Mimopezil is a novel cholinesterase inhibitor, non-enzymatically transformed after administration into the active compound Huperzine A. Huperzine A is a quinolizidine alkaloid with potent and selective acetylcholinesterase inhibition properties, originally isolated from a Chinese club moss (Huperzia serrata or Lycopodium serrata). The plant has been used for centuries in China to treat disorders such as memory loss, schizophrenia and hypertension. Huperzine A's pharmacokinetic profile implies a two to four times a day dosing schedule. In the search for huperzine A derivatives adapted to clinical use, mimopezil was selected among over 100 other compounds for its optimal profile in potency, selectivity, and progressive biotransformation into huperzine A. These characteristics allowed to target a once daily oral dosing schedule and to develop an injectable, monthly sustained-release formulation.
Mimopezil is undergoing clinical development for the treatment of Alzheimer's Disease. The safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of oral mimopezil in humans have been assessed in 5 phase I studies. Efficacy, safety and tolerance of mimopezil administered orally (1.5mg and 2mg 1x/day) versus placebo and donepezil was assessed in a phase IIa study in patients with mild to moderate AD, with positive results on cognitive impairment. However, it is well-known that treatment by the oral route in AD patients is often associated with lack of compliance resulting in variable drug exposure and potentially reduced treatment effect. To overcome this drawback, a sustained-release formulation of mimopezil (implants for s.c. injection) was developed. In a phase I study, single or repeated administration of these implants to healthy volunteers at doses of 3 to 15mg monthly resulted in a prolonged release of huperzine A for up to four weeks. The safety and efficacy of mimopezil monthly implants versus daily oral administration of donepezil is currently being tested in a phase IIb, randomised, double-blind, double-dummy, active controlled study. A total of 158 patients have been enrolled at 27 sites over 3 continents. Preliminary results of this study will be available and disclosed at the conference.