Additional Phase 1 Data with CST-2032/CST-107 Reinforce Potential of Adrenoceptor Agonist Class of Drugs in Patients with Cognitive Impairment
March 30, 2023 – Gothenburg, Sweden – CuraSen Therapeutics, Inc., a clinical-stage company developing small molecule drugs to treat neurodegenerative symptoms and disease progression, announced that it will present Phase 2 clinical data showing improvements in cognition and mood in Parkinson’s disease patients treated with CST-103/CST-107, a novel combination therapy that restores adrenergic stimulus to the brain. Additionally, the company will present promising Phase 1 data with a second program, CST-2032/CST-107, in healthy participants and patients with mild cognitive impairment (MCI). Data will be shared in two oral presentations at the International Alzheimer’s Disease and Parkinson’s Disease (AD/PD’23) conference, being held March 28 – April 1, 2023, in Gothenburg, Sweden. Presentation details are below.
CST-103, also known as clenbuterol, and CST-2032 are oral, brain-permeant, beta2 adrenoceptor (β2-AR) agonists, and CST-107, known as nadolol, is a brain-sparing β-AR blocker. In these studies, clenbuterol and CST-2032 are co-administered with nadolol to minimize known peripheral cardiometabolic side effects of β2-AR agonists. The company is developing fixed-dose combinations for both drugs.
“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. 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,” said Anthony Ford, PhD, chief executive officer, CuraSen Therapeutics. “These data, coupled with promising Phase 1 results from our second program, CST-2032/nadolol, validate our novel approach to providing meaningful treatment options to neurodegenerative patients with high unmet needs.”
Clenbuterol is an established drug that has been used in pulmonology for decades, while CST-2032 was discovered and developed at CuraSen, with properties providing the ability to differentiate and de-risk the two products in distinct neurodegenerative patient populations and outcome measures.
Phase 2 Proof-of-Concept Study with Clenbuterol/Nadolol in Parkinson’s Disease
Parkinson’s disease is a progressive, neurodegenerative disease that is associated with slow movement, tremor, rigidity and imbalance, as well as non-motor complications such as cognitive impairment, depression, pain, dysautonomia and sleep disorders.The Phase 2 trial was an exploratory, randomized, double-blinded, crossover study in 25 patients with Parkinson’s disease with cognitive deficits. An additional 13 patients were enrolled with mild cognitive impairment without a PD diagnosis. Patients received either the once-daily clenbuterol (80 µg)/nadolol (1 mg) combination treatment or matched placebo, with 14 days treatment on each period and at least 14 days of washout between periods. All PD subjects had impaired cognition at baseline with evidence of impaired cerebral noradrenergic signaling, as assessed by neuromelanin MRI of the locus coeruleus. The study took place at sites in the UK, Australia, New Zealand and Belgium.
Results in PD patients showed:
- Statistically significant improvements in several quantitative test measures of episodic memory, attentiveness and depressive emotional bias in patients treated with clenbuterol/nadolol, with several effect sizes (Cohen’s d) in the range 0.3-0.6 which are predictive of clinically meaningful results in a larger, longer trial
- Rapid onset of drug effect – improvements observed as early as one day after treatment and in some cases, persisting beyond the two weeks of daily treatment
- No serious or severe adverse events attributed to study drug; most adverse events observed were mild
CuraSen’s next Phase 2 study with clenbuterol/nadolol is anticipated later this year and will enroll Parkinson’s patients with significant non-motor symptoms with a similar combination dosing plan in a 12-week parallel design.
Phase 1 Study with CST-2032/Nadolol in Mild Cognitive Impairment (MCI)
The Phase 1 study with CST-2032/nadolol included 79 healthy volunteers and patients with MCI. The study involved single-ascending and multiple-ascending dose cohorts.
Results showed that treatment with CST-2032/nadolol:
- Was safe and well tolerated
- Increased cerebral blood flow, a biomarker for target engagement, in brain regions involved in memory, alertness and arousal
- Led to performance changes in cognitive tasks associated with memory
- Offered clear guidance on optimal combination dose levels of each substance for Phase 2 assessment
Based on the strength of these data, CuraSen has initiated a Phase 2a exploratory, randomized, placebo-controlled, double-blinded crossover study with CST-2032/CST-107 in up to 60 patients with MCI or mild dementia due to either Alzheimer’s or Parkinson’s disease. The trial is taking place at 20 centers in the U.S. and New Zealand, with results anticipated later in 2023.
Oral Presentation Details
Abstract #: 368
Title: “Effects of a Beta-2 Adrenoceptor Agonist on Cognition in Parkinson’s Disease Patients with REM Sleep Behavior Disorder”
Date/Time: Sat, April 1, 3:15-3:30 pm CET; 9:15 am-9:30 am ET
Session: #4450 – Advances in PD and LBD Diagnosis and Drug Development
Presenter: Gabriel Vargas, MD, PhD, chief medical officer, CuraSen Therapeutics
Abstract #: 338
Title: “A Phase 1 Safety, Pharmacokinetics and Pharmacodynamic Study of CST-2032: A Novel, Selective, CNS Penetrating Beta-2 Adrenoceptor Agonist for the Treatment of Cognitive Impairment”
Date/Time: Sat, April 1, 6:25-6:40 pm CET; 12:25-12:40 pm ET
Session: #4540 – SOC Drugs and Other Targeted Therapies in AD
Presenter: Professor Thomas Lodeweyckx, MD, KU Leuven, Belgium
About CuraSen Therapeutics
CuraSen is developing novel treatments for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and other related orphan conditions. CuraSen’s drugs are designed to activate certain receptor populations in the brain to compensate for critical neuronal and glial functions that have otherwise been lost early in degeneration and represent a unique approach in the field, addressing core symptoms and the progression of pathology. The company is evaluating CST-103 and CST-2032, both selective β2-ARs agonists, in combination with CST-107, a β-AR blocker, in multiple Phase 2 clinical studies. For more information, please visit www.curasen.com.