Novel Anti-Seizure Compound ANAVEX 2-73 a Sigma-1 Receptor Agonist in Multiple Seizure Models

Authors: C. Missling, N. Rebowe

Content: Rationale: Epilepsy is a serious brain disorder with symptoms that can be treated successfully in most patients with one or more anti-seizure drugs (ASDs). Despite the fact that drug therapy is effective for the majority of patients, significant unmet medical needs and treatment challenges remain. These include: drug-resistant epilepsy, adverse reactions and the development of comorbidities, including, depression, anxiety and compromised memory. Mortality in patients with epilepsy, including SUDEP, is three times the rate observed in the general population.[1] ANAVEX 2-73 (AV2-73) is a novel cholinergic and selective sigma-1 receptor agonist under development as potential agent for Alzheimer’s disease or dementia with neuroprotective properties. In this study, we investigated the anti-seizure effects of AV2-73 in multiple seizure models. [1] Ventola CL. Epilepsy Management. Pharmacy and Therapeutics. 2014; 39(11):776-792Methods: The anti-seizure effects of AV2-73 were investigated in the maximal electroshock seizure (MES) model, pentylenetetrazole (PTZ)- and semicarbazide (SCZ)-induced convulsion models. AV2-73 was also studied in combination with three generations of drugs currently on the market. Lastly, in order to test for potential side effects often seen with epilepsy drugs currently on the market, AV2-73 was assessed in preclinical depression and mobility models with the Porsolt swim test and open field test, as well as the chimney test.Results: ANAVEX 2-73 exhibited dose-dependent significant anti-convulsive action by providing almost complete to complete protection from tonic seizures in three established seizure models. 30 mg/kg AV2-73 provided between 85% and 90% seizure protection in MES and PTZ models, while 60 mg/kg AV2-73 had also a long-lasting effect with 100 % seizure protection after both 4 and 6 hours in the PTZ model, respectively. AV2-73 and its metabolite demonstrated robust synergistic effect in combination with three drugs currently on the market, Ethosuximide (ETS) (Zarontin®), Valproic acid (VPA) (Depakene®), and Gabapentin (Neurontin®). The combination of 10 mg/kg AV2-73 and 200 mg/kg ETS provided 80% protection in MES-induced convulsions, while no protection at all was observed at the same dose of ETS alone. In the (PTZ)-induced convulsion model, the combination of 10 mg/kg AV2-73 metabolite and 200 mg/kg VPA showed 92% protection from tonic seizures, compared with 12.5% protection when 200 mg/kg VPA was administered on its own. In the MES test, the combination of 5 mg/kg AV2-73 metabolite with 100 mg/kg gabapentin resulted in 90% protection from tonic seizures as compared to 40% protection with 100 mg/kg gabapentin alone.Conclusions: AV2-73 demonstrated convincing data in three well-established and predictive preclinical anti-seizure models with potentially more favorable side effect profile than currently marketed epilepsy drugs. The cognitive-enhancing features of AV2-73 might be a differentiating factor since seizures cause neuro-cognitive impairments, which can be worsened by current epilepsy medications.