical efficacy and effects on imaging and plasma biomarkers. Design/Methods: Mild-to-moderate AD patients (50–90 years-old) with an amyloid-positive PET scan were enrolled in 3 consecutive cohorts administering 4 infusions of 30 or 45 (cohort 1, n=26), 60 (cohort 2, n=26), or 120 mg/kg (cohort 3, n=23) IV q4w Crenezumab, or corresponding placebo (5:1 ratio). Following the double-blind placebo-controlled portion of the study, patients were offered to continue on active drug at the dose assigned at randomization, except for cohort 3 patients who would receive 60 mg/kg. Recently, the protocol was amended to now offer 60 mg/kg IV q4w to all patients in the active extension. All patients undergo regular brain MRI to monitor for ARIA-E and ARIA-H. Results: Safety and tolerability data collected as of 30 November 2017, and PK data will be presented: patients will have been exposed to Crenezumab for up to 32.3, 27.8 or 17.5 months in cohorts 1, 2, and 3 respectively. Conclusions: The long-term safety and tolerability of Crenezumab is evaluated in mild-to-moderate AD patients. Updated safety and Crenezumab serum concentration data will be presented. Disclosure: Dr. Lin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Schneider has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Quartino has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Bittner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Hu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Cho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Ostrowitzki has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech.

Flavia Brunstein - One of the best experts on this subject based on the ideXlab platform.

  • amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti amyloid beta antibody double blind placebo controlled randomized phase ii study in mild to moderate alzheimer s disease blaze
    Alzheimer's Research & Therapy, 2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah L Mortensen, Tobias Bittner
    Abstract:

    We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD). 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. 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 Aβ(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. The primary endpoint was not met. Exploratory findings suggest potential Aβ 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. ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

  • abby a phase 2 randomized trial of Crenezumab in mild to moderate alzheimer disease
    Neurology, 2018
    Co-Authors: Jeffrey L Cummings, Sharon Cohen, Christopher H Van Dyck, Mark Brody, Craig Curtis, William Cho, Michael Ward, Michel Friesenhahn, Christina Rabe, Flavia Brunstein
    Abstract:

    Objective To evaluate the safety and efficacy of Crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (Crenezumab:placebo). Patients received low-dose subcutaneous Crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous Crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer9s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid 1-42 levels that correlated with Crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose Crenezumab. Together with the safety profile for Crenezumab, these data support the exploration of Crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, Crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because

  • Additional file 6: of Amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)
    2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah Mortensen, Tobias Bittner
    Abstract:

    Figure S4. CSF Aβ(1–42) Crenezumab correlation analysis. Correlation analysis of change in CSF Aβ(1–42) from baseline and Crenezumab concentrations at week 69 in patients in the low-dose SC cohort (circles) and high-dose cohort (triangles). (PDF 98 kb

  • Amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Stephen Salloway, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah Mortensen, Lee A. Honigberg, Tobias Bittner
    Abstract:

    Abstract Background We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) 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 Aβ(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 Aβ 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

Michel Friesenhahn - One of the best experts on this subject based on the ideXlab platform.

  • amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti amyloid beta antibody double blind placebo controlled randomized phase ii study in mild to moderate alzheimer s disease blaze
    Alzheimer's Research & Therapy, 2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah L Mortensen, Tobias Bittner
    Abstract:

    We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD). 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. 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 Aβ(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. The primary endpoint was not met. Exploratory findings suggest potential Aβ 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. ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

  • abby a phase 2 randomized trial of Crenezumab in mild to moderate alzheimer disease
    Neurology, 2018
    Co-Authors: Jeffrey L Cummings, Sharon Cohen, Christopher H Van Dyck, Mark Brody, Craig Curtis, William Cho, Michael Ward, Michel Friesenhahn, Christina Rabe, Flavia Brunstein
    Abstract:

    Objective To evaluate the safety and efficacy of Crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (Crenezumab:placebo). Patients received low-dose subcutaneous Crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous Crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer9s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid 1-42 levels that correlated with Crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose Crenezumab. Together with the safety profile for Crenezumab, these data support the exploration of Crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, Crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because

  • Additional file 6: of Amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)
    2018
    Co-Authors: Stephen Salloway, Lee Honigberg, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah Mortensen, Tobias Bittner
    Abstract:

    Figure S4. CSF Aβ(1–42) Crenezumab correlation analysis. Correlation analysis of change in CSF Aβ(1–42) from baseline and Crenezumab concentrations at week 69 in patients in the low-dose SC cohort (circles) and high-dose cohort (triangles). (PDF 98 kb

  • Amyloid positron emission tomography and cerebrospinal fluid results from a Crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Stephen Salloway, Angelica Quartino, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, David Clayton, Deborah Mortensen, Lee A. Honigberg, Tobias Bittner
    Abstract:

    Abstract Background We investigated the effect of Crenezumab, a humanized anti-amyloid-beta (Aβ) 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 Aβ(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 Aβ 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