Increased Cerebral Blood Flow is Correlated with Increased Neuronal Activity and Cognitive Efficacy Signals
Data Presented at the 14th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference
November 9, 2021 – Boston, MA and San Carlos, CA – CuraSen Therapeutics, Inc, a clinical-stage company developing novel small molecule therapies to treat neurodegenerative disease, announced data from a Phase 1b trial showing that patients with mild cognitive impairment or Parkinson’s disease experienced a significant increase in regional cerebral blood flow (rCBF) in key areas of the brain after being treated with CST-103, a beta-2 adrenoceptor agonist. Increased rCBF, a measure of tissue perfusion, occurs as a consequence of increased neuronal activity, and both are diminished by the noradrenergic decline that precedes cognitive deficits in neurodegenerative disease. Data were presented at the 14th Annual Clinical Trials on Alzheimer’s Disease (CTAD) conference, held in Boston and online November 9-12, 2021.
“We are excited to present the results of this study, confirming that CST-103 and potentially other proprietary beta-2 adrenergic agonists in the CuraSen pipeline offer a promising new strategy to improve cognitive deficits resulting from neurodegenerative disease,” said Anthony Ford, PhD, chief executive officer. “Beta-2 agonists like CST-103 activate multiple cell types in the brain, leading to both maintenance of cognitive function and restoration of complex homeostatic pathways critical for protecting brain health. This approach represents an important step towards improving daily activities for millions of poorly managed patients, and offers a longer term option for limiting and potentially reversing pathological decline.”
Patients with neurodegeneration experience a loss of neurons in the locus coeruleus (LC) very early in the disease process, decades before functional decline. The LC, known as a key orchestrator of arousal and brain health, delivers all adrenergic input to forebrain structures and activates beta-2 adrenoceptors essential for maintaining mood, memory, cognition, metabolic support, perfusion, inflammatory control and clearance of protein debris. When the LC declines, cerebral neuroprotection is undermined, triggering the pathological hallmarks of this progressive disease.
“By activating these excitatory adrenergic receptors with CST-103, we observed significant increases in cerebral perfusion in patients, especially in cognitively critical areas such as the hippocampus, thalamus and amygdala. Research has shown that increased cerebral perfusion correlates with increased neuronal activity and cognitive benefit. This phenomenon of ‘neurovascular coupling’ occurs in response to increased demand by metabolic activation of neurons, glial and other cell types,” said Gabriel Vargas, MD, PhD, chief medical officer, CuraSen. “The study also demonstrated that the common peripheral side effects of systemic administration of beta-2 agonists, such as increased heart rate, can be well managed by co-administering low doses of CST-107, a beta blocker, with CST-103.”
Study Objectives, Design and Results
The primary objectives of this study, conducted at KUMC, Leuven (Belgium), were to evaluate safety and cerebral blood flow effects of CST-103 and secondary objectives were to evaluate the effects of pre-administration of CST-107, a beta blocker with minimal brain penetration, on the central nervous system and peripheral effects of clenbuterol.
Eight patients with mild cognitive impairment or Parkinson’s disease were administered a single 80 µg (microgram) dose of CST-103. Following a one-week washout period, they received a second 80 µg dose of CST-103 with half of the patients (n=4) receiving 1 mg of CST-107 in addition to CST-103. Arterial spin-labeling magnetic resonance imaging was used to measure cerebral blood flow before and three hours after CST-103 administration.
Results showed that:
• Patients who received the initial dose of CST-103 showed significant increases in cerebral blood flow in multiple areas of the brain, including the hippocampus. (20.3%, p=0.001), thalamus (13.1%, p=0.004) and amygdala (14.3%, p=0.005).
• Increases in cerebral blood flow were consistent one week later in patients who received a second dose of CST-103 as monotherapy.
• Administration of CST-107 had minimal effects on the CST-103-induced regional changes in cerebral blood flow.
• CST-103 was generally safe and well tolerated, with side effects including increased heart rate, tremor and palpitations. These known side effects of beta-2 agonists were mostly eliminated when patients were pre-treated with 1 mg of CST-107.
The poster can be accessed here.
CuraSen is currently conducting a Phase 2 randomized, placebo-controlled, crossover study with CST-103, co-administered with CST-107, in 40 patients with mild cognitive impairment, Parkinson’s disease with rapid eye movement sleep disorder (RBD) or Lewy body dementia. The study, which includes multiple endpoints related to cognitive and executive function, mood, attentiveness, arousal and bioactivity, will help further identify patient populations with common core symptoms most likely to respond to treatment. Data are expected in the second quarter of 2022.
Additionally, the company is planning to initiate a Phase 2a trial with CST-2032, a novel beta-2 adrenoceptor agonist, in patients with mild cognitive impairment or mild dementia due to either Parkinson’s disease or Alzheimer’s disease in early 2022. The trial will take place at multiple sites throughout the U.S.
CuraSen is developing fixed-dose drug combinations of CST-103 and CST-107, and CST-2032 and CST-107 for ease of administration in commercial use.
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 evaluating CST-103 and CST-2032, beta-2 adrenoceptor agonists, in combination with CST-107, a beta blocker, in multiple Phase 1 and 2 clinical studies. The trials include patients with mild cognitive impairment, Parkinson’s disease with rapid eye movement sleep disorder (RBD), Lewy body dementia, and mild cognitive impairment or mild dementia due to either Parkinson’s or Alzheimer’s disease. For more information, please visit www.curasen.com.