SA4503 is an orally active, new chemical entity with high affinity for human and rodent sigma-1 receptors. This compound exhibits approximately 100-fold less affinity for sigma-2 receptors and has shown little affinity for other evaluated receptors, ion channels, or enzymes. 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 pharmacological effects in SA4503 present a unique product profile and SA4503 thus represents a novel opportunity for the therapy of several CNS disorders.
 |
 |
 |
| SA4503 stronly enhances neurite outgrowth in primary neuronal cultures. This activity is indicative of SA4503's ability to activate regenerative pathways in neurons. |
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. Although thrombolytic treatments for ischemic stroke can help reduce damage to brain tissue and improve outcome for some stroke patients, their use is limited by the very narrow window of time during which they must be administered to be effective. On the contrary, SA4503 has been shown to be effective in animal models when first administered 2 days after experimental stroke. Therefore, the activation of the sigma-1 receptor by SA4503 has the potential to lead to a novel therapy of stroke with an extended time-window of treatment initiation. SA4503 promotes neuroregeneration and enhances functional recovery after experimental stroke. If proven effective in clinical studies, SA4503 will address a significant unmet medical need.
The activation of the sigma-1 receptor by SA4503 may lead to innovative therapies in additional indications that require the regeneration of damaged tissues. SA4503 has shown efficacy in experimental models of traumatic brain injury and multiple sclerosis.
SA4503 is currently entering into 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 affecting 5 to 20% of the general population. All currently used anti-depressant drugs target monoaminergic transmitter 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 mode-of-actions. Depression may have a structural component to its disease mechanism as evidenced by cortical and hippocampal shrinkage observed in this disorder. Therefore, novel treatment modalities enhancing regeneration of nervous tissue may play an important role in the future of the therapy of depression. SA4503 has been shown to promote survival and neurite outgrowth of primary cortical neurons. Consequently, SA4503 displayed efficacy in a comprehensive set of pre-clinical depression models. Most importantly, SA4503 was efficacious in a chronic mild stress model and displayed a rapid onset of action. SA4503, if proven effective in human studies, may thus address the large unmet medical need of rapid anti-depressant action.
A Phase-IIa study with SA4503 for the treatment of depression has been approved in Europe.
Clinical Development
Four human Phase 1 studies, including one PET study, have been completed by the end of 2006. SA4503 will enter into Phase 2a studies for both major depression and post-stroke recovery in Europe in 2007.
An international, multi-center, double-blind and placebo-controlled Phase 2a study of SA4503 in major depression was approved in Europe in September 2007. This study enrolls approximately 150 patients and assesses the efficacy and safety of SA4503 in this patient population.
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 and to estimate the brain pharmacokinetics of this compound. 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.
|
