Therapeutics

CST-2032

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Overview

Name: CST-2032
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Mild Cognitive Impairment, Parkinson's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Parkinson's Disease (Phase 2)
Company: CuraSen Therapeutics, Inc.

Background

CST-2032 is a proprietary, brain-penetrant β2-adrenergic receptor agonist. Like clenbuterol, CST-2032 activates norepinephrine receptors in cortical and limbic brain regions to compensate for the loss of this neurotransmitter in neurodegenerative diseases. The sole source of norepinephrine in the brain is the locus coeruleus, and those neurons die early in AD and PD (e.g., Jacobs et al., 2021).

Multiple lines of research implicate the loss of norepinephrine in the progression of AD and PD pathology and symptoms (e.g., Dec 2010 conference news). β2-adrenergic agonists were reported to suppress α-synuclein expression, show neuroprotective effects, and be associated epidemiologically with lower PD incidence (Sep 2017 news). β2 agonists were reported to show activity in mouse models of AD and ALS (Chai et al., 2017; Teng et al., 2006). The effects may stem from their anti-inflammatory actions (e.g., Evans et al., 2021; O’Neill et al., 2020).

No preclinical work is published on CST-2032 by name. CuraSen was founded by Stanford researchers who have published on a novel, brain permeable, β1-receptor partial agonist with anti-inflammatory, anti-amyloid, and pro-cognitive actions in mouse models of AD and Down’s syndrome (Yi et al., 2017; Ardestani et al., 2017; Salehi et al., 2009).

CuraSen has presented data at conferences that β2-receptor agonists increase regional blood flow in the brain, a marker of metabolic health. At the March 2021 AD/PD meeting, company scientists reported that salbutamol (albuterol) significantly increased thalamic perfusion measured by arterial spin labeling-MRI in 12 healthy people (press release). A second study, presented at CTAD 2021, used clenbuterol, which the company is developing under the name CST-103. In eight people with MCI or PD, a single clenbuterol dose significantly increased perfusion in the hippocampus, thalamus, and amygdala (see poster, press release). In both studies, administration of the non-brain penetrant β-blocker nadolol (aka CST-107) mostly eliminated adrenergic side effects like increased heart rate, tremor, and palpitations, but did not change clenbuterol’s effect on brain perfusion.

Findings

In September 2020, CuraSen began a first-in-human study in New Zealand and Belgium to assess the safety and pharmacokinetics of CST-2032 in 118 healthy subjects and people with PD or MCI (ANZCTR). Dosing began at 1 mg, with or without concomitant CST-107/nadolol. In addition to safety outcomes, the single- and multiple-ascending dose design also included neuroimaging for blood flow, autonomic function tests, and cognition. The trial was stopped early in January 2021, with data on 79 participants. According to information in the registry, the company stopped the study for business reasons, and there were no safety concerns with the drug. According to a presentation at the 2023 AD/PD conference, the drug increased regional brain blood flow, similar to clenbuterol. Adverse events were typical for β2 agonists and inhibited by naldolol.

A Phase 1 trial, set to begin in October 2021, was withdrawn for business reasons. The study had intended to enroll 16 people with mild cognitive impairment or PD.

A Phase 2 trial began in April 2022, recruiting 60 participants with mild dementia or MCI due to AD or PD. The crossover trial tests two weeks of 3 or 6 mg CST-2032 plus 3 mg CST-107/nadolol, and two weeks of placebo, against primary outcomes of adverse events, vital signs, and ECG. Secondary outcomes include CANTAB tests of attention, memory, and learning, and a test of facial emotional expression recognition. The study, at 15 sites in the U.S. and New Zealand, is expected to finish in November 2023.

For details on CST-2032 trials, see clinicaltrials.gov.

Last Updated: 07 Nov 2023

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References

News Citations

  1. San Diego: Subcortical Blues—Locus Ceruleus in AD, Neurodegeneration
  2. Asthma Drugs Suppress α-Synuclein, Reduce Parkinson’s Risk

Paper Citations

  1. Jacobs HI, Becker JA, Kwong K, Engels-Domínguez N, Prokopiou PC, Papp KV, Properzi M, Hampton OL, d'Oleire Uquillas F, Sanchez JS, Rentz DM, El Fakhri G, Normandin MD, Price JC, Bennett DA, Sperling RA, Johnson KA. In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer's disease pathology and cognitive decline. Sci Transl Med. 2021 Sep 22;13(612):eabj2511. PubMed.
  2. Chai GS, Wang YY, Zhu D, Yasheng A, Zhao P. Activation of β2-adrenergic receptor promotes dendrite ramification and spine generation in APP/PS1 mice. Neurosci Lett. 2017 Jan 1;636:158-164. Epub 2016 Nov 9 PubMed.
  3. Teng YD, Choi H, Huang W, Onario RC, Frontera WR, Snyder EY, Sabharwal S. Therapeutic effects of clenbuterol in a murine model of amyotrophic lateral sclerosis. Neurosci Lett. 2006 Apr 10-17;397(1-2):155-8. PubMed.
  4. Evans AK, Park HH, Saw NL, Singhal K, Ogawa G, Leib RD, Shamloo M. Age-related neuroinflammation and pathology in the locus coeruleus and hippocampus: beta-adrenergic antagonists exacerbate impairment of learning and memory in aged mice. Neurobiol Aging. 2021 Oct;106:241-256. Epub 2021 Jun 20 PubMed.
  5. O'Neill E, Yssel JD, McNamara C, Harkin A. Pharmacological targeting of β2 -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease. Br J Pharmacol. 2020 Jan;177(2):282-297. Epub 2019 Dec 12 PubMed.
  6. Yi B, Jahangir A, Evans AK, Briggs D, Ravina K, Ernest J, Farimani AB, Sun W, Rajadas J, Green M, Feinberg EN, Pande VS, Shamloo M. Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders. PLoS One. 2017;12(7):e0180319. Epub 2017 Jul 26 PubMed.
  7. Ardestani PM, Evans AK, Yi B, Nguyen T, Coutellier L, Shamloo M. Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist. Neuropharmacology. 2017 Apr;116:371-386. Epub 2017 Jan 13 PubMed.
  8. Salehi A, Faizi M, Colas D, Valletta J, Laguna J, Takimoto-Kimura R, Kleschevnikov A, Wagner SL, Aisen P, Shamloo M, Mobley WC. Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ra17. PubMed.

Other Citations

  1. clenbuterol

External Citations

  1. ANZCTR
  2. clinicaltrials.gov
  3. press release
  4. poster
  5. press release

Further Reading

Papers

  1. Gleeson LC, Ryan KJ, Griffin EW, Connor TJ, Harkin A. The β2-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity. Brain Behav Immun. 2010 Nov;24(8):1354-61. PubMed.
  2. Gleeson LC, Ryan KJ, Griffin EW, Connor TJ, Harkin A. The β2-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity. Brain Behav Immun. 2010 Nov;24(8):1354-61. PubMed.
  3. McNamee EN, Ryan KM, Griffin EW, González-Reyes RE, Ryan KJ, Harkin A, Connor TJ. Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: implications for neurodegeneration. Brain Behav Immun. 2010 May;24(4):660-71. PubMed.
  4. Ryan KJ, Griffin EW, Connor TJ. Complementary anti-inflammatory actions of the β₂-adrenoceptor agonist clenbuterol and the glucocorticoid dexamethasone in rat brain. J Neuroimmunol. 2011 Mar;232(1-2):209-16. PubMed.
  5. Riaz SS, Tomlinson DR. Clenbuterol stimulates neurotrophic support in streptozotocin-diabetic rats. Diabetes Obes Metab. 1999 Jan;1(1):43-51. PubMed.
  6. Evans AK, Ardestani PM, Yi B, Park HH, Lam RK, Shamloo M. Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease. Neurobiol Dis. 2020 Dec;146:105089. Epub 2020 Sep 22 PubMed.