Safety, pharmacokinetics, and pharmacodynamics of Gln‐1062, a prodrug of galantamine

Abstract

Introduction: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine.

Methods: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine.

Results: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median T_max of 0.5 hour [range 0.5-1.0]). C_max and AUC_0-last increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance.

Discussion: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.

Keywords: Alzheimer's disease; cholinesterase inhibitor; dementia; galantamine; pharmacodynamics; pharmacokinetics; pharmacology; randomized controlled trial; safety; side effects.

Introduction: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine.

Methods: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine.

Results: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median T_max of 0.5 hour [range 0.5-1.0]). C_max and AUC_0-last increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance.

Discussion: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.

Keywords: Alzheimer's disease; cholinesterase inhibitor; dementia; galantamine; pharmacodynamics; pharmacokinetics; pharmacology; randomized controlled trial; safety; side effects.