A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer’s disease

Brody, Mark; Liu, Enchi; Di, Jianing; Lu, Ming; Margolin, Richard; Werth, John; Booth, Kevin; Shadman, Anna; Brashear, H. Robert; Novak, Gerald

doi:10.3233/jad-160369

Cited by 28 publications

(41 citation statements)

References 11 publications

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“…Currently available treatments only target the symptoms of AD, as there are no disease-modifying therapies available for the treatment of AD. New therapeutic approaches include vaccines targeted against Aβ and infusions of antibodies targeting Aβ such as bapineuzumab; however, these approaches have failed in clinical trials to improve clinical outcomes [134] despite being well-tolerated by patients [135,136,137]. While these results were disappointing, there is renewed hope in the clinical effectiveness of aducanumab, an antibody that selectively targets aggregated Aβ which appears to show promise in preclinical studies and clinical trials [138].…”

Section: The Role Of Aging On the Microglial Response To Brain Injmentioning

confidence: 99%

Old Maids: Aging and Its Impact on Microglia Function

Koellhoffer

McCullough

Ritzel

2017

IJMS

176

128

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Microglia are highly active and vigilant housekeepers of the central nervous system that function to promote neuronal growth and activity. With advanced age, however, dysregulated inflammatory signaling and defects in phagocytosis impede their ability to perform the most essential of homeostatic functions, including immune surveillance and debris clearance. Microglial activation is one of the hallmarks of the aging brain and coincides with age-related neurodegeneration and cognitive decline. Age-associated microglial dysfunction leads to cellular senescence and can profoundly alter the response to sterile injuries and immune diseases, often resulting in maladaptive responses, chronic inflammation, and worsened outcomes after injury. Our knowledge of microglia aging and the factors that regulate age-related microglial dysfunction remain limited, as the majority of pre-clinical studies are performed in young animals, and human brain samples are difficult to obtain quickly post-mortem or in large numbers. This review outlines the impact of normal aging on microglial function, highlights the potential mechanisms underlying age-related changes in microglia, and discusses how aging can shape the recovery process following injury.

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Section: The Role Of Aging On the Microglial Response To Brain Injmentioning

confidence: 99%

Old Maids: Aging and Its Impact on Microglia Function

Koellhoffer

McCullough

Ritzel

2017

IJMS

176

128

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“…3,11,15 No dose-related trend was observed for the severity of TEAEs. 16 Furthermore, AAB-003, a humanized antibody derived from bapineuzumab with reduced Fc-receptor-mediated effector function, was developed to reduce the incidence rate of ARIA-E. 17 The PK evaluation of a single SC dose administration of bapineuzumab demonstrated a low volume of distribution, slow clearance, and a prolonged terminal half-life, which were consistent with the kinetics of other IV-administered IgG monoclonal antibodies. 11 Population PK modeling and simulations based on the data from the present study (Janssen Internal Report) demonstrated that mean exposures at steady state (AUC) following the monthly SC doses of 7 mg and 20 mg bapineuzumab were comparable with the observed values following IV doses of 0.15 mg/kg and 0.5 mg/kg every 13 weeks, respectively; however, C max values were much lower.…”

Section: Discussionmentioning

confidence: 71%

“…A subsequent phase 2a study confirmed that the incidence of ARIA-E was lower following monthly SC administrations of 7 and 20 mg bapineuzumab compared with their equivalent IV dose groups, suggesting a safety advantage with SC administration. 16 Furthermore, AAB-003, a humanized antibody derived from bapineuzumab with reduced Fc-receptor-mediated effector function, was developed to reduce the incidence rate of ARIA-E. 17 The PK evaluation of a single SC dose administration of bapineuzumab demonstrated a low volume of distribution, slow clearance, and a prolonged terminal half-life, which were consistent with the kinetics of other IV-administered IgG monoclonal antibodies. 18 The PD assay measured only total plasma Aβ x-40 .…”

Section: Discussionmentioning

confidence: 71%

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single‐Ascending‐Dose Study in Patients With Mild to Moderate Alzheimer Disease

Brashear

2018

Clinical Pharm in Drug Dev

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This study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending subcutaneous doses of bapineuzumab in patients with mild to moderate Alzheimer disease. Forty patients were randomized across 5 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 80 mg; 8 patients each [bapineuzumab 6; placebo 2]). The incidence of treatment-emergent adverse events (TEAEs) was higher in pooled bapineuzumab cohorts (83%) than in the pooled placebo group (27.7%). Most common TEAEs in the bapineuzumab group were gastrointestinal disorders and musculoskeletal and connective tissue disorders (bapineuzumab 17% each; placebo 0%). Serious TEAEs were observed in 7% of bapineuzumab-treated patients without any deaths or adverse event-related discontinuation. The median times to reach peak measurable concentration (C ) of bapineuzumab were 14 days for 5-, 10-, and 20-mg cohorts, 11 days for 40-mg, and 7 days for 80-mg cohorts. The apparent volume of distribution of bapineuzumab was 134.29 to 204.68 mL/kg. The total body clearance was consistent at 10 to 80 mg. The average terminal half-life ranged from 26 to 46 days (5- to 80-mg groups). Exposure to bapineuzumab increased dose-proportionally from 10 to 80 mg. There was a positive correlation between C and area under the concentration-time curve to the last measurable concentration (AUC ) of plasma amyloid-β, and between the C and AUC of serum bapineuzumab.

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“…Bapineuzumab, a fully humanized immunoglobulin G1 IgG1N-terminal-specific anti-Aβ monoclonal antibody (Kerchner & Boxer, 2010;Salloway et al, 2014), was evaluated in several phase II and III studies investigating efficacy on clinical and biomarker outcome measures in participants with mild-to-moderate AD (Blennow et al, 2012;Brody et al, 2016;Rinne et al, 2010;Salloway et al, 2009Salloway et al, , 2014 (Siemers et al, 2016). Results of these secondary analyses served as the basis for EXPEDITION 3, a phase III placebo-controlled, double-blind study in participants with mild AD who were amyloid-positive by florbetapir positron emission tomography (PET) or by CSF Aβ(1-42) measurements (Honig et al, 2018).…”

Section: Rofecoxibmentioning

confidence: 99%

What works and what does not work in Alzheimer’s disease? From interventions on risk factors to anti‐amyloid trials

Bullain

Doody

2020

Journal of Neurochemistry

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no approved disease-modifying therapy (DMT). In this review, we summarize the various past approaches taken in an attempt to find treatments capable of altering the longterm course for individuals with AD, including: translating epidemiological observations into potential treatment options; seeking a single-treatment approach across the continuum of AD severity; utilizing biomarkers for assessing target engagement; using biomarkers as early surrogates of clinical efficacy; and enriching study populations to demonstrate adequate placebo decline during the limited duration of clinical trials. Although targeting the amyloid-β (Aβ) pathway has been central to the search for an effective DMT, to date, trials of anti-Aβ monoclonal antibodies have failed to consistently demonstrate significant clinical efficacy. Key learnings from these anti-Aβ trials, as well as the trials that came before them, have shifted the focus within clinical development programs to identifying target populations thought most likely to benefit from treatments (i.e., individuals at an earlier stage of disease). Other learnings include strategies to increase the likelihood of showing measurable improvements within the clinical trial setting by better predicting decline in placebo participants, as well as developing measures to quantify the needed treatment exposure (e.g., higher doses). Given the complexity associated with AD pathology and progression, treatments targeting non-amyloid AD pathologies in combination with anti-amyloid therapies may offer an alternative for the successful development of DMTs.

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A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer’s disease

Abstract: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.

Cited by 28 publications

References 11 publications

Old Maids: Aging and Its Impact on Microglia Function

Old Maids: Aging and Its Impact on Microglia Function

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single‐Ascending‐Dose Study in Patients With Mild to Moderate Alzheimer Disease

What works and what does not work in Alzheimer’s disease? From interventions on risk factors to anti‐amyloid trials

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