Therapeutics

ABBV-CLS-7262

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Overview

Name: ABBV-CLS-7262
Synonyms: Fosigotifator, Fosigotifator sodium tromethamine
Chemical Name: [(2S)-1,4-Bis[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-bicyclo[2.2.2]octanyl]oxymethyl dihydrogen phosphate
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2)
Company: AbbVie, Calico Life Sciences LLC.

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). ISRIB was reported to normalize protein synthesis in the hippocampus and abrogate learning and memory deficits due to Aβ42 oligomer toxicity in rats (Hu et al., 2022). It also prevented Tau phosphorylation at residues 181 and 217 that occurred in response to synaptic long-term depression (Zhang et al., 2022).

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 up to three years of open-label treatment. The placebo-controlled portion finished in January 2023. Trial completion is set for December 2025.

In March 2023, the company began an open-label exploratory Phase 1b/2 study in adults and children with vanishing white-matter disease. This genetic degenerative condition is caused by reduced EIF2b activity due to mutations affecting its subunit proteins. Three age-defined cohorts will receive treatment for 96 weeks, against primary outcomes of adverse events and plasma drug concentration. Completion is slated for October 2026.

Also in March 2023, a Phase 2/3 trial began testing ABBV-CLS-7262 in ALS. This study is part of the Healey ALS platform trial, a multicenter clinical collaboration testing different interventions in parallel against a common placebo group. The study will compare two different doses in 300 patients, enrolled 3:1 to active treatment or placebo. The primary outcome is disease progression on the ALS-Functional Rating Scale-Revised, and mortality. Secondary outcomes include muscle strength, respiratory function, and serum neurofilament light chain levels. Enrollment was completed in April 2024 (press release). The trial is planned to finish in September 2024.

In 2023 and 2024, the company completed three additional Phase 1 studies in healthy adults. One explored the effects of ABBV-CLS-7262 on the pharmacokinetics of rosuvastatin and digoxin in 12 participants. Another assessed food effects. From March to June 2024, the company tested the effects of ABBV-CLS-7262 on heart electrical activity. This study evaluated possible effects on the electrocardiogram QTc interval in 72 healthy adults. An ongoing Phase 1 study is assessing safety, pharmacokinetics, elimination, and major drug metabolites after a single dose of radioactive [14C] ABBV-CLS-7262 in healthy men.

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

Last Updated: 14 Jul 2024

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References

Therapeutics Citations

  1. DNL343

Paper Citations

  1. Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, PSP Genetics Study Group, Lee VM, Trojanowski JQ, Devlin B, Schellenberg GD. 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. Smith HL, Mallucci GR. The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain. 2016 Aug;139(Pt 8):2113-21. Epub 2016 May 11 PubMed.
  3. Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK, Wilson C, Okreglak V, Ashkenazi A, Hann B, Nader K, Arkin MR, Renslo AR, Sonenberg N, Walter P. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013;2:e00498. PubMed.
  5. Sidrauski C, McGeachy AM, Ingolia NT, Walter P. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. 2015 Feb 26;4 PubMed.
  6. Chou A, Krukowski K, Jopson T, Zhu PJ, Costa-Mattioli M, Walter P, Rosi S. 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.
  7. Zhu PJ, Khatiwada S, Cui Y, Reineke LC, Dooling SW, Kim JJ, Li W, Walter P, Costa-Mattioli M. Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science. 2019 Nov 15;366(6467):843-849. PubMed.
  8. Abbink TE, Wisse LE, Jaku E, Thiecke MJ, Voltolini-González D, Fritsen H, Bobeldijk S, Ter Braak TJ, Polder E, Postma NL, Bugiani M, Struijs EA, Verheijen M, Straat N, van der Sluis S, Thomas AA, Molenaar D, van der Knaap MS. 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.
  9. Bugallo R, Marlin E, Baltanás A, Toledo E, Ferrero R, Vinueza-Gavilanes R, Larrea L, Arrasate M, Aragón T. 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.
  10. Hosoi T, Kakimoto M, Tanaka K, Nomura J, Ozawa K. 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.
  11. Briggs DI, Defensor E, Memar Ardestani P, Yi B, Halpain M, Seabrook G, Shamloo M. 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.
  12. Johnson EC, Kang J. 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.
  13. Oliveira MM, Lourenco MV, Longo F, Kasica NP, Yang W, Ureta G, Ferreira DD, Mendonça PH, Bernales S, Ma T, De Felice FG, Klann E, Ferreira ST. 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.
  14. Zyryanova AF, Weis F, Faille A, Alard AA, Crespillo-Casado A, Sekine Y, Harding HP, Allen F, Parts L, Fromont C, Fischer PM, Warren AJ, Ron D. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science. 2018 Mar 30;359(6383):1533-1536. PubMed.
  15. Tsai JC, Miller-Vedam LE, Anand AA, Jaishankar P, Nguyen HC, Renslo AR, Frost A, Walter P. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science. 2018 Mar 30;359(6383) PubMed.
  16. Marintchev A, Ito T. 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. press release
  2. clinicaltrials.gov
  3. Hu et al., 2022
  4. Zhang et al., 2022

Further Reading

Papers

  1. Huang TC, Luo L, Jiang SH, Chen C, He HY, Liang CF, Li WS, Wang H, Zhu L, Wang K, Guo Y. 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. Xu H, Bensalel J, Capobianco E, Lu ML, Wei J. 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. Hao Q, Heo JM, Nocek BP, Hicks KG, Stoll VS, Remarcik C, Hackett S, LeBon L, Jain R, Eaton D, Rutter J, Wong YL, Sidrauski C. Sugar phosphate activation of the stress sensor eIF2B. Nat Commun. 2021 Jun 8;12(1):3440. PubMed.