Background

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).

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). Vaccination of young APPxPS-1 mice led to local microglia activation around plaques, amyloid clearance, and fewer dystrophic neurites (Rudan Njavro et al., 2022). This vaccine uses the lipid adjuvant MPLA.

In a mouse model of Down's syndrome, immunization at 5 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).

More recently, AC Immune tested an optimized version of ACI-24 in mice and nonhuman primates (Vukicevic et al., 2022; Mar 2022 conference news). ACI-24.060 contains additional non-Aβ peptides (e.g. tetanus) to boost helper T cell responses. The vaccine was well-tolerated. It induced high titers of IgG reactive to pyroGlu-Aβ, an N-terminally truncated and modified form of Aβ that is highly amyloidogenic and toxic. PyroGlu-Aβ is also the target of donanemab, a monoclonal antibody approved to treat AD. In a presentation at the 2024 AAIC, the company showed that antibodies elicited in nonhuman primates preferentially recognize Aβ oligomers over monomers, with a similar selectivity as the approved anti-oligomer antibody Leqembi.

Findings

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 with a positive amyloid PET scan and on stable acetylcholinesterase inhibitor therapy. This adaptive study compared doses of 10, 100, 300, and 1,000 μg 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 included, 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. This study, in Finland, Sweden, and Great Britain, was to enroll 45 people ages 50 to 85 who have mild AD confirmed by amyloid PET. Primary outcomes included safety, tolerability, induction of Aβ antibodies, and changes in brain amyloid assessed by PET. Secondary objectives comprised 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. The study was completed in March 2021, and AC Immune presented results at the November 2021 CTAD conference. Twenty-one participants received injections of 1,000 μg ACI-24 or placebo, eight times over 18 months, with six months of follow-up. In this study, ACI-24 produced a clear IgM antibody response, but low IgG titers. CSF Aβ40 and Aβ42 were increased from baseline, suggesting target engagement, but there was no change on amyloid-PET. No ARIA or CNS inflammation were reported. Results are posted on 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 meeting presentation, the DS trial enrolled 16 participants aged 25 to 45 years who received seven injections of 300 or 1,000 μg versus placebo. In each dose cohort, six received the vaccine, two placebo. Most are Caucasian; the group has a high rate of obesity. Of 12 vaccinated participants, four had increased anti-Aβ IgG antibodies; none of the placebo group did. Plasma Aβ rose after vaccination. Safety and tolerability appeared favorable, with no dropouts, serious adverse events, or MRI abnormalities such as ARIA (May 2021 news). Results were published after peer review (Rafii et al., 2022).

In May 2020, AC Immune registered a Phase 2 trial in people with Down’s. Slated to begin in October 2020, the trial was to enroll 72 participants aged 40 to 50 years who had brain amyloid deposition but no dementia. The COVID-19 pandemic delayed the start of this trial, and in October 2021 it was withdrawn before enrollment began. The given reason was a decision to proceed with an optimized study design and vaccine formulation.

In June 2022, the ABATE Phase 1/2 trial began testing a new formulation called ACI-24.060 in people with prodromal Alzheimer’s disease or Down’s syndrome. All participants must have PET evidence of brain amyloid. AD patients will receive multiple shots of vaccine or placebo over one year, in up to four different doses or dose regimens. In people with Down’s syndrome, a dose identified in the AD part of the study will be given over 1.5 years, with the option of one additional dose cohort. Primary outcomes for both groups are adverse events, including abnormal MRI results, and for the Down’s group, production of Aβ antibodies. Other outcomes include change in amyloid and tau PET scans, and cognitive testing. The trial is currently running at 18 sites in the U.S., Spain, and the U.K., and will last until June 2026.

In January 2023, AC Immune announced positive interim results in AD patients (press release). At its lowest dose, the vaccine elicited antibodies after six weeks, with no safety concerns observed. By January 2024, the trial had completed enrollment of the first two dose cohorts, with no additional safety signs (press release). The company expects to report six- and 12-month PET data in 2024.

In June 2023, ACI-24.060 received Fast Track designation from the U.S. FDA (press release).

On May 13, 2024, Takeda Pharmaceuticals and AC Immune announced an exclusive license agreement (press release). Once ABATE is completed, Takeda will have the option to take over development of ACI-24.060.

For trial details, see clinicaltrials.gov.