Therapeutics

CST-103

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Overview

Name: CST-103
Synonyms: Clenbuterol
Chemical Name: (RS)-1-(4-Amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethan-1-ol
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Mild Cognitive Impairment, Parkinson's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Parkinson's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Phase 2)
Approved for: Asthma, in countries outside the U.S.

Background

CST-103 is CuraSen’s name for clenbuterol, a β2-adrenergic receptor agonist. Clenbuterol is related to common asthma drugs such as albuterol but is not approved for use in the U.S. It is abused by athletes and others for its steroid-like actions, to increase muscle mass, and for weight loss.

Its repurposing for neurological disorders stems from its ability to activate norepinephrine receptors in the brain, in an effort to compensate for the loss of this neurotransmitter in neurodegenerative diseases. The sole source of brain norepinephrine 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). Clenbuterol likewise reduced synucleinopathy, mitochondrial damage, and memory deficits in mice with post-surgical cognitive deficits (Li et al., 2021). In aged mice, the β2 agonist mabuterol decreased inflammation in the hippocampus and locus coeruleus, and improved learning and memory (Evans et al., 2021). A more recent study found clenbuterol had only a transient effect on α-synuclein mRNA, and no effect on protein levels in mice (Patterson et al., 2022). Clenbuterol was reported to reduce microglia activation, immune cell infiltration, and dopamine neuron degeneration in a mouse model of α-syn neurotoxicity (Torrente et al., 2023).

In the APP/PS1 mouse model of amyloid accumulation, clenbuterol was reported to lessen plaques, increase neurogenesis and synapse formation, and improve memory deficits (Chai et al., 2016; Chai et al., 2017). It prevented mitochondrial dysfunction and tau pathology after brain infusion of Aβ in mice (Chai et al., 2022). Clenbuterol slowed disease progression in a mouse model of amyotrophic lateral sclerosis (Teng et al., 2006). In a model of inflammation-induced Parkinson’s disease, it prevented dopamine neuron loss and loss of motor function (O’Neill et al., 2020).

Anti-inflammatory effects of clenbuterol have been reported in mouse and rat brain, as well as a rat excitotoxicity model  (McNamee et al., 2010; Ryan et al., 2011; Gleeson et al., 2010). A controlled-release formulation was reported to deliver clenbuterol for two weeks after intramuscular injection (Lin et al, 2023). It reduced inflammation and improved behavior in a rat model of aluminum-induced cognitive impairment.

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) increased thalamic perfusion measured by arterial spin labeling-MRI in 12 healthy people (press release). Co-administration of the peripherally restricted β-blocker nadolol largely eliminated adrenergic side effects of increased heart rate and tremor, but did not affect brain perfusion.

Findings

At the November 2021 CTAD conference, CuraSen reported findings of a Phase 1 study with clenbuterol. In eight people with MCI or PD, a single 80 microgram dose increased perfusion in the hippocampus, thalamus, and amygdala (see poster, press release). Consistent with earlier work, co-administration of nadolol (CST-107) mostly eliminated the adrenergic side effects of increased heart rate, tremor, and palpitations, but did not alter clenbuterol’s ability to increase brain perfusion.

In 2019-2020, CuraSen ran a Phase 2 trial in the Netherlands to evaluate central nervous system effects of single or multiple doses of clenbuterol in healthy people or people with PD. The primary outcome was the NeuroCart battery, which includes physiological and cognitive measures. Secondary outcomes included heart rate and blood pressure. A substudy evaluated the feasibility of smartwatch-based heart rate monitoring in 12 patients with PD; published results document average increases of 3.79 and 8.79 bpm during sleep or wake times, respectively (Elzinga et al., 2021).

In June 2021, CuraSen began a Phase 2 study in 38 patients with mild cognitive impairment or Parkinson’s disease with rapid-eye-movement sleep disorder (RBD). Run at sites in Australia, New Zealand, the U.K., and Belgium, the crossover study compared two weeks of clenbuterol plus nadolol to two weeks of placebo on outcomes related to cognitive and executive function, mood, attentiveness, arousal, and activity. At the March 2023 AD/PD conference in Gothenburg, Sweden, the company presented results, claiming rapid improvements in cognition and mood with a daily dose of 80 micrograms clenbuterol and 1 mg nadolol (press release). The regimen was well tolerated, with no serious adverse events and no side effects associated with peripheral activation of β2-ARs.

A Phase 2 study is planned to begin in June 2024, to evaluate the effects of clenbuterol plus nadolol on walking in people with Parkinson’s. The single-center trial at the University of Sydney will enroll 25 participants for a two-week crossover treatment of drug or placebo. The primary outcome will be a measure of gait freezing, i.e., the number of times participants interrupt normal foot progression while walking, based on analysis of video recordings. Other endpoints include cognitive tests and tracking of physical activity and sleep. The study will finish in March 2025.

Clenbuterol was tested in an open-label pilot trial to improve motor function in people with amyotrophic lateral sclerosis. It ended in March 2021, and results were published after peer review (Li et al., 2023). Clenbuterol was safe at the dose of 80 microgram twice daily, but 13 of 25 patients withdrew from the trial due to adverse events. Clenbuterol appeared to slow progression during treatment. In a previous study, clenbuterol was reported to have improved the efficacy of enzyme replacement therapy for the lysosome storage disorder Pompe disease (Koeberl et al., 2018).

CuraSen is also evaluating a related, proprietary β2-receptor agonist (see CST-2032).

For details on CST-103 trials, see clinicaltrials.gov.

Last Updated: 07 Nov 2023

Comments

    • User Profile Image Clemens Scherzer
      Harvard Medical School, Brigham and Women's Hospital
    • Posted:

    β2-adrenoreceptor agonists, such as clenbuterol, that regulate the α-synuclein gene, are protective in PD mouse models, and are associated with reduced risk of Parkinson's disease in real-world big data.

    References:

    Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease. Science. 2017 Sep 1;357(6354):891-898. PubMed.

    View all comments by Clemens Scherzer

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References

Therapeutics Citations

  1. CST-2032

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. Elzinga WO, Prins S, Borghans LG, Gal P, Vargas GA, Groeneveld GJ, Doll RJ. Detection of Clenbuterol-Induced Changes in Heart Rate Using At-Home Recorded Smartwatch Data: Randomized Controlled Trial. JMIR Form Res. 2021 Dec 30;5(12):e31890. PubMed.
  2. Li X, Koeberl DD, Lutz MW, Bedlack R. Clenbuterol Treatment Is Safe and Associated With Slowed Disease Progression in a Small Open-Label Trial in Patients With Amyotrophic Lateral Sclerosis. J Clin Neuromuscul Dis. 2023 Jun 1;24(4):214-221. PubMed.
  3. Koeberl DD, Case LE, Smith EC, Walters C, Han SO, Li Y, Chen W, Hornik CP, Huffman KM, Kraus WE, Thurberg BL, Corcoran DL, Bali D, Bursac N, Kishnani PS. Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease. Mol Ther. 2018 Sep 5;26(9):2304-2314. Epub 2018 Jul 5 PubMed.
  4. 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.
  5. Li Y, Yuan Y, Li Y, Han D, Liu T, Yang N, Mi X, Hong J, Liu K, Song Y, He J, Zhou Y, Han Y, Shi C, Yu S, Zou P, Guo X, Li Z. Inhibition of α-Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice. Oxid Med Cell Longev. 2021;2021:5572899. Epub 2021 May 28 PubMed.
  6. 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.
  7. Patterson JR, Hirst WD, Howe JW, Russell CP, Cole-Strauss A, Kemp CJ, Duffy MF, Lamp J, Umstead A, Kubik M, Stoll AC, Vega IE, Steece-Collier K, Chen Y, Campbell AC, Nezich CL, Glajch KE, Sortwell CE. Beta2-adrenoreceptor agonist clenbuterol produces transient decreases in alpha-synuclein mRNA but no long-term reduction in protein. NPJ Parkinsons Dis. 2022 May 24;8(1):61. PubMed.
  8. Torrente D, Su EJ, Schielke GP, Warnock M, Mann K, Lawrence DA. Opposing effects of β-2 and β-1 adrenergic receptor signaling on neuroinflammation and dopaminergic neuron survival in α-synuclein-mediated neurotoxicity. J Neuroinflammation. 2023 Mar 2;20(1):56. PubMed.
  9. Chai GS, Wang YY, Yasheng A, Zhao P. Beta 2-adrenergic receptor activation enhances neurogenesis in Alzheimer's disease mice. Neural Regen Res. 2016 Oct;11(10):1617-1624. PubMed.
  10. 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.
  11. Chai GS, Wu JJ, Gong J, Zhou JL, Jiang ZQ, Yi HY, Gu Y, Huang HH, Yao ZY, Zhang YQ, Zhao P, Nie YJ. Activation of β2-adrenergic Receptor Ameliorates Amyloid-β-induced Mitophagy Defects and Tau Pathology in Mice. Neuroscience. 2022 Nov 21;505:34-50. Epub 2022 Oct 5 PubMed.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Lin YW, Fang CH, Liang YJ, Yang CY, Kuo WT, Lin FH. Controlled release of Clenbuterol from a hydroxyapatite carrier for the treatment of Alzheimer's Disease. Biomater Res. 2023 Oct 5;27(1):98. PubMed.

External Citations

  1. poster
  2. press release
  3. Phase 2 trial
  4. press release
  5. clinicaltrials.gov
  6. press release

Further Reading

Papers

  1. Riaz SS, Tomlinson DR. Clenbuterol stimulates neurotrophic support in streptozotocin-diabetic rats. Diabetes Obes Metab. 1999 Jan;1(1):43-51. PubMed.
  2. 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.