Anavex Life Sciences Corp. has announced full data results from the Phase 1 clinical trial of ANAVEX 2-73, the Company's lead investigational oral treatment for Alzheimer's, which has shown potential in preclinical studies to prevent, halt and/or reverse the course of the disease. Observed adverse events included moderate and reversible headache and dizziness, which is common in drugs that target central nervous system (CNS) conditions, including Alzheimer's. No serious side effects were reported in this randomized, double-blind, placebo-controlled study, there was no study discontinuation due to adverse events, ANAVEX 2-73 was found to be safe and well tolerated, and the results indicate a favorable pharmacokinetics profile. Findings from the Phase 1 clinical trial were presented at CNS Summit 2014 in Boca Raton, Florida. A Phase 2a clinical trial of ANAVEX 2-73 and ANAVEX PLUS, the combination of ANAVEX 2-73 and donepezil (Aricept®), is now underway.
"We are extremely encouraged by the strong safety profile of ANAVEX 2-73 as evidenced by the Phase 1 trial data. Treatment of Alzheimer's disease generally requires ongoing drug administration, which underscores the importance for any potential new drug to have a low side effect profile," said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. "Following recent regulatory approval to start a Phase 2a efficacy study of ANAVEX 2-73 in Alzheimer's patients, we are excited to advance our investigational compound as a potential treatment option for this devastating disease with high unmet medical needs."
The Phase 1 clinical trial was a randomized, double-blind, placebo-controlled study in 22 healthy male volunteers. The participants received single, ascending oral doses of ANAVEX 2-73 ranging from 1 mg to 60 mg. The primary objective of the trial was to evaluate safety and tolerability together with pharmacokinetic parameters.
Safety: No serious side effects were reported. There was no study discontinuation due to adverse events. No dose-limiting adverse events or lab abnormalities at doses of 1, 10, 30, 40 and 50mg were observed.
Tolerability: Maximum tolerated dose (MTD) of ANAVEX 2-73 was defined as 55mg. Observed adverse events at doses above the MTD included dizziness and headache, which were moderate in severity and reversible. These side effects are often seen with drugs that target CNS conditions, including Alzheimer's disease. Across all doses, there were no differences in blood pressure and resting heart rate. Analysis of electrocardiograms (ECG) did not reveal any dose-related or time-dependent changes and the QT interval did not reveal any clinically significant changes. Additionally, no sign could be detected for any dose- or time-dependent changes for any of the hematology, biochemistry, and coagulation parameters.
Pharmacokinetics (PK): ANAVEX 2-73 was determined to be suitable for daily oral dosing based on its PK profile. 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. Both maximum plasma concentration (Cmax), which relates to absorption and distribution of the drug in the blood, and area under the plasma concentration-time curve (AUC), which represents the total drug exposure over time, showed dose-proportional linear increases for both ANAVEX 2-73 and its metabolite. The biological half-life (T1/2) for ANAVEX 2-73 was 8.56 hours and 28.74 hours for its metabolite.
The poster entitled "A Phase 1 Dose Escalation Study to Investigate Safety, Tolerability, and Pharmacokinetics of ANAVEX 2-73 in Healthy Male Subjects" was co-authored by Ole Voges and Ingo Weigmann both of ABX-CRO, Norman Bitterlich of Medizin & Service GmbH, Christoph Schindler of Clinical Research Center, and Christopher U. Missling, President and CEO of Anavex.
About ANAVEX 2-73 and ANAVEX PLUS
ANAVEX 2-73 is an orally available small molecule being investigated for the treatment of Alzheimer's disease. In addition to preclinical data indicating that ANAVEX 2-73 has the potential to prevent, halt and/or reverse the course of Alzheimer's disease, there was a highly encouraging synergistic effect observed between ANAVEX 2-73 and donepezil (Aricept®). The combined therapeutic, called ANAVEX PLUS, produced up to 80% greater reversal of memory loss in Alzheimer's disease models versus when the drugs were used individually.