SA4503 is an orally active compound with high affinity and selectivity for the human sigma-1 receptor. SA4503 enhances neuroregeneration and facilitates the recovery of damaged CNS tissues from stress or ischemia-induced insults. In addition, SA4503 has neuromodulatory and cognitive enhancer activities. The combination of these mechanisms in SA4503 result in a unique product profile. SA4503 represents thus a novel opportunity for the therapy of several CNS disorders.
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| Neuronal plasticity - Stimulation of neurite outgrowth by SA4503 |
Indications
- Post Stroke Recovery, Traumatic Brain Injury, Spinal Cord Injury
- Major Depression
- Alzheimer's Disease, Cognitive Deficit in Schizophrenia
- Multiple Sclerosis
SA4503 and Stroke: A long time-window and novel neuroregenerative mechanism
Stroke is a serious medical condition with high incidence, associated with significant mortality and considerable morbidity, functional impairment and disability in survivors. SA4503 promotes neuroregeneration and enhances functional recovery after experimental stroke. SA4503 was effective when treatment was initiated two days after experimental stroke and administered for several weeks thereafter. The activation of the sigma-1 receptor by SA4503 has thus the potential to lead to a novel therapy of stroke with an extended time-window of treatment initiation. If proven effective in clinical studies, SA4503 will address a significant unmet medical need. Moreover, the activation of the sigma-1 receptor by SA4503 may lead to innovative therapies in additional indications that require the regeneration of damaged tissues since SA4503 was also efficacious in experimental models of traumatic brain injury and multiple sclerosis.
SA4503 is currently being investigated in a Phase-IIa study in post-stroke recovery.
SA4503 and Depression: Rapid on-set of action and novel neuroregenerative mechanism
Depression is one of the most common diseases of the central nervous system. All currently used anti-depressants target monoaminergic neurotransmitter mechanisms. The most prescribed drugs for treatment of depression belong to the classes of selective serotonin/norepinephrin reuptake inhibitors (SSRI / SNRI). Although these drugs have led to effective therapies for some depression patients their slow onset of action and side-effect profile leave significant room for novel drugs with different modes-of-action. Cortical and hippocampal shrinkage observed in this disorder may point to a structural component of the disease mechanism of depression. Therefore, novel treatment modalities enhancing regeneration of nervous tissue may play an important role future therapies of depression. SA4503 promotes survival and neurite outgrowth of primary cortical neurons and stimulates hippocampal neurogenesis. Consequently, SA4503 displayed efficacy in a comprehensive set of pre-clinical depression models. Most importantly, SA4503 was efficacious in a chronic mild stress model with a rapid onset of action. SA4503, if proven effective in human studies, may thus address the significant unmet medical need of rapid onset of anti-depressant action.
A Phase-IIa study with SA4503 for the treatment of depression is currently on-going in Europe.
Clinical Development
Four human Phase 1 studies, including one PET study, have been completed by the end of 2006. SA4503 entered into Phase 2a studies for both major depression and post-stroke recovery in Europe in 2007.
An international, multi-center, randomized, double-blind and placebo-controlled Phase 2a study of SA4503 in major depression was started in Europe in September 2007. This study is currently enrolling approximately 150 patients and assesses the efficacy and safety of SA4503 in this patient population.
A randomized, double-blind, placebo-controlled Phase 2a study in patients to be treated with SA4503 following acute ischemic stroke was started in Europe in late 2007 and is currently on-going. This study enrolls patients who experienced a stroke from 48 to 72 hours before randomization and assesses the safety of SA4503 in this patient population and the ability of this compound to restore motor function.
Positron Emission Tomography (PET) is a powerful tool to investigate specific ligand binding to receptors in the human brain. SA4503 is a PET ligand with very low non-specific binding to brain tissues. A clinical study using PET technology was performed to measure the receptor occupancy of SA4503 in the human brain at different doses. These data suggest that a relatively low dose of SA4503 fully occupies the human brain sigma-1 receptors and that a once daily oral administration of SA4503 would maintain significant receptor occupancy.
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