Therapeutics

ACI-3024

Overview

Name: ACI-3024
Synonyms: Tau MorphomerTM
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Other Tauopathy
U.S. FDA Status: Alzheimer's Disease (Phase 1), Other Tauopathy (Phase 1)
Company: AC Immune SA

Background

ACI-3024 is a small-molecule inhibitor of tau aggregation. It originated from screening of AC Immune’s proprietary compound library of low-molecular-weight compounds that disrupt Aβ-sheet structures (Kroth et al., 2012). With additional medicinal chemistry, the company has created conformation-specific candidates targeting tau, Aβ, α-synuclein, and the NLRP3-ASC inflammasome; ACI-3024 is the first to enter clinical trials.

No preclinical information on ACI-3024 is formally published. According to data presented at conferences, the compound disrupts tau aggregates in vitro, independent of the presence of pathogenic mutations (see March 2019 AAT-AD/PD slides). Reportedly, ACI-3024 does not cross-react with monomeric tau, or with Aβ- or α-synuclein aggregates from human brain, and it disaggregates tau neurofibrillary tangles in human brain sections ex vivo, even in the presence of amyloid plaques. In cell-based assays, nanomolar concentrations of ACI-3024 were claimed to cause a dose-dependent reduction of intracellular pathological tau, and to prevent microglial activation and neuron death induced by tau paired helical filaments in primary brain cell cultures. One month of ACI-3024 treatment was claimed to reduce brain aggregated and insoluble tau in the rTg4510 mouse model of tauopathy due to expression of mutated human tau. Treatment also reportedly reduced microglia activation and CSF total tau in these mice, in proportion to plasma drug concentration. 

In December 2018, AC Immune struck up a partnership with Lilly to develop ACI-3024 (news story). AC Immune has used the same technology to discover PET ligands, and is developing the tau tracer PI-2620 in partnership with Life Molecular Imaging (Kroth et al., 2019; Jan 2020 newsBullich et al., 2019).

Findings

In July 2019, the company began a Phase 1 safety and tolerability study in healthy volunteers (press release). The placebo controlled, single- and multiple-ascending-dose study will also evaluate ACI-3024’s pharmacokinetics, food effects, and pharmacodynamics. No registry entry for this trial was found. However, in March 2020, AC Immune announced that recruitment and treatment were complete, and data release is anticipated in the second half of 2020 (press release).

Last Updated: 08 Oct 2020

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References

Research Models Citations

  1. rTg(tauP301L)4510

News Citations

  1. Tau PET Scans Turn Positive When Amyloid Does; Symptoms Follow

Paper Citations

  1. . Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation. J Biol Chem. 2012 Oct 5;287(41):34786-800. PubMed.
  2. . Discovery and preclinical characterization of [18F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer's disease and other tauopathies. Eur J Nucl Med Mol Imaging. 2019 Sep;46(10):2178-2189. Epub 2019 Jul 1 PubMed.
  3. . Evaluation of dosimetry, quantitative methods and test-retest variability of 18F-PI-2620 PET for the assessment of tau deposits in the human brain. J Nucl Med. 2019 Nov 11; PubMed.

External Citations

  1. press release
  2. press release
  3. March 2019 AAT-AD/PD
  4. news story

Further Reading

No Available Further Reading