Two Phase 2 Multiple Ascending–Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer’s Disease

Pasquier, Florence; Sadowsky, Carl; Holstein, Ann R; Leterme, Ghislaine Le Prince; Peng, Yahong; Jackson, Nicholas; Fox, Nick C.; Ketter, Nzeera; Liu, Enchi; Ryan, Joanne

doi:10.3233/jad-150376

Cited by 87 publications

(70 citation statements)

References 32 publications

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“…In addition to ACI-24, these new-generation active vaccines include ACC-001 [51] and CAD-106 [52]. Phase I trials for these approaches showed positive antibody responses with no signs of adverse inflammation [53,54].…”

Section: Alzheimer's Disease In Down Syndromementioning

confidence: 97%

Improving Memory and Cognition in Individuals with Down Syndrome

Rafii

2016

CNS Drugs

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Down syndrome (DS), often due to trisomy 21, is the most common genetic cause of intellectual disability (ID). In addition, virtually all individuals with DS develop the neuropathology of Alzheimer's disease (AD) by the age of 40 years and almost 60 % will manifest symptoms of AD dementia by the age of 65 years. Currently, there are no pharmacological treatments available for ID in individuals with DS and only limited symptomatic treatments for AD dementia. Advances in our understanding in both the molecular basis of ID and the pathogenesis of AD have created opportunities to study potential therapeutic targets. Recent studies in animal models of DS continue to provide a rational basis for translating specific compounds into human clinical trials. However, target and compound selection are only initial steps in the drug development pathway. Other necessary considerations include appropriate study designs to assess efficacy in the DS population, as well as operational aspects specifically tailored to assess cognition in this population. We discuss recent progress in the development of compounds for both ID and AD in individuals with DS, as well as concepts for the design and conduct of clinical trials with such compounds.

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Section: Alzheimer's Disease In Down Syndromementioning

confidence: 97%

Improving Memory and Cognition in Individuals with Down Syndrome

Rafii

2016

CNS Drugs

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“…In preclinical studies, it was shown to generate Nterminal Aβ Abs in adult nonhuman primates without inducing Aβ-directed T cell response, supporting further clinical studies. Several phase II trials in patients with mild to moderate AD were conducted in USA, Europe, and Japan by using 3 doses of ACC-001 (3, 10 and 30 μg) with and without the adjuvant QS-21 (50 μg) or placebo to investigate doserange, safety, immunogenicity and long term treatment (Arai et al, 2015;Pasquier et al, 2016). ACC-001+QS-21 elicited high, sustained anti-Aβ IgG Ab titers compared with ACC-001 alone, highlighting the role of QS-21 in this effect.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

2019

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Background: Vaccine adjuvants are compounds that significantly enhance/prolong the immune response to a coadministered antigen. The limitations of the use of aluminium salts that are unable to elicite cell responses against intracellular pathogens such as those causing malaria, tuberculosis, or AIDS, have driven the development of new alternative adjuvants such as QS-21, a triterpene saponin purified from Quillaja saponaria. Purpose: The aim of this review is to attempt to clarify the mechanism of action of QS-21 through either receptors or signaling pathways in vitro and in vivo with special emphasis on the co-administration with other immunostimulants in new adjuvant formulations, called adjuvant systems (AS). Furthermore, the most relevant clinical applications will be presented. Methods: A literature search covering the period 2014-2018 was performed using electronic databases from Sci finder, Science direct, Medline/Pubmed, Scopus, Google scholar. Results: Insights into the mechanism of action of QS-21 can be summarized as follows: 1) in vivo stimulation of Th2 humoral and Th1 cell-mediated immune responses through action on antigen presenting cells (APCs) and T cells, leading to release of Th1 cytokines participating in the elimination of intracellular pathogens. 2) activation of the NLRP3 inflammasome in mouse APCs with subsequent release of caspase-1 dependent cytokines, Il-1β and Il-18, important for Th1 responses. 3) synthesis of nearly 50 QS-21 analogs, allowing structure/activity relationships and mechanistic studies. 4) unique synergy mechanism between monophosphoryl lipid A (MPL A) and QS-21, formulated in a liposome (AS01) in the early IFN-γ response, promoting vaccine immunogenicity. The second part of the review is related to phase I-III clinical trials of QS-21, mostly formulated in ASs, to evaluate efficacy, immunogenicity and safety of adjuvanted prophylactic vaccines against infectious diseases, e.g. malaria, herpes zoster, tuberculosis, AIDS and therapeutic vaccines against cancer and Alzheimer's disease. Conclusion: The most advanced phase III clinical applications led to the development of two vaccines containing QS-21 as part of the AS, the Herpes Zoster vaccine (HZ/su) (Shingrix™) which received a license in 2017 from the FDA and a marketing authorization in the EU in 2018 and the RTS,S/AS01 vaccine (Mosquirix™) against malaria, which was approved by the EMA in 2015 for further implementation in Sub-Saharan countries for routine use.2014 have made the research on vaccines very attractive in the last decades (Lee and Nguyen, 2015). Modern subunit vaccines comprising homogeneous molecular antigens have been developed to prevent and treat many human diseases, but they are weakly immunogenic and must be administered with an adjuvant to elicit a potent immune response. Adjuvants whose name originates from the Latin word adjuvare https://doi.

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“…To date, none of the treatments available for AD slow or stop neurodegeneration. Clinical trials with Aβ therapies, including immunotherapy, have thus far failed to show any reduction in neurofibrillary pathology or improvement in cognitive performance of patients with AD [5–10]. …”

Section: Introductionmentioning

confidence: 99%

Tau passive immunization inhibits not only tau but also Aβ pathology

et al. 2017

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BackgroundAccumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6–18 and 77E9 against tau 184–195 on tau and amyloid-β (Aβ) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.MethodsWe immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 μg of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and Aβ pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.ResultsWe found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing Aβ40 and Aβ42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding Aβ plaques.ConclusionsThese findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6–18 as a disease-modifying approach to AD and related tauopathies.

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Two Phase 2 Multiple Ascending–Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer’s Disease

Cited by 87 publications

References 32 publications

Improving Memory and Cognition in Individuals with Down Syndrome

Improving Memory and Cognition in Individuals with Down Syndrome

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

Tau passive immunization inhibits not only tau but also Aβ pathology

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