Anavex Life Sciences Corp. has confirmed positive preclinical data for its lead drug candidate ANAVEX 2-73 for the potential treatment of epilepsy, validating it also as a prospective platform drug for the treatment of other neurodegenerative diseases beyond Alzheimer's. The data demonstrates significant improvement in the reduction of seizures relative to three generations of epilepsy drugs currently on the market, as well as significant synergy with each of these drugs. ANAVEX 2-73 has successfully completed a Phase 1 human clinical trial, in which it was shown to be safe, and is currently in a Phase 2a clinical trial for Alzheimer's disease.
"Efficacy is important in an anticonvulsant drug candidate. The key, however, to the next generation of epilepsy therapies is safety since most currently used epilepsy drugs require therapeutic drug monitoring given their significant differences in individuals' therapeutic dosages. Adding ANAVEX 2-73 to a current epilepsy drug regimen has the potential to increase safety by means of a dose reduction, while at the same time significantly improving anti-seizure efficacy. This data also suggests that ANAVEX 2-73 has the potential to become a platform drug for additional indications beyond Alzheimer's disease," said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. "Another important implication is a recent finding that Alzheimer's disease and seizures together seem to accelerate the worsening of symptoms, suggesting that the seizure disorder adds to the degenerative Alzheimer's disease pathology to exacerbate the cognitive decline. We are encouraged to explore this additional indication in parallel with our ongoing Phase 2a Alzheimer's study."
ANAVEX 2-73 for Epilepsy
To study the anticonvulsant effect of ANAVEX 2-73, three generations of epilepsy drug candidates were tested in multiple standard seizure-inducing animal models. The results noted below were following administration of ANAVEX 2-73, both alone and in combination with three drugs currently on the market.
On its own, ANAVEX 2-73 exhibited significant anticonvulsive dose-dependent action by providing almost complete protection from tonic seizures. In maximum electroshock (MES)-induced convulsions, it was observed that 30 mg/kg ANAVEX 2-73 alone was able to provide 90% protection.
ANAVEX 2-73 in combination with Ethosuximide (ETS) (Zarontin®), a first-generation antiepileptic drug, showed a strong synergistic effect in the MES test. In MES-induced convulsions, the combination of 10 mg/kg of ANAVEX 2-73 and 200 mg/kg of ETS provided 80% protection, while no protection at all was observed at the same dose ETS alone.
ANAVEX 2-73 in combination with the first line anti-epileptic drug Valproic acid (VPA) (Depakene®) displayed a strong synergistic effect. In the pentylenetetrazole (PTZ)-induced convulsion model, the combination of 10 mg/kg of ANAVEX 2-73 metabolite and 200 mg/kg of VPA showed 92% protection from tonic seizures, compared with modest 12.5% protection when 200 mg/kg of VPA was administered on its own. The combination with ANAVEX 2-73 also prolonged life during a seizure, compared to when VPA was used alone.
ANAVEX 2-73 in combination with the newer generation anti-epileptic drug gabapentin (Neurontin®) also showed a statistically strong effect in the reduction of seizures, compared to gabapentin alone. The combination of 5 mg/kg of ANAVEX 2-73 metabolite with 100 mg/kg of gabapentin resulted in 90% protection from tonic seizures as compared to 40% protection with 100 mg/kg of gabapentin alone in the MEZ test.
Anavex plans to release the full preclinical anti-seizure data for ANAVEX 2-73 at an upcoming scientific conference.
About ANAVEX 2-73
ANAVEX 2-73 is an orally available small molecule that targets sigma-1 and muscarinic receptors, which have shown in preclinical studies to reduce stress levels in the brain. ANAVEX 2-73 is currently undergoing a Phase 2a clinical trial for Alzheimer's disease. A Phase 1 trial was successfully completed and showed no safety issues or toxicity signals. A total of 22 healthy male volunteers received single ascending oral doses of ANAVEX 2-73 to determine the maximum tolerated dose and investigate what, if any, side effects may result. ANAVEX 2-73 was well tolerated even at the highest tested dose of 55 mg. Study participants did not exhibit any serious side effects, nor was there any study discontinuation due to adverse events. In addition, ANAVEX 2-73 demonstrated a pharmacokinetics (PK) profile to potentially support once-daily oral dosing. PK data revealed biotransformation of ANAVEX 2-73 to its main metabolite, which also actively targets sigma-1 and muscarinic receptors like its parent drug ANAVEX 2-73.