Combination of Clenbuterol and Nadolol Formulations Show Positive Cognitive Impacts for Parkinson Disease

Anthony Ford, PhD

Presented at the Alzheimer’s Disease and Parkinson’s Disease (AD/PD’23) conference, held March 28 to April 1, 2023, new findings showed that a combination of CST-103, also known as clenbuterol, and CST-107, known as nadolol, improved performance in tests of cognition and was well tolerated among patients with PD with REM sleep behavior disorder (RBD).

CuraSen, the drug manufacturer for both candidates, also presented positive data on CST-2032, another beta-2 adrenoceptor (ß2-AR) agonist, in healthy volunteers and patients with mild cognitive impairment (MCI). The company has already initiated a phase 2a exploratory study with CST-2032/CST-107 and plans to initiate a phase 2 study in clenbuterol/nadolol later this year.

The phase 2 proof-of-concept study enrolled 25 patients with PD and RBD who were blinded to oral CST-103 or placebo for 2 weeks, with cognition evaluated by multiple measures including the Cambridge neuropsychological test automated battery (CANTAB). Locus coeruleus (LC) integrity, a primary source of forebrain noradrenaline and one of the earliest signs of pathology in neurodegenerative disorders, was quantified using neuromelanin-MRI. CST-107, a ß2 antagonist with negligible central nervous system absorption, was co-administered with CST-103 to inhibit known peripheral effects of ß2-AR agonists.

Results showed that on neuromelanin MRI, conducted in 18 of the 25 individuals, the median observed LC integrity in patients with PD and RBD were below those of previously measured age-matched healthy controls. After 1, 7 or 14 days of dosing with CST-103/CST-107, several cognitive domains witnessed improvement, most notably, statistically significant increases relative to placebo were observed in the number of words recalled immediately (1.12 words; P = .003) and 45 minutes (1.72 words; P = .003) after presentation of an 18-item word list.

"For the first time, we have been able to show improved outcomes in cognition and mood with adrenergic agonism in patients with neurodegenerative disease, by safely restoring a stimulus to the brain that is lost early in the pathologic process," Anthony Ford, PhD, chief executive officer, CuraSen Therapeutics, said in a statement. "With its strong safety profile and impressive effect sizes in key domains, we look forward to testing this fast-acting combination treatment in a longer-term study in Parkinson’s patients later this year."

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Clenbuterol is an established drug that has been used in pulmonology for years, while CST-2032 was discovered and developed at CuraSen, with properties providing the ability to differentiate and de-risk the 2 products in distinct neurodegenerative patient populations and outcome measures. The other study, a phase 1 trial, included 79 healthy volunteers and patients with MCI to assess the safety, pharmacokinectic and effects of CST-2032/nadolol on cognition and cerebral perfusion.

In the trial, single or multiple oral doses of CST-2032 or placebo were administered in cohorts of healthy adults aged 18-50 years (n = 67), 55-75 years (n = 8), or those with MCI (n = 4). All told, the therapy was considered safe and well tolerated, with reported adverse events mild-to-moderate in nature and transient. Increases in heart rate, and common AEs typical for ß2 agonists were reported and inhibited when CST-107 was added.

Additional findings showed that CST-2032, not CST-107, distributed efficiently into the CNS based on cerebrospinal fluid concentrations, consistent with tendencies toward increased regional cerebral perfusion, and cognitive benefit in older healthy participants. Specifically, regional cerebral perfusion was increased by 31% in the hippocampus of patients with MCI, and older healthy adults saw 8.8 fewer adjusted errors in Paired Associated Learning, and 24.25 msec faster average response time in the Reaction Time Index following 3 mg CST-2032.

REFERENCES
1. CuraSen Therapeutics to present phase 2 data showing rapid-onset cognition and mood benefit with CST-103/CST-107 (Clenbuterol/Nadolol) in Parkinson’s disease at the Alzheimer’s Disease and Parkinson’s Disease (AD/PD’23) conference. News release. March 30, 2023. Accessed March 30, 2023. https://www.biospace.com/article/releases/curasen-therapeutics-to-present-phase-2-data-showing-rapid-onset-cognition-and-mood-benefit-with-cst-103-cst-107-clenbuterol-nadolol-in-parkinson-s-disease-at-the-alzheimer-s-disease-and-parkinson-s-disease-ad-pd-23-conference/
2. Vargas GA. Effects of beta-2 adrenoceptor (AR) agonist on cognition in Parkinson’s disease patients with REM Sleep Behavior disorder (RBD). Presented at: 2023 AD/PD Conference. March 28 to April 1; Gothenburg, Sweden. Abstract 368
3. Lodeweyckx T. A phase 1 safety, pharmacokinectics, and pharmcodynamic study of CST-2032: a novel, selective, CNS penetrating beta-2 adrenoceptor agonist for the treatment of cognitive impairment. Presented at: 2023 AD/PD Conference. March 28 to April 1; Gothenburg, Sweden. Abstract 338