Therapeutics

Sabirnetug

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Overview

Name: Sabirnetug
Synonyms: ACU-193
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Acumen Pharmaceuticals, Inc.

Background

This humanized IgG2 monoclonal antibody selectively binds soluble Aβ oligomers, aka Aβ-derived diffusible ligands (ADDLs). Though they constitute a minor fraction of Aβ in the brain, soluble oligomers are believed to be the most neurotoxic, and to be responsible for memory loss and neuronal death (e.g., Gong et al., 2003; Hong et al., 2018). This antibody emerged from a research and development collaboration forged in 2004 between Acumen and Merck. The partnership ended in 2011, at which point Acumen regained development rights.

Preclinical work on ACU193 has been presented at meetings. In 2013, Acumen reported that the antibody binds to soluble Aβ oligomers with low nanomolar affinity and greater than 500-fold selectivity over Aβ monomers or fibrils. ACU193 blocked oligomers from interacting with cultured hippocampal neurons at an IC50 of 17 nM, and was unaffected by addition of excess Aβ monomer. In Tg-AD mice, ACU193 bound soluble oligomers in brain tissue, lessened plaque deposition, and was claimed to reduce abnormal nighttime hyperactivity. Based on ACU193's pharmacokinetics in animals, the company expects to achieve brain levels of ACU193 more than 200 times higher than soluble oligomer concentrations measured in Alzheimer’s patient CSF (Krafft et al., 2013). In 2015, the company described the use of ACU193 in an ultrasensitive immunoassay to detect soluble Aβ oligomers in mice (Cline et al., 2015).

The mouse version of ACU193, ACU-3B3, reportedly blocks Aβ oligomer-induced calcium elevation in hippocampal neurons in culture, and reduces amyloid pathology and behavioral deficits in AD mouse models (Wang et al., 2018; Ma et al., 2019). ACU193 was also used experimentally in studies proposing a physiological signaling role for transient formation of Aβ oligomers in embryonic tissue development (Bartley et al., 2022).

ACU193 coupled to magnetic nanoparticles was used to detect Aβ oligomers in rabbit brain by MRI (Rozema et al., 2020). For a description of the treatment rationale and preclinical data, see Krafft et al., 2022.

Findings

In June 2021, Acumen began a Phase 1 trial of intravenous ACU193 in 65 people with MCI or mild AD. The study evaluated safety and tolerability, including 12-lead EEG, as well as pharmacokinetic and pharmacodynamic parameters, of up to three different single and multiple doses. Co-sponsored by the National Institute on Aging, this trial ran at 17 sites across the U.S., and finished in July 2023. The rationale and design are published (Siemers et al., 2023). The company presented top-line results at the July 2023 AAIC. The study tested single doses of 2, 10, 25, or 60 mg/kg, and three doses of 10 or 60 mg/kg monthly, or 25 mg/kg every two weeks. Three serious adverse events were deemed unrelated to drug. Four cases of ARIA-H and five of ARIA-E were detected in 48 treated participants, with one symptomatic case in the 60 mg/kg monthly cohort. All improved or resolved by the end of the study. Blood and CSF pharmacokinetics were dose-dependent, with CSF concentrations exceeding reported oligomer levels. Target engagement was assessed by measuring antibody-oligomer complexes in CSF, which were found to increase with dose. Maximum target engagement occurred after 25 mg/kg biweekly or 60 mg/kg monthly. These doses generated a small reduction in plaque load. The antibody had no clear effect on exploratory outcomes of computerized cognitive testing or cerebral blood flow.

At the 2023 CTAD, the company described pharmacokinetic and target engagement modeling that informed dose selection for a planned Ph 2/3 study. Projected to start in 2024, the trial will compare 35 mg/kg monthly, 50 mg/kg monthly with titration to mitigate ARIA, and placebo. This trial is not yet registered.

For details on ACU193 trials, see clinicaltrials.gov.

Last Updated: 22 Nov 2023

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References

Paper Citations

  1. . ACU193, a Monoclonal Antibody that Selectively Binds Soluble Aß Oligomers: Development Rationale, Phase 1 Trial Design, and Clinical Development Plan. J Prev Alzheimers Dis. 2023;10(1):19-24. PubMed.
  2. . Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10417-22. PubMed.
  3. . Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer's disease brain. Acta Neuropathol. 2018 Jul;136(1):19-40. Epub 2018 Apr 23 PubMed.
  4. . O2–06–03: ACU-193: A candidate therapeutic antibody that selectively targets soluble beta-amyloid oligomers. Alzheimer's & Dementia, July 2013 Alzheimer's & Dementia
  5. . P4-177: An ultrasensitive immunoassay detects soluble Aβ oligomers in tg mice prior to memory loss. Alzheimer's & Dementia, 01 July 2015 Alzheimer's & Dementia
  6. . An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging. Sci Rep. 2018 Mar 15;8(1):4634. PubMed.
  7. . P2-063: Soluble Aβ-Oligomer–Selective Antibody Acu-3b3 Reduces Amyloid Pathology and Improves Multiple Behavioral Domains in a Mouse Model of Alzheimer's Disease. Alzheimer's & Dementia, 1 July 2019 Alzheimer's & Dementia
  8. . An Essential Role for Alzheimer's-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis. Int J Mol Sci. 2022 Feb 17;23(4) PubMed.
  9. . Aβ oligomer induced cognitive impairment and evaluation of ACU193-MNS-based MRI in rabbit. Alzheimers Dement (N Y). 2020;6(1):e12087. Epub 2020 Oct 10 PubMed. Correction.
  10. . ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer's Disease. Front Neurosci. 2022;16:848215. Epub 2022 Apr 26 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading