Synonyms: Pal1-15 acetate salt
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease, Down's Syndrome
U.S. FDA Status: Alzheimer's Disease (Phase 2), Down's Syndrome (Phase 2)
Company: AC Immune SA
ACI-24 is a liposome vaccine designed to elicit an antibody response against aggregated Aβ peptides without concomitant pro-inflammatory T cell activation. This vaccine grew out of work with tetrapalmitoylated preparations of N-terminal Aβ fragments, which rapidly stimulated anti-Aβ antibodies that dissolve amyloid fibers in vitro and in vivo. ACI-24 is based on the truncated Aβ-15 sequence, which is devoid of T-cell epitopes located closer to the peptide’s C-terminus. An array of Aβ1-15 sequences, sandwiched between palmitoylated lysines at either end, is anchored into the surface of liposomes in such a way that the peptides adopt an aggregated β-sheet structure, forming a conformational epitope (Feb 2002 news story).
In preclinical studies, repeated subcutaneous injection of ACI-24 into APPxPS-1 transgenic mice and into cynomolgus monkeys was reported to generate high titers of anti-Aβ IgG1 and IgG2b antibodies, which involve a non-inflammatory Th2 helper cell response. In a three-month treatment study in APPxPS-1 mice, ACI-24 reportedly decreased the concentration of insoluble Aβ40 and 42 and of soluble Aβ42; it also improved novel object recognition while prompting neither gliosis nor increases in measures of pro-inflammatory cytokines. Antisera from immunized monkeys stain human Alzheimer’s disease brain (Muhs et al., 2007; Hickman et al., 2011). This vaccine uses the lipid adjuvant MPLA.
In a mouse model of Down's syndrome, immunization at five months of age elicited anti-Aβ IgG, and led to a modest reduction in brain Aβ at 8 months. Vaccination improved memory deficits, and reduced cholinergic neuron atrophy, with no signs of inflammation or hemorrhage (Belinchenko et al., 2016).
In 2009, AC Immune began a Phase 1/2 trial of ACI-24 to evaluate safety, immunogenicity, and efficacy. Five sites in Finland, Sweden, and Denmark planned to enroll up to 198 participants age 40 and older with mild to moderate Alzheimer’s disease who had a positive amyloid PET scan and are on stable acetylcholinesterase inhibitor therapy. This adaptive study compared doses of 10, 100, 300, and 1,000 μg/ml to placebo, delivered subcutaneously. Patients were treated for one year and followed for one or two more. Some received a booster shot 2.5 to 3.5 years after their last dose. Primary outcomes included safety and tolerability measures, as well as serum titers of anti-Aβ42 IgG antibodies and one-year change from baseline of total cognitive score on the neuropsychological test battery. Secondary outcomes include, besides clinical endpoints, amyloid PET scanning with Piramar Imaging’s tracer Neuroceq (formerly Bayer’s florbetaben), as well as biomarker measures such as MRI volumetry, tau, phospho-tau and Aβ levels in CSF, and measures of T-cell activation.
The trial finished in October 2018; results are posted in the EU Clinical Trials Register. The trial ultimately enrolled only 48 patients. In the responder analysis, anti-Aβ42 antibodies were detected in only one of 36 treated patients, and the planned expansion into a Phase 2 efficacy stage was cancelled.
In August 2018, a Phase 2 trial started testing a new formulation, injecting 340 to 460 μg/ml intramuscularly. This study, in Finland, Sweden and Great Britain, is enrolling 45 people age 50 to 85 who have mild AD confirmed by amyloid PET. Primary outcomes include safety, tolerability, induction of Aβ antibodies, and changes in brain amyloid assessed by PET. Secondary objectives comprise biomarkers of amyloid and tau in blood and/or CSF, T cell activation and inflammatory markers in blood, volumetric MRI, and a variety of clinical and cognitive endpoints.
For details on these trials, see the EU Clinical Trials Register.
In March 2016, ACI-24 became the first anti-Aβ vaccine to be evaluated for the treatment of Alzheimer's disease in Down's syndrome, a genetic condition that leads to brain amyloid deposition, and dementia in midlife. Co-funded by the NIH and the LuMind Research Down Syndrome Foundation, this trial ran at UC San Diego and four other centers in the United States that specialize in treatment and research of Down's. It planned to enroll 24 trisomy 21 patients aged 35 to 55 and treat them with ACI-24 injected subcutaneously for one year, with an additional year of follow-up. Primary endpoints include measures of safety, tolerability, and immunogenicity, i.e. Aβ titers. Effects on biomarkers of AD pathology, as well as cognitive and clinical function, constitute secondary endpoints. The study ended in June 2020. According to a presentation at AAIC, the trial enrolled 16 patients age 25 to 45 years, who received seven injections of 300 or 1,000 μg versus placebo. Most are Caucasian; the group has a high rate of obesity. To date, safety and tolerability appear favorable, with no dropouts, serious adverse events, or MRI abnormalities such as ARIA. Top line results are expected in late 2020.
In May 2020, AC Immune registered a Phase 2 trial in people with Down’s. Slated to start in October 2020, the trial will enroll 72 participants between 40 and 50 years old who have brain amyloid deposition but no dementia. They will come from 15 sites in the United States and the European Union. The trial compares drug to placebo; dose and route of injection are not specified. The primary outcome comprises extensive safety and adverse event measures, including changes in blood pressure, heart rate, body temperature, suicidal ideation, ARI, up to two years out. Secondary outcome measures include measures of brain amyloid and tau by PET imaging, blood Aβ antibody titers, blood markers of amyloid, tau, and neurodegeneration, and changes in cognitive and behavioral measures. The trial is expected to finish in October 2024.
For U.S. trial details, see clinicaltrials.gov.
Last Updated: 08 Oct 2020
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