Nadolol

Additional Phase 1 Data with CST-2032/CST-107 Reinforce Potential of Adrenoceptor Agonist Class of Drugs in Patients with Cognitive Impairment GOTHENBURG, Sweden--(BUSINESS WIRE)-- 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 pro 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 .

SAN CARLOS, Calif.--(BUSINESS WIRE)-- CuraSen Therapeutics, Inc., a privately held, clinical-stage biotechnology company, announced Phase 1 proof-of-principle data demonstrating that salbutamol, a drug approved to treat respiratory disease, significantly improved brain perfusion as measured by increased cerebral blood flow (CBF) in healthy subjects. Reductions in regional cerebral perfusion are an early sign of Alzheimer’s and other neurodegenerative diseases, and are associated with reduced cognition, attention and mood. This study, along with emerging data using other tool compounds and the company’s proprietary Phase 1 compound, CST-2032, lay the foundation for a potential new therapeutic class to treat neurodegenerative diseases as well as a more accessible biomarker to evaluate new therapies. Data were presented at the 15th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2021), held in a virtual format from March 9-14, 2021, by Gabriel Vargas, MD, PhD, chief medical officer of CuraSen Therapeutics. The presentation was included in a session entitled “Diagnostics, Biomarkers, Imaging in AD, PD and LBD2,” which featured a live discussion and Q&A on March 14th. In the Phase 1 study of 12 healthy subjects, CuraSen evaluated the effects of three doses of salbutamol (0.3, 0.9 and 1.8 mg), administered by intravenous infusion, on perfusion in the brain. Salbutamol, also known as albuterol, is an established beta-2 adrenoceptor agonist. Magnetic resonance imaging with arterial spin labeling (ASL), a non-invasive technique for monitoring brain perfusion, was undertaken before and after administration of salbutamol. Some subjects receiving the highest dose of 1.8 mg were also administered nadolol, a peripherally restricted beta blocker, to counteract associated side effects of salbutamol, which include increased heart rate, hyperglycemia, hypokalemia and tremors. Hemodynamic and glycemic monitoring were done in parallel. Results showed: -A statistically significant increase in cerebral blood flow in the thalamic region of the brain at the highest dose of 1.8 mg, from 40.0±6 to 50.6±9.4 ml/100g/min, representing an increase of 27.4% (P=0.0081). An increase in cerebral blood flow was not observed at the lower dose levels, despite substantial increases in heart rate and other systemic signals. -Dose-dependent increases in heart rate observed with salbutamol were eliminated by pre-treatment with nadolol (10-40 mg), along with side effects such as hyperglycemia, hypokalemia and tremor. In contrast, thalamic perfusion responses to salbutamol following pre-treatment with nadolol were preserved, demonstrating the independence of perfusion responses from hemodynamic effects alone. “Our objective in this study was to demonstrate that a beta-2 adrenoceptor agonist such as salbutamol can impact cell types in key regions of the brain associated with cognition and arousal,” said Dr. Vargas. “Even when controlling for hemodynamic effects of salbutamol with nadolol, these data show that we preserve the perfusion impact in the brain, an encouraging result that supports CuraSen’s clinical hypothesis. Perfusion and metabolic function progressively decline hand-in-hand in early phases of Alzheimer’s, and lead to clinical cognitive decline. Pharmacological restoration of these functions may lead to breakthrough therapeutics in many neurodegenerative diseases.” Patients developing neurodegenerative diseases experience a loss of critical neurons early in the process, causing adrenergic decline. The loss of neurons occurs in the locus coeruleus (LC), which is located in the brain stem and provides all the norepinephrine, or noradrenaline, to cortical and limbic brain regions. These signals from the LC are normally responsible for maintaining a person’s cognitive function, attentiveness and mood, as well as providing nutritional support to the neurons and to glial cells controlling inflammation and clearing protein debris. Symptoms of adrenergic decline include low attentiveness, loss of memory and mood dysfunction. These symptoms, similar across all neurodegenerative diseases, are poorly managed by existing therapeutic options and significantly impact quality of life for patients and caregivers. “By activating specific receptors in the brain that can substitute for the ‘lost’ or damaged norepinephrine signals, our goal is to restore diminished adrenergic activation, re-establish cognitive performance and arousal, and potentially halt or reverse the underlying disease pathology and progression,” said Anthony Ford, PhD, chief executive officer, CuraSen. “Importantly, with recent advancements in neuro-imaging techniques, we can now objectively measure the drug-target engagement in a non-invasive way, giving us confidence that our drug is hitting the intended CNS targets. This study underscores the impact that beta adrenoceptor agonism can impart on brain perfusion and function, and supports our ongoing clinical studies with CST-2032, a brain-permeant, adrenoceptor activator slated to enter a Phase 2 trial later this year.” Neuro-imaging techniques, such as magnetic resonance imaging with arterial spin labeling (ASL), along with FDG-PET imaging of glucose uptake, are also being used to diagnose neurodegenerative diseases, allowing for consistent measurements of changes in the brain over time. Ultimately, they may offer an important avenue to identify and stratify patients most likely to benefit from certain therapeutics. In addition to this preliminary study, CuraSen has initiated clinical studies using other beta agonists, or tool compounds, with more widespread brain penetration than salbutamol. These emerging data, which demonstrate a robust global increase in perfusion, as well as evidence of cognitive benefit, will be presented at future medical meetings. About CuraSen Therapeutics CuraSen is focused on the development of new treatments for a variety of 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 due to degeneration, and represent a unique approach in the field. The company is currently evaluating CST-2032, its first proprietary compound intended for the treatment of neurodegenerative disease, in a multi-part, Phase 1 clinical study. For more information, please visit .