Abstracts

Rationale: Rationale: Huperzine A is a small naturally occurring alkaloid displaying potent and reversible cholinesterase inhibitory properties. Huperzine, extracted from Huperziaceae, has been used in Chinese medicine for hundreds of years to treat cognitive-related disorders. Due to a nearly 20 year growth time to reach full maturity, Huperziaceae as a source for huperzine production is not commercially viable. By utilizing a proprietary, validated synthetic route for huperzine production, Biscayne Pharmaceuticals is developing synthetic huperzine (BIS-001) as a treatment for adults with refractory focal epilepsy and for children with Dravet Syndrome, a disorder characterized by frequent intractable seizures and cognitive impairment. This synthetically prepared huperzine is identical to the natural extract in structure. Exhibiting a novel mechanism of action for seizure prevention, huperzine A displays potent seizure protection in several highly predictive animal seizure models, including complete seizure prevention in the SCN1A mutant mouse models of Dravet Syndrome. The current study sought to confirm BIS-001 displays similar levels of seizure protection to natural huperzine in a predictive animal seizure model.Methods: 6 Hz Seizure Model: The comparison of natural huperzine to BIS-001 occurred with the assistance of the Anticonvulsant Screening Program (ASP) through the NIH. Briefly, mice were pre-treated with either natural huperzine or BIS-001 15 min prior to 6 Hz corneal stimulation (32 mA). Following stimulation, mice underwent behavioral observation for up to four hours to identify signs of seizure activity.Results: Current studies comparing the anti-seizure capabilities of huperzine (99% pure natural huperzine) to BIS-001 (99% pure synthetic huperzine) demonstrates the same anti-seizure profile in the NIH ASP battery of anticonvulsant animal models. In the 6Hz (32 mA) animal seizure model in mice, huperzine demonstrated 25% seizure protection 1 hr after treatment at a dose of 0.3 mg/kg, and 100% seizure protection 1 hr after 1 mg/kg treatment. Comparatively, at a dose of 0.3 mg/kg 1 hr after dosing, BIS-001 elicited 50% seizure protection, and 100% with 1 mg/kg 1 hr after treatment. These studies comparing the anti-seizure activity of naturally sourced huperzine to BIS-001 indicate that BIS-001 induces seizure protection similar to its natural counterpart in predictive animal seizure models.Conclusions: The benefit/risk profile of BIS-001 is differentiated from current anti-epileptic medications, not only because it has the ability to significantly suppress seizures, but also because it has cognition-enhancing characteristics with an established use history which substantially minimizes the risk of new safety and tolerability issues.