Therapeutics

AKST4290

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Overview

Name: AKST4290
Synonyms: ALK4290, lazucirnon
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Alkahest, Inc.

Background

AKST4290 is an antagonist of the G protein-coupled C-C chemokine receptor type 3 (CCR3). Blocking CCR3 is expected to have broad anti-inflammatory and immune-modulating effects. Alkahest acquired this molecule from Boehringer-Ingelheim; it is taken by mouth.

CCR3 inhibition is of interest for age-related and neurodegenerative diseases because it is the receptor for eotaxin, aka CCL11, a chemokine implicated in cognitive decline. Blood eotaxin levels increase with age, and it was identified as a critical component of old plasma that reduces hippocampal neurogenesis and promotes cognitive decline when given to young mice (Villeda et al., 2011). This chemokine freely enters the brain, and it has been shown to activate microglia (Parajuli et al., 2015). Plasma eotaxin is elevated in people with neurodegenerative diseases, and multiple studies have associated higher plasma concentrations with worse cognitive function in the elderly and in people with AD (e.g., Yang et al., 2021; Elkind et al., 2021; Bettcher et al., 2016).

Elevated plasma and brain eotaxin also have been documented in traumatic brain injury and psychiatric diseases (Hiskins et al., 2021; Cherry et al., 2017; Teixeira et al., 2018). 

Genetic studies implicate eotaxin in Alzheimer’s disease. Variants in CCL11 can delay the onset of familial AD by up to a decade, presumably by lowering eotaxin protein levels (Lalli et al., 2015; Guerreiro and Bras, 2015; Andrews et al., 2019).

In aged mice, an anti-CL11 antibody was reported to benefit spatial memory; in a Parkinson's model, a different anti-CL11 antibody, administered peripherally, reduced T cell infiltration into the substantia nigra and suppressed glial cell activation there (Scabia et al., 2021; Chandra et al., 2016).

Some preclinical data on AKST4290 was presented at conferences. The drug reportedly reversed eotaxin-induced memory deficits in healthy mice. In a model of Parkinson’s disease, six weeks of treatment was claimed to improve grip strength and balance, and reduce gliosis in the striatum. AKST4290 was reported to prevent microglial activation and cognitive decline in mice given chronic low-dose lipopolysaccharide to mimic chronic inflammation (Dec 2018 news).

Findings

From January 2020 to April 2021, Alkahest ran a Phase 2 trial in 110 people with Parkinson’s disease. Participants received 400 mg AKST4290 or placebo pills twice daily for 12 weeks. The primary outcome was change in motor function, measured by the MDS-UPRDS Part 3 motor examination while patients were between levodopa doses. Secondary measures included safety plus cognitive, functional, and motor symptom assessments while on levodopa. The trial, at 22 study locations in US and Europe, was supported in part by the Michael J Fox Foundation. No results have been made public. 

Other Phase 2 trials are ongoing for age-related macular degeneration, diabetic retinopathy, and the autoimmune skin condition bullous pemphigoid.

For details on AKST4290 trials, see clinicaltrials.gov.

Last Updated: 06 Oct 2021

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References

News Citations

  1. How Immune Cells From Blood Beget Aging in Brain

Paper Citations

  1. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Sep 1;477(7362):90-4. PubMed.
  2. Parajuli B, Horiuchi H, Mizuno T, Takeuchi H, Suzumura A. CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia. Glia. 2015 Dec;63(12):2274-84. Epub 2015 Jul 17 PubMed.
  3. Yang J, Kong C, Jia L, Li T, Quan M, Li Y, Lyu D, Li F, Jin H, Li Y, Wang Q, Jia J. Association of accelerated long-term forgetting and senescence-related blood-borne factors in asymptomatic individuals from families with autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2021 May 27;13(1):107. PubMed.
  4. Elkind MS, Moon M, Rundek T, Wright CB, Cheung K, Sacco RL, Hornig M. Immune markers are associated with cognitive performance in a multiethnic cohort: The Northern Manhattan Study. Brain Behav Immun. 2021 Oct;97:186-192. Epub 2021 Jul 25 PubMed.
  5. Bettcher BM, Fitch R, Wynn MJ, Lalli MA, Elofson J, Jastrzab L, Mitic L, Miller ZA, Rabinovici GD, Miller BL, Kao AW, Kosik KS, Kramer JH. MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes. Alzheimers Dement (Amst). 2016;3:91-7. Epub 2016 Jun 22 PubMed.
  6. Hiskens MI, Schneiders AG, Vella RK, Fenning AS. Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points. PLoS One. 2021;16(5):e0251315. Epub 2021 May 7 PubMed.
  7. Cherry JD, Stein TD, Tripodis Y, Alvarez VE, Huber BR, Au R, Kiernan PT, Daneshvar DH, Mez J, Solomon TM, Alosco ML, McKee AC. CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer's disease. PLoS One. 2017;12(9):e0185541. Epub 2017 Sep 26 PubMed.
  8. Teixeira AL, Gama CS, Rocha NP, Teixeira MM. Revisiting the Role of Eotaxin-1/CCL11 in Psychiatric Disorders. Front Psychiatry. 2018;9:241. Epub 2018 Jun 14 PubMed.
  9. Lalli MA, Bettcher BM, Arcila ML, Garcia G, Guzman C, Madrigal L, Ramirez L, Acosta-Uribe J, Baena A, Wojta KJ, Coppola G, Fitch R, de Both MD, Huentelman MJ, Reiman EM, Brunkow ME, Glusman G, Roach JC, Kao AW, Lopera F, Kosik KS. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease. Mol Psychiatry. 2015 Nov;20(11):1294-300. Epub 2015 Sep 1 PubMed.
  10. Guerreiro R, Bras J. The age factor in Alzheimer's disease. Genome Med. 2015 Oct 20;7:106. PubMed.
  11. Andrews SJ, Fulton-Howard B, Goate A. Protective Variants in Alzheimer's Disease. Curr Genet Med Rep. 2019 Mar;7(1):1-12. Epub 2019 Jan 24 PubMed.
  12. Scabia G, Testa G, Scali M, Del Turco S, Desiato G, Berardi N, Sale A, Matteoli M, Maffei L, Maffei M, Mainardi M, “Train the Brain” Consortium. Reduced ccl11/eotaxin mediates the beneficial effects of environmental stimulation on the aged hippocampus. Brain Behav Immun. 2021 Nov;98:234-244. Epub 2021 Aug 19 PubMed.
  13. Chandra G, Rangasamy SB, Roy A, Kordower JH, Pahan K. Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease. J Biol Chem. 2016 Jul 15;291(29):15267-81. Epub 2016 May 12 PubMed.

External Citations

  1. Michael J Fox Foundation
  2. clinicaltrials.gov

Further Reading

Papers

  1. Samanta A, Aziz AA, Jhingan M, Singh SR, Khanani AM, Chhablani J. Emerging Therapies in Neovascular Age-Related Macular Degeneration in 2020. Asia Pac J Ophthalmol (Phila). 2020 May-Jun;9(3):250-259. PubMed.
  2. Zhu C, Xu B, Sun X, Zhu Q, Sui Y. Targeting CCR3 to Reduce Amyloid-β Production, Tau Hyperphosphorylation, and Synaptic Loss in a Mouse Model of Alzheimer's Disease. Mol Neurobiol. 2016 Nov 23; PubMed.
  3. Ivanovska M, Abdi Z, Murdjeva M, Macedo D, Maes A, Maes M. CCL-11 or Eotaxin-1: An Immune Marker for Ageing and Accelerated Ageing in Neuro-Psychiatric Disorders. Pharmaceuticals (Basel). 2020 Sep 2;13(9) PubMed.
  4. Sui Y, Zhang Y, Dong C, Xu B, Sun X. The small molecular CCR3 antagonist YM344031 attenuates neurodegenerative pathologies and improves learning and memory performance in a mouse model of Alzheimer's disease. Brain Res. 2019 Sep 15;1719:1-10. Epub 2019 May 20 PubMed.
  5. Huber AK, Giles DA, Segal BM, Irani DN. An emerging role for eotaxins in neurodegenerative disease. Clin Immunol. 2016 Sep 21; PubMed.
  6. Scabia G, Testa G, Scali M, Del Turco S, Desiato G, Berardi N, Sale A, Matteoli M, Maffei L, Maffei M, Mainardi M, “Train the Brain” Consortium. Reduced ccl11/eotaxin mediates the beneficial effects of environmental stimulation on the aged hippocampus. Brain Behav Immun. 2021 Nov;98:234-244. Epub 2021 Aug 19 PubMed.
  7. Chandra G, Rangasamy SB, Roy A, Kordower JH, Pahan K. Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease. J Biol Chem. 2016 Jul 15;291(29):15267-81. Epub 2016 May 12 PubMed.
  8. Jorda A, Aldasoro M, Aldasoro C, Valles SL. Inflammatory Chemokines Expression Variations and Their Receptors in APP/PS1 Mice. J Alzheimers Dis. 2021;83(3):1051-1060. PubMed.