Bapineuzumab

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H. Robert Brashear - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies.
    Journal of Alzheimer's disease : JAD, 2018
    Co-Authors: H. Robert Brashear, Stephen Salloway, Nzeera Ketter, Jennifer Bogert, Reisa A. Sperling
    Abstract:

    BACKGROUND Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer's disease in Bapineuzumab phase III studies. OBJECTIVES Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. METHODS A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. RESULTS Treatment-emergent ARIA-E occurred in 15.8% of Bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. CONCLUSIONS Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302).

  • Long-Term Safety and Efficacy of Bapineuzumab in Patients with Mild-to-Moderate Alzheimer’s Disease: A Phase 2, Open-Label Extension Study
    Current Alzheimer Research, 2018
    Co-Authors: Stephen Salloway, Gad A Marshall, Ming Lu, H. Robert Brashear
    Abstract:

    Bapineuzumab is a humanized anti-amyloid-beta (Aβ) monoclonal antibody directed at lowering the cerebral Aβ deposit in Alzheimer's disease (AD). This phase 2, open-label extension (OLE) study evaluated long-term safety and efficacy of Bapineuzumab in patients with the mild-to-moderate AD. Patients (58-78 years) who completed either of two randomized, placebo-controlled, doubleblind studies (subcutaneous [SC] single-dose-escalation, or intravenous (IV) multiple-ascending-dose)) entered the OLE. Three groups were assessed: Bapineuzumab or placebo SC, and Bapineuzumab (IV) in OLE (bapi SC/bapi IV); Bapineuzumab (IV) in Study 201 and OLE (bapi/bapi); and placebo in Study 201 and Bapineuzumab IV in OLE (placebo/bapi). Of 194 patients enrolled, 158 withdrew from OLE; primarily due to withdrawal by subject (n=85) and AE (n=30). Mean (SD) Bapineuzumab exposure was 2.9 (1.90) years. There were no significant differences for efficacy endpoints (AD Assessment Scale-cognitive subscale [ADAS-Cog], Disability Assessment for Dementia [DAD] and MMSE scores) between the bapi/bapi and placebo/bapi groups. Most patients (94.8%, 184/194) reported ≥1 treatment-emergent adverse events (TEAEs) in OLE. Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) occurred in 22 (11.3%) patients. The most common TEAEs (>20% patients) were fall, agitation and urinary tract infection with similar incidences between bapi/bapi and placebo/bapi groups. No significant difference was seen in cognitive and functional decline between early and delayed treatment groups. No new safety concerns emerged. ARIA-E incidence was higher in patients first exposed to Bapineuzumab in OLE versus previously exposed. No clear pattern of etiology contributed to death events. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  • Long-Term Safety and Efficacy of Bapineuzumab in Patients with Mild-to-Moderate Alzheimer's Disease: A Phase 2, Open-Label Extension Study.
    Current Alzheimer research, 2018
    Co-Authors: Stephen Salloway, Gad A Marshall, H. Robert Brashear
    Abstract:

    Background Bapineuzumab is a humanized anti-amyloid-beta (Aβ) monoclonal antibody directed at lowering the cerebral Aβ deposit in Alzheimer's disease (AD). Objective This phase 2, open-label extension (OLE) study evaluated long-term safety and efficacy of Bapineuzumab in patients with the mild-to-moderate AD. Methods Patients (58-78 years) who completed either of two randomized, placebo-controlled, doubleblind studies (subcutaneous [SC] single-dose-escalation, or intravenous (IV) multiple-ascending-dose)) entered the OLE. Three groups were assessed: Bapineuzumab or placebo SC, and Bapineuzumab (IV) in OLE (bapi SC/bapi IV); Bapineuzumab (IV) in Study 201 and OLE (bapi/bapi); and placebo in Study 201 and Bapineuzumab IV in OLE (placebo/bapi). Results Of 194 patients enrolled, 158 withdrew from OLE; primarily due to withdrawal by subject (n=85) and AE (n=30). Mean (SD) Bapineuzumab exposure was 2.9 (1.90) years. There were no significant differences for efficacy endpoints (AD Assessment Scale-cognitive subscale [ADAS-Cog], Disability Assessment for Dementia [DAD] and MMSE scores) between the bapi/bapi and placebo/bapi groups. Most patients (94.8%, 184/194) reported ≥1 treatment-emergent adverse events (TEAEs) in OLE. Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) occurred in 22 (11.3%) patients. The most common TEAEs (>20% patients) were fall, agitation and urinary tract infection with similar incidences between bapi/bapi and placebo/bapi groups. Conclusion No significant difference was seen in cognitive and functional decline between early and delayed treatment groups. No new safety concerns emerged. ARIA-E incidence was higher in patients first exposed to Bapineuzumab in OLE versus previously exposed. No clear pattern of etiology contributed to death events.

  • Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single‐Ascending‐Dose Study in Patients With Mild to Moderate Alzheimer Disease
    Clinical pharmacology in drug development, 2018
    Co-Authors: H. Robert Brashear
    Abstract:

    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 (Cmax ) 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 Cmax and area under the concentration-time curve to the last measurable concentration (AUClast ) of plasma amyloid-β, and between the Cmax and AUClast of serum Bapineuzumab.

  • Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients.
    Journal of Alzheimer's disease : JAD, 2017
    Co-Authors: Nzeera Ketter, H. Robert Brashear, Frederik Barkhof, Jennifer Bogert, Achim Gass, Yves Miaux, Derk D Purcell, H. Michael Arrighi
    Abstract:

    BACKGROUND: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). OBJECTIVES: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer’s disease randomized to Bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers). METHODS: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. RESULTS: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second Bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs

Francesco Panza - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and safety studies of gantenerumab in patients with Alzheimer's disease.
    Expert review of neurotherapeutics, 2014
    Co-Authors: Francesco Panza, Bruno P. Imbimbo, Davide Seripa, Vincenzo Solfrizzi, Andrea Santamato, Michele Giannini, Giancarlo Logroscino
    Abstract:

    Among active and passive anti-b-amyloid (Ab) immunotherapies for Alzheimer’s disease (AD), Bapineuzumab and solanezumab, two humanized monoclonal antibodies, failed to show significant clinical benefits in mild-to-moderate AD patients in large Phase III clinical trials. Another ongoing Phase III trial of solanezumab aims to confirm positive findings in mild AD patients. Gantenerumab is the first fully human anti-Ab monoclonal antibody directed to both N-terminal and central regions of Ab. A 6-month PET study in 16 AD patients showed that gantenerumab treatment dose-dependently reduced brain Ab deposition, possibly stimulating microglial-mediated phagocytosis. Two ongoing Phase III trials of gantenerumab in patients with prodromal or mild dementia due to AD will determine if any reduction in brain Ab levels will translate into clinical benefits. An ongoing secondary prevention trial of gantenerumab in presymptomatic subjects with genetic mutations for autosomal-dominant AD will verify the utility of anti-Ab monoclonal antibodies as prevention therapy.

  • Amyloid-directed monoclonal antibodies for the treatment of Alzheimer's disease: the point of no return?
    Expert opinion on biological therapy, 2014
    Co-Authors: Francesco Panza, Bruno P. Imbimbo, Vincenzo Solfrizzi, Giancarlo Logroscino
    Abstract:

    Introduction: Two humanized monoclonal antibodies, Bapineuzumab and solanezumab, directed against the N terminus and mid-region of β-amyloid (Aβ), respectively, were recently tested in large, long-term Phase III trials in patients with mild-to-moderate Alzheimer’s disease (AD).Areas covered: This review discusses current clinical data on solanezumab, Bapineuzumab and their failure in Phase III trials to show significant clinical benefits, as well as other monoclonal antibodies under investigation for AD.Expert opinion: Solanezumab showed some beneficial cognitive effects in mildly affected AD patients and this subgroup of AD patients is currently being tested in another Phase III trial to this subgroup of AD patients to confirm previous encouraging observations. Two other monoclonal antibodies, gantenerumab, which preferentially binds to fibrillar Aβ, and crenezumab, which preferentially binds to soluble, oligomeric and fibrillar Aβ deposits, are being tested in secondary prevention trials in presymptomat...

  • Amyloid-related imaging abnormalities associated with immunotherapy in Alzheimer’s disease patients
    Future Neurology, 2012
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Giancarlo Logroscino, Davide Seripa, Alberto Pilotto, Vincenzo Solfrizzi
    Abstract:

    Evaluation of: Sperling R, Salloway S, Brooks DJ et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with Bapineuzumab: a retrospective analysis. Lancet Neurol. 11(3), 241–249 (2012). Amyloid-related imaging abnormalities (ARIAs) have been reported in patients with Alzheimer’s disease treated with Bapineuzumab, a monoclonal antibody targeting β-amyloid (Aβ). The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recovery sequences thought to represent ‘vasogenic edema’ and/or sulcal effusion (ARIA-E), as well as signal hypointensities on gradient echo/T2* thought to represent hemosiderin deposits. This study was a retrospective analysis in which two neuroradiologists independently reviewed 2572 fluid attenuation inversion recovery MRI scans from 262 participants in two Phase II studies of Bapineuzumab and an open-label extension study. In this analysis, several ARIA-E cases were identified that were initially missed in the reported studie...

  • Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies.
    Immunotherapy, 2012
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Giancarlo Logroscino, Davide Seripa, Andrea Santamato, V. Solfrizzi, Antonio Greco, Alberto Pilotto
    Abstract:

    The exact mechanisms leading to Alzheimer’s disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular b-amyloid (Ab), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Ab. The most innovative of the pharmacological approaches was the stimulation of Ab clearance from the brain of AD patients via the administration of Ab antigens (active vaccination) or anti-Ab antibodies (passive vaccination). Several active and passive anti-Ab vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Ab and an immune adjuvant, QS - 21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Ab monoclonal antibodies (Bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with Bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after Bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E e4 carriers), has raised concerns on the safety of these antibodies directed against the N - terminus of the Ab peptide. Solanezumab, a humanized anti-Ab monoclonal antibody directed against the midregion of the Ab peptide, was shown to neutralize soluble Ab species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with Bapineuzumab and solanezumab will tell us if monoclonal anti-Ab antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Ab drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.

  • Anti-β-amyloid immunotherapy for Alzheimer's disease: focus on Bapineuzumab.
    Current Alzheimer research, 2011
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Giancarlo Logroscino, Davide Seripa, Alberto Pilotto, Grazia D'onofrio, Francesco Paris, Andrea Santamato, Vincenzo Solfrizzi
    Abstract:

    Recent advances in our understanding of the neurobiology of Alzheimers disease (AD) have led to the development of putative disease-modifying treatments. The most revolutionary of these approaches consists in the removal of brain β-amyloid (Aβ) via anti-Aβ antibodies. Brain imaging and neuropathological studies have shown the ability of both active and passive anti-Aβ immunotherapies of clearing Aβ deposits from the brain of the AD patients. An active anti-Aβ vaccine preparation, AN1792, has been used in AD patients with some clues of clinical efficacy but causing meningoencephalitis in about 6% of patients and it has been abandoned. Several second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is Bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Aβ burden in the brain of AD patients. However, the preliminary cognitive efficacy of Bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg). The results of four ongoing large Phase III trials on Bapineuzumab will tell us if passive anti-Aβ immunization is able to alter the course if this devastating disease.

Stephen Salloway - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies.
    Journal of Alzheimer's disease : JAD, 2018
    Co-Authors: H. Robert Brashear, Stephen Salloway, Nzeera Ketter, Jennifer Bogert, Reisa A. Sperling
    Abstract:

    BACKGROUND Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer's disease in Bapineuzumab phase III studies. OBJECTIVES Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. METHODS A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. RESULTS Treatment-emergent ARIA-E occurred in 15.8% of Bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. CONCLUSIONS Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302).

  • Long-Term Safety and Efficacy of Bapineuzumab in Patients with Mild-to-Moderate Alzheimer’s Disease: A Phase 2, Open-Label Extension Study
    Current Alzheimer Research, 2018
    Co-Authors: Stephen Salloway, Gad A Marshall, Ming Lu, H. Robert Brashear
    Abstract:

    Bapineuzumab is a humanized anti-amyloid-beta (Aβ) monoclonal antibody directed at lowering the cerebral Aβ deposit in Alzheimer's disease (AD). This phase 2, open-label extension (OLE) study evaluated long-term safety and efficacy of Bapineuzumab in patients with the mild-to-moderate AD. Patients (58-78 years) who completed either of two randomized, placebo-controlled, doubleblind studies (subcutaneous [SC] single-dose-escalation, or intravenous (IV) multiple-ascending-dose)) entered the OLE. Three groups were assessed: Bapineuzumab or placebo SC, and Bapineuzumab (IV) in OLE (bapi SC/bapi IV); Bapineuzumab (IV) in Study 201 and OLE (bapi/bapi); and placebo in Study 201 and Bapineuzumab IV in OLE (placebo/bapi). Of 194 patients enrolled, 158 withdrew from OLE; primarily due to withdrawal by subject (n=85) and AE (n=30). Mean (SD) Bapineuzumab exposure was 2.9 (1.90) years. There were no significant differences for efficacy endpoints (AD Assessment Scale-cognitive subscale [ADAS-Cog], Disability Assessment for Dementia [DAD] and MMSE scores) between the bapi/bapi and placebo/bapi groups. Most patients (94.8%, 184/194) reported ≥1 treatment-emergent adverse events (TEAEs) in OLE. Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) occurred in 22 (11.3%) patients. The most common TEAEs (>20% patients) were fall, agitation and urinary tract infection with similar incidences between bapi/bapi and placebo/bapi groups. No significant difference was seen in cognitive and functional decline between early and delayed treatment groups. No new safety concerns emerged. ARIA-E incidence was higher in patients first exposed to Bapineuzumab in OLE versus previously exposed. No clear pattern of etiology contributed to death events. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  • Long-Term Safety and Efficacy of Bapineuzumab in Patients with Mild-to-Moderate Alzheimer's Disease: A Phase 2, Open-Label Extension Study.
    Current Alzheimer research, 2018
    Co-Authors: Stephen Salloway, Gad A Marshall, H. Robert Brashear
    Abstract:

    Background Bapineuzumab is a humanized anti-amyloid-beta (Aβ) monoclonal antibody directed at lowering the cerebral Aβ deposit in Alzheimer's disease (AD). Objective This phase 2, open-label extension (OLE) study evaluated long-term safety and efficacy of Bapineuzumab in patients with the mild-to-moderate AD. Methods Patients (58-78 years) who completed either of two randomized, placebo-controlled, doubleblind studies (subcutaneous [SC] single-dose-escalation, or intravenous (IV) multiple-ascending-dose)) entered the OLE. Three groups were assessed: Bapineuzumab or placebo SC, and Bapineuzumab (IV) in OLE (bapi SC/bapi IV); Bapineuzumab (IV) in Study 201 and OLE (bapi/bapi); and placebo in Study 201 and Bapineuzumab IV in OLE (placebo/bapi). Results Of 194 patients enrolled, 158 withdrew from OLE; primarily due to withdrawal by subject (n=85) and AE (n=30). Mean (SD) Bapineuzumab exposure was 2.9 (1.90) years. There were no significant differences for efficacy endpoints (AD Assessment Scale-cognitive subscale [ADAS-Cog], Disability Assessment for Dementia [DAD] and MMSE scores) between the bapi/bapi and placebo/bapi groups. Most patients (94.8%, 184/194) reported ≥1 treatment-emergent adverse events (TEAEs) in OLE. Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) occurred in 22 (11.3%) patients. The most common TEAEs (>20% patients) were fall, agitation and urinary tract infection with similar incidences between bapi/bapi and placebo/bapi groups. Conclusion No significant difference was seen in cognitive and functional decline between early and delayed treatment groups. No new safety concerns emerged. ARIA-E incidence was higher in patients first exposed to Bapineuzumab in OLE versus previously exposed. No clear pattern of etiology contributed to death events.

  • Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study.
    Journal of Alzheimer's disease : JAD, 2018
    Co-Authors: Stephen Salloway, Nick C. Fox, Reisa A. Sperling, Marwan N. Sabbagh, Lawrence S. Honig, Anton P. Porsteinsson, Hany Rofael, Nzeera Ketter, Daniel Wang, Enchi Liu
    Abstract:

    Background A 3-year extension of two Phase III parent studies of intravenous (IV) Bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. Objectives The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of Bapineuzumab. Methods A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of Bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received Bapineuzumab or placebo in the parent studies. Results A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received Bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to Bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions Infusion of Bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

  • Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with Bapineuzumab
    Neurology, 2018
    Co-Authors: Enchi Liu, Stephen Salloway, Philip Scheltens, Nick C. Fox, Reisa A. Sperling, Kaj Blennow, Dai Wang, Mark E. Schmidt, Johannes Streffer, Gerald Novak
    Abstract:

    Objective To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in Bapineuzumab clinical trials was associated with specific biomarker patterns. Methods Bapineuzumab, an anti-β-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed. Results A total of 1,512 participants underwent one or more biomarker assessments; 154 developed incident ARIA-E. No differences were observed at baseline between ARIA-E and non-ARIA-E participants in brain amyloid burden by PET, the majority of vMRI measures, or CSF biomarkers, with the exception of lower baseline CSF Aβ 42 in APOE e4 noncarrier ARIA-E vs non-ARIA-E groups (Bapineuzumab non-ARIA-E p = 0.027; placebo non-ARIA-E p = 0.012). At week 71, Bapineuzumab-treated participants with ARIA-E vs non-ARIA-E showed greater reduction in brain amyloid PET, greater reductions in CSF phosphorylated tau (p-tau) (all comparisons p p p 40 concentrations was observed for ARIA-E versus both non-ARIA-E groups (Bapineuzumab/placebo non-ARIA-E p = 0.015/0.049). No group differences were observed at week 71 for changes in whole brain volume or CSF Aβ 42 . Conclusions Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in Bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.

Reisa A. Sperling - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies.
    Journal of Alzheimer's disease : JAD, 2018
    Co-Authors: H. Robert Brashear, Stephen Salloway, Nzeera Ketter, Jennifer Bogert, Reisa A. Sperling
    Abstract:

    BACKGROUND Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer's disease in Bapineuzumab phase III studies. OBJECTIVES Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. METHODS A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. RESULTS Treatment-emergent ARIA-E occurred in 15.8% of Bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. CONCLUSIONS Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302).

  • Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study.
    Journal of Alzheimer's disease : JAD, 2018
    Co-Authors: Stephen Salloway, Nick C. Fox, Reisa A. Sperling, Marwan N. Sabbagh, Lawrence S. Honig, Anton P. Porsteinsson, Hany Rofael, Nzeera Ketter, Daniel Wang, Enchi Liu
    Abstract:

    Background A 3-year extension of two Phase III parent studies of intravenous (IV) Bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. Objectives The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of Bapineuzumab. Methods A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of Bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received Bapineuzumab or placebo in the parent studies. Results A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received Bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to Bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions Infusion of Bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

  • Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with Bapineuzumab
    Neurology, 2018
    Co-Authors: Enchi Liu, Stephen Salloway, Philip Scheltens, Nick C. Fox, Reisa A. Sperling, Kaj Blennow, Dai Wang, Mark E. Schmidt, Johannes Streffer, Gerald Novak
    Abstract:

    Objective To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in Bapineuzumab clinical trials was associated with specific biomarker patterns. Methods Bapineuzumab, an anti-β-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed. Results A total of 1,512 participants underwent one or more biomarker assessments; 154 developed incident ARIA-E. No differences were observed at baseline between ARIA-E and non-ARIA-E participants in brain amyloid burden by PET, the majority of vMRI measures, or CSF biomarkers, with the exception of lower baseline CSF Aβ 42 in APOE e4 noncarrier ARIA-E vs non-ARIA-E groups (Bapineuzumab non-ARIA-E p = 0.027; placebo non-ARIA-E p = 0.012). At week 71, Bapineuzumab-treated participants with ARIA-E vs non-ARIA-E showed greater reduction in brain amyloid PET, greater reductions in CSF phosphorylated tau (p-tau) (all comparisons p p p 40 concentrations was observed for ARIA-E versus both non-ARIA-E groups (Bapineuzumab/placebo non-ARIA-E p = 0.015/0.049). No group differences were observed at week 71 for changes in whole brain volume or CSF Aβ 42 . Conclusions Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in Bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.

  • Amyloid-β 11C-PiB-PET imaging results from 2 randomized Bapineuzumab phase 3 AD trials
    Neurology, 2015
    Co-Authors: Enchi Liu, Stephen Salloway, Richard Margolin, Reisa A. Sperling, William E Klunk, Chester A Mathis, Mark E. Schmidt, Robert A. Koeppe, N.s. Mason, Nick C. Fox
    Abstract:

    Objective: To evaluate the effects of Bapineuzumab on brain β-amyloid (Aβ) burden using 11 C-Pittsburgh compound B ( 11 C-PiB)-PET. Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE e4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an 11 C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Results: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in 11 C-PiB-PET GCA between Bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = −0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = −0.068; p = 0.027; 1.0 mg/kg vs placebo δ = −0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results. Conclusions: The 11 C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with Bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that Bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.

  • two phase 3 trials of Bapineuzumab in mild to moderate alzheimer s disease
    The New England Journal of Medicine, 2014
    Co-Authors: Stephen Salloway, Nick C. Fox, Reisa A. Sperling, Marwan N. Sabbagh, Lawrence S. Honig, Anton P. Porsteinsson, William E Klunk, Kaj Blennow, Murray A Raskind, Steven H Ferris
    Abstract:

    Background Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. Methods We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) e4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. Results There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (Bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of Bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving Bapineuzumab, which increased with Bapineuzumab dose and APOE e4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE e4 allele carriers but not in noncarriers. Conclusions Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE e4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

Alberto Pilotto - One of the best experts on this subject based on the ideXlab platform.

  • Amyloid-related imaging abnormalities associated with immunotherapy in Alzheimer’s disease patients
    Future Neurology, 2012
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Giancarlo Logroscino, Davide Seripa, Alberto Pilotto, Vincenzo Solfrizzi
    Abstract:

    Evaluation of: Sperling R, Salloway S, Brooks DJ et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with Bapineuzumab: a retrospective analysis. Lancet Neurol. 11(3), 241–249 (2012). Amyloid-related imaging abnormalities (ARIAs) have been reported in patients with Alzheimer’s disease treated with Bapineuzumab, a monoclonal antibody targeting β-amyloid (Aβ). The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recovery sequences thought to represent ‘vasogenic edema’ and/or sulcal effusion (ARIA-E), as well as signal hypointensities on gradient echo/T2* thought to represent hemosiderin deposits. This study was a retrospective analysis in which two neuroradiologists independently reviewed 2572 fluid attenuation inversion recovery MRI scans from 262 participants in two Phase II studies of Bapineuzumab and an open-label extension study. In this analysis, several ARIA-E cases were identified that were initially missed in the reported studie...

  • Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies.
    Immunotherapy, 2012
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Giancarlo Logroscino, Davide Seripa, Andrea Santamato, V. Solfrizzi, Antonio Greco, Alberto Pilotto
    Abstract:

    The exact mechanisms leading to Alzheimer’s disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular b-amyloid (Ab), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Ab. The most innovative of the pharmacological approaches was the stimulation of Ab clearance from the brain of AD patients via the administration of Ab antigens (active vaccination) or anti-Ab antibodies (passive vaccination). Several active and passive anti-Ab vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Ab and an immune adjuvant, QS - 21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Ab monoclonal antibodies (Bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with Bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after Bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E e4 carriers), has raised concerns on the safety of these antibodies directed against the N - terminus of the Ab peptide. Solanezumab, a humanized anti-Ab monoclonal antibody directed against the midregion of the Ab peptide, was shown to neutralize soluble Ab species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with Bapineuzumab and solanezumab will tell us if monoclonal anti-Ab antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Ab drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.

  • Anti-β-amyloid immunotherapy for Alzheimer's disease: focus on Bapineuzumab.
    Current Alzheimer research, 2011
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Giancarlo Logroscino, Davide Seripa, Alberto Pilotto, Grazia D'onofrio, Francesco Paris, Andrea Santamato, Vincenzo Solfrizzi
    Abstract:

    Recent advances in our understanding of the neurobiology of Alzheimers disease (AD) have led to the development of putative disease-modifying treatments. The most revolutionary of these approaches consists in the removal of brain β-amyloid (Aβ) via anti-Aβ antibodies. Brain imaging and neuropathological studies have shown the ability of both active and passive anti-Aβ immunotherapies of clearing Aβ deposits from the brain of the AD patients. An active anti-Aβ vaccine preparation, AN1792, has been used in AD patients with some clues of clinical efficacy but causing meningoencephalitis in about 6% of patients and it has been abandoned. Several second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is Bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Aβ burden in the brain of AD patients. However, the preliminary cognitive efficacy of Bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg). The results of four ongoing large Phase III trials on Bapineuzumab will tell us if passive anti-Aβ immunization is able to alter the course if this devastating disease.

  • Monoclonal antibodies against β-amyloid (Aβ) for the treatment of Alzheimer's disease: the Aβ target at a crossroads
    Expert opinion on biological therapy, 2011
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Davide Seripa, Vincenzo Solfrizzi, Alberto Pilotto
    Abstract:

    Several second-generation active β-amyloid (Aβ) vaccines and passive Aβ immunotherapies are under clinical investigation with the aim of boosting Aβ clearance from the brain of the Alzheimer's disease (AD) patients. However, the preliminary cognitive efficacy of Bapineuzumab, a humanized anti-Aβ monoclonal antibody, appears uncertain. Moreover, the occurrence of vasogenic edema and, more rarely, brain microhemorrhages, especially in apolipoprotein E ϵ4 carriers, have led to abandoning of the highest dose of the drug. Solanezumab, another humanized anti-Aβ monoclonal antibody, was shown to neutralize soluble Aβ oligomers, which is believed to be the more neurotoxic Aβ species. Phase II studies showed a good safety profile of solanezumab while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. However, the preliminary equivocal cognitive results obtained with Bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD. The results of four ongoing large Phase III trials on Bapineuzumab and two Phase III trials on solanezumab will tell us if passive anti-Aβ immunization is able to alter the course of this devastating disease, and if Aβ is still a viable target for anti-AD drugs.

  • Bapineuzumab: anti-β-amyloid monoclonal antibodies for the treatment of Alzheimer's disease.
    Immunotherapy, 2010
    Co-Authors: Francesco Panza, Vincenza Frisardi, Bruno P. Imbimbo, Davide Seripa, Alberto Pilotto, Grazia D'onofrio, Giuseppe Pietrarossa, Vincenzo Solfrizzi
    Abstract:

    In the last decade, new therapeutic approaches targeting b-amyloid (Ab) have been discovered and developed with the hope of modifying the natural history of Alzheimer’s disease (AD). The most revolutionary of these approaches consists in the removal of brain Ab via anti - Ab antibodies. After an active vaccine (AN1792) was discontinued in 2002 due to occurrence of meningoencephalitis in approximately 6% of patients, several other second-generation active Ab vaccines and passive Ab immunotherapies have been developed and are under clinical investigation with the aim of accelerating Ab clearance from the brain of AD patients. The most advanced of these immunological approaches is Bapineuzumab, which is composed of humanized anti - Ab monoclonal antibodies that has been tested in two Phase II trials. Bapineuzumab has been shown to reduce Ab burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE e4 carriers, and vasogenic edema may limit its clinical use. The results of four ongoing large Phase III trials on Bapineuzumab will provide answers regarding whether passive anti - Ab immunization is able to alter the course of this devastating disease.

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