Therapeutics

ABBV-CLS-7262

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Overview

Name: ABBV-CLS-7262
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 1)

Background

ABBV-CLS-7262 is an activator of the eukaryotic initiation factor EIF2b, which participates in starting up protein synthesis from mRNA. In some neurodegenerative diseases, accumulation of misfolded proteins in the endoplasmic reticulum shuts down protein production by inhibiting EIF2b as part of the so-called unfolded protein response, or integrated stress response (for example, see Stutzbach et al., 2013). The resulting deficit in global protein synthesis contributes to synaptic dysfunction and memory impairment.

Restoring EIF2b activity has been shown to protect against neurodegeneration in preclinical models of prion disease, frontotemporal dementia, and ALS (reviewed in Smith and Mallucci, 2016).

Calico licensed ABBV-CLS-7262 from Peter Walter's laboratory at the University of California at San Francisco. This group has published multiple papers on the integrated stress response inhibitor ISRIB, an activator of EIF2b that improves learning and memory in mice (Sidrauski et al., 2013; Sidrauski et al., 2015; Sidrauski et al., 2015). In preclinical work, ISRIB was neuroprotective in models of head trauma, Down's syndrome, and vanishing white-matter disease (Chou et al., 2017; Zhu et al., 2019; Abbink et al., 2019). It also protected neurons from SOD-1 toxicity in a cellular model of ALS (Bugallo et al., 2020).

In Alzheimer’s models, ISRIB generated mixed results. It prevented Aβ-induced cell death (Hosoi et al., 2016) but did not improve cognition in either the APPswe or hAPP-J20 models of AD, and daily dosing led to significant mortality in the former (Briggs et al., 2017; Johnson and Kang, 2016). Other researchers reported that ISRIB prevented synaptic loss and memory deficits in an Aβ toxicity model, and restored synaptic function and memory in older APP/PS1 mice (Oliveira et al., 2021).

The ISRIB binding site on EIF2b has been resolved by X-ray crystallography (Zyryanova et al., 2018; Tsai et al., 2018; and review by Marintchev and Ito, 2020).

Denali Therapeutics also has an EIF2b activator in clinical trials for ALS (see DNL343).

Findings

In September 2021, Calico and AbbVie began a Phase 1 study of the safety and pharmacokinetics of ABBV-CLS-7262 in 30 people with ALS, conducted at two sites in Canada. The design calls for a four-week comparison of three oral doses with placebo, followed by 44 weeks of open-label treatment. Completion is set for May 2023.

For details on ABBV-CLS-7262 trials, see clinicaltrials.gov.

Last Updated: 08 Oct 2021

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References

Therapeutics Citations

  1. DNL343

Paper Citations

  1. . The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol Commun. 2013 Jul 6;1(1):31. PubMed.
  2. . The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain. 2016 Aug;139(Pt 8):2113-21. Epub 2016 May 11 PubMed.
  3. . Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013;2:e00498. PubMed.
  4. . The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. 2015 Feb 26;4 PubMed.
  5. . Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6420-E6426. Epub 2017 Jul 10 PubMed.
  6. . Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science. 2019 Nov 15;366(6467):843-849. PubMed.
  7. . Vanishing white matter: deregulated integrated stress response as therapy target. Ann Clin Transl Neurol. 2019 Aug;6(8):1407-1422. Epub 2019 Jul 18 PubMed.
  8. . Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. Cell Death Dis. 2020 May 26;11(5):397. PubMed.
  9. . Unique pharmacological property of ISRIB in inhibition of Aβ-induced neuronal cell death. J Pharmacol Sci. 2016 Aug;131(4):292-5. Epub 2016 Aug 12 PubMed.
  10. . Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSwe Mouse Models of Tauopathy and Amyloidosis. eNeuro. 2017 Jul-Aug;4(4) Epub 2017 Jul 14 PubMed.
  11. . A small molecule targeting protein translation does not rescue spatial learning and memory deficits in the hAPP-J20 mouse model of Alzheimer's disease. PeerJ. 2016;4:e2565. Epub 2016 Oct 19 PubMed.
  12. . Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease. Sci Signal. 2021 Feb 2;14(668) PubMed.
  13. . Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science. 2018 Mar 30;359(6383):1533-1536. PubMed.
  14. . Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science. 2018 Mar 30;359(6383) PubMed.
  15. . eIF2B and the Integrated Stress Response: A Structural and Mechanistic View. Biochemistry. 2020 Apr 7;59(13):1299-1308. Epub 2020 Mar 26 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat. Cell Signal. 2021 Sep;85:110048. Epub 2021 May 17 PubMed.
  2. . Impaired Restoration of Global Protein Synthesis Contributes to Increased Vulnerability to Acute ER Stress Recovery in Huntington's Disease. Cell Mol Neurobiol. 2021 Aug 4; PubMed.
  3. . Sugar phosphate activation of the stress sensor eIF2B. Nat Commun. 2021 Jun 8;12(1):3440. PubMed.