Therapy Type: Immunotherapy (active) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: AC Immune SA, Janssen
ACI-35 is a liposome-based vaccine. The rationale behind it is that the vaccine will treat tauopathy in Alzheimer’s disease by eliciting an immune response targeted to certain pathological conformers of phosphorylated tau without also mounting autoimmune B cell or T cell responses against physiological forms of this ubiquitous intracellular protein. The vaccine contains 16 copies of a synthetic tau fragment that is phosphorylated at the protein’s pathological phosphorylation residues S396 and S404 and is anchored into a lipid bilayer. It uses the adjuvant MPLA (Hickman et al., 2011, and Jun 2012 conference story).
In both wild-type C57BL/6 and P301L mutant tau transgenic mice, a three-month regimen of subcutaneous ACI-35 injection rapidly generated high titers of polyclonal IgG antibodies specifically directed against phosphorylated tau, rather than non-phosphorylated tau. The resulting antibodies were reported to bind neurofibrillary tangles in mouse brain tissue sections and to reduce soluble tau as well as insoluble, aggregated tau in brain extracts. ACI-35 also reportedly improved three of four tested clinical parameters: It increased retention of body weight, delayed onset of a clasping motor phenotype, and extended lifespan, but it did not improve endurance on a rotarod test. This preclinical study also reported that tests of gliosis, T cell activation, and other inflammatory markers were negative (Theunis et al., 2013). Similar data in non-human primates were presented at the 2013 Society for Neuroscience conference.
In December 2013, AC Immune began the first human trial of a phospho-tau-specific vaccine. This Phase 1b study compared a six-month course of undisclosed low, medium, and high doses of ACI-35 to placebo in 24 people with mild to moderate AD. The initial dosing regimen was followed by a subsequent booster shot, and a further six-month safety observation period. This was a safety, tolerability, immunogenicity study with secondary outcomes to take an initial look at biomarkers and clinical/functional outcomes, according to a company (Aug 2014 news story). Besides routine safety measures, primary outcomes included MRI scans taken five times, biochemistry measures from CSF collected twice, as well as antibody titre measurements from blood collected throughout the study. Secondary outcomes included ADAS-cog, MMSE, Trail Making and Fluency tests, Clinical Global Impression of Change Disability Assessment in Dementia, and Neuropsychiatric Inventory Scale. This trial was registered in May 2015 and is ongoing at sites in Finland and the UK (see World Health Organization’s clinical trial registry).
In 2015, ACI-35 was licensed to Janssen.
As of 2014, AC Immune is partnering with Piramal Imaging to develop tau PET tracers for localization and quantification of tau pathology in the brain. Piramal also bought florbetaben, now called NeuraceqTM, the amyloid imaging tracer being used in AC Immune’s clinical Phase 1/2 trial of the anti-Aβ vaccine ACI-24.
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- Theunis C, Crespo-Biel N, Gafner V, Pihlgren M, López-Deber MP, Reis P, Hickman DT, Adolfsson O, Chuard N, Ndao DM, Borghgraef P, Devijver H, Van Leuven F, Pfeifer A, Muhs A. Efficacy and Safety of A Liposome-Based Vaccine against Protein Tau, Assessed in Tau.P301L Mice That Model Tauopathy. PLoS One. 2013;8(8):e72301. PubMed.
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