Epilepsy is a brain disorder characterized by recurrent episodes of paroxysmal dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Advantx‘s lead candidate ADV127 has been designed precisely to bind a specific domain of Sigma-1 proteins in neurons and restore normal synaptic function.
Epilepsy is one of the most common neurological disorders and refers to a group of heterogeneous neurological conditions in which brain activity becomes abnormal, causing seizures or periods of unusual behavior, sensations, and sometimes loss of awareness. Epilepsy affects people of all ages and may be related to a brain injury, genetics, immune, brain structure, or metabolic cause. Over the past years, various genetic studies implied Sigma1R function (or dysfunction) is linked to multiple facets of the Epilepsy phenotype, including both seizures and non-seizure comorbidities.
Sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggests that sigma-1 receptors may play a role in the pathogenesis of developmental and epileptic encephalopathies (DEE) and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation. Control of calcium flux via Sigma1R-mediated mechanisms further helps to restore the balance between inhibitory and excitatory input to decrease seizure activity. Further research into the role of Sigma1R in DEE pathology is warranted, including its role in seizure control and in non-seizure outcomes associated with DEE.
Potential market for Advantx candidate in Epilepsy
Prevalence>5.4m people in US/EU/UK/JP
Treated Population>4.7m patients
Market Growthest. 3.7% CAGR
data from Globaldata
Different types of Epileptic Disorders
Types of epilepsy are classified by the types of seizures involved and are generally divided into two main groups: generalized and focal epilepsy. Generalized epileptic disorders are those consisting of seizures of generalized onset on both sides of the brain and causing a disturbance or loss of consciousness. Focal seizure disorders are those in which the predominant symptom is recurrent seizures affecting one hemisphere (half) of the brain.
ADULT FOCAL EPILEPSY
Focal onset seizures are the most common type of seizure in adults with epilepsy and are more likely to be refractory to treatment. Focal epilepsy can develop at any point in life but is more likely to develop in older adults. It is widely accepted that glutamate-mediated neuronal hyperexcitation causes focal seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major targets in focal epilepsy. Excessive brain excitability due to increased AMPA receptor expression at the seizure focus is the main cause of focal seizures in humans. Sigma-1 protein switches the phenotype of postsynaptic AMPARs by disrupting heteromeric receptor tetramerization. Because of its dual role in concurrently potentiating the number of NMDARs and CP-AMPARs at synapses, Sigma-1 has remarkable abilities in elevating intracellular Ca 2+ levels, being a pivotal AMPAR-interacting protein to control the subunit composition and Ca2+ permeability of postsynaptic AMPARs. In focal epileptic disorders, Sigma-1 agonists disrupts the α2δ-1-AMPAR complex fully restore the intracellular assembly and synaptic dominance of heteromeric GluA1/GluA2 receptors.
ADV127 is Advantx’s potential candidate for the treatment of Adult Focal Epilepsy.