Therapeutics

ACI-24

Overview

Name: ACI-24
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 1/2), Down's Syndrome (Phase 1)
Company: AC Immune SA

Background

ACI-24 is a liposome vaccine that is 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.

Findings

In 2009, AC Immune began a Phase 1/2 trial of ACI-24 that aims to address safety, immunogenicity, and efficacy. Five sites in Finland, Sweden, and Denmark are enrolling up to 198 patients age 40 and older with mild to moderate Alzheimer’s disease who had a positive amyloid PET scan and are on stable acetyl cholinesterase inhibitor therapy. This double-blind, randomized, placebo-controlled, adaptive study compares three doses to placebo, all delivered subcutaneously. Patients are being treated for one year and followed for two more. Primary outcomes include 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.

For more details on this trial, see the WHO Trials Registry or EU Clinical Trials Register.

In Jan 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 mid-life. Co-funded by the NIH and the LuMind Research Down Syndrome Foundation, this trial will occur at UC San Diego as well as four other centers in the United States that specialize in treatment and research of Down's. It will enroll 24 trisomy 21 patients aged 35 to 55 and treat them with ACI-24 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 (see clinicaltrials.gov).

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References

News Citations

  1. Early-Stage Alternative Vaccine Reported: Better Antibody Response with Liposomes?

Paper Citations

  1. . Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9810-5. PubMed.
  2. . Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases. J Biol Chem. 2011 Apr 22;286(16):13966-76. PubMed.

External Citations

  1. WHO Trials Registry
  2. EU Clinical Trials Register
  3. clinicaltrials.gov

Further Reading

Papers

  1. . Modulation of the humoral and cellular immune response in Abeta immunotherapy by the adjuvants monophosphoryl lipid A (MPL), cholera toxin B subunit (CTB) and E. coli enterotoxin LT(R192G). Vaccine. 2005 Oct 25;23(44):5149-59. PubMed.
  2. . TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice. Blood. 2013 Jan 3;121(1):85-94. Epub 2012 Nov 8 PubMed.