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Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer's Disease.

ABSTRACT: OBJECTIVES:Long-term safety and tolerability of ACC-001 (vanutide cridificar), an antiamyloid- beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimer's disease. DESIGN:Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan. METHODS:Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 ?g) to subjects randomized in the parent studies; ACC-001 was administered with QS-21 adjuvant. Safety, tolerability, and immunogenicity were assessed during active treatment and 6-month follow-up. RESULTS:ACC-001 + QS-21 was well tolerated in the United States (N=110) and European Union (N=50), and Japan (N=53) extension studies; safety profile was similar to that observed in the parent studies, and no new safety signals were identified. Overall, injection site reactions were the most common adverse event in these studies. Anti-amyloid antibody titers were elicited in all groups, with the highest titers observed in subjects who received ACC-001 + QS-21 in both the parent and extension studies. CONCLUSIONS:Long-term exposure to ACC-001 + QS-21 was well tolerated in subjects with Alzheimer's disease, suggesting that side effects do not pose a principal limitation for anti-amyloid active immunotherapy. The highest anti-amyloid-beta IgG titers are elicited during long-term therapy with ACC-001 + QS-21 compared with other regimens.

SUBMITTER: Hull M

PROVIDER: S-EPMC5543567 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer's Disease.

Hull Michael M Sadowsky Carl C Arai Heii H Le Prince Leterme Ghislaine G Holstein Ann A Booth Kevin K Peng Yahong Y Yoshiyama Tamotsu T Suzuki Hideo H Ketter Nzeera N Liu Enchi E Ryan J Michael JM

Current Alzheimer research 20170101 7

<h4>Objectives</h4>Long-term safety and tolerability of ACC-001 (vanutide cridificar), an antiamyloid- beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimer's disease.<h4>Design</h4>Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan.<h4>Methods</h4>Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 μg) to subjects randomized in the parent studies; ACC-001 was adm ...[more]

PMID: 28124589

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Project description:BackgroundBapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.MethodsWe 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) ε4 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.ResultsThere 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 ε4 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 ε4 allele carriers but not in noncarriers.ConclusionsBapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

Project description:BackgroundAlzheimer's disease (AD) is a globally prevalent neurodegenerative condition, clinically characterized by progressive memory loss and gradual impairment of cognitive functions. Bapineuzumab is a fully humanized monoclonal antibody that binds to neurotoxic amyloid proteins in the brain, enhancing their clearance. We performed this systematic review and meta-analysis to evaluate the safety and efficacy of bapineuzumab in patients with mild to moderate Alzheimer's disease.MethodsWe performed a web-based literature search of PubMed, Ovid, EBSCO, Scopus, Embase, Cochrane CENTRAL, and web of science using the relevant keywords. Data were extracted from eligible records and pooled as mean difference (MD) or risk ratio (RR) values with their 95% confidence interval (CI), using Review Manager software (version 5.3 for windows). Heterogeneity was measured by Chi-square and I-square tests.ResultThe pooled effect estimate from six randomized clinical trials (n = 2380) showed that bapineuzumab significantly reduced the cerebrospinal fluid concentration of phosphorylated tau proteins (Standardized MD = -5.53, 95% CI [-8.29, -2.76]). However, the bapineuzumab group was not superior to the placebo group in terms of change from baseline in Alzheimer's disease assessment scale (ADAS)-Cog11 (MD = 0.14, 95% CI [-0.72, 0.99]), disability assessment for dementia (DAD) scale (MD = 1.35, 95% CI [-1.74, 4.43]), and mini-mental state examination (MMSE) scores (MD = 0.08, 95% CI [-0.31, 0.47]). Regarding safety, bapineuzumab increased the risk of serious treatment-emergent adverse events (RR = 1.18, 95% CI [1.02, 1.37]) and cerebral vasogenic edema (RR = 40.88, 95% CI [11.94, 135.95]). All bapineuzumab doses (0.15, 0.5, 1, and 2 mg/kg) were similar to placebo in terms of change from baseline in ADAS-cog11, DAD, and MMSE scores, except for the 0.15 mg/kg dose, which caused a significant worsening on the ADAS-cog11 scale (MD = 5.6, 95% CI [0.22, 10.98]).ConclusionsConsidering the lack of clinical efficacy, combined with the significant association with serious adverse events, bapineuzumab should not be used to treat patients with mild to moderate AD. Future studies should investigate the effect of combining bapineuzumab with other therapeutic strategies and reevaluate the efficacy of targeting amyloid β proteins in AD therapy.

Project description:BACKGROUND AND OBJECTIVES:QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials. METHODS:A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality. RESULTS:Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04-6.24). No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10-15.35 and RR 2.55, 95% CI 1.41-4.59, respectively). ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08-10.97). CONCLUSIONS:Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. This meta-analysis is limited by the relatively small number of individuals recruited in the included trials, especially in the control groups.

Dataset Information

Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer's Disease.

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Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer's Disease.

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