Een dubbel-blind, gerandomizeerd, placebo-gecontrolleerd onderzoek om de veiligheid , verdraagbaarheid, pharmacokinetiek en pharmacodynamiek van enkelvoudige opklimmende doseringen van ASP2905 in gezonde jonge mannen te onderzoeken, inclusief een open-label gerandomizeerd onderzoek met twee perioden om de pharmacokinetiek onder nuchtere omstandigheden te vergelijken met die na het nuttigen van een vetrijk ontbijt

Alzheimer*s disease is associated with deficiencies in various
neurotransmitters, notably that in acetylcholine (ACh). In addition to
cholinergic hypofunction, other neurotransmitter deficits have been observed in
AD, including somatostatin, norepinephrine, serotonin, gamma-aminobutyric acid
and corticotropin-releasing factor .
ASP2905 is an orally available antagonist of BEC1 channels, which are partially
associated with GABAergic interneurons located in the various brain regions. In
vitro, the inhibition of BEC1 channels leads to decreased release of GABA,
which could subsequently influence the release of other neurotransmitters, such
as ACh, dopamine and glutamate. Ex vivo, ASP2905 has been shown to elevate the
release of dopamine and ACh in the PFC, both of which is thought to improve
cognition. In vivo, ASP2905 is efficacious in models of impaired cognition,
such as the scopolamine challenge and aged rat models. Therefore, AD and
cognitive symptoms of schizophrenia are a rational target disease for this new
molecule.
In addition to cognitive improvement, ASP2905 has been shown efficacious in
animal models for negative and positive symptoms of schizophrenia, suggesting
activity on the overall symptoms of schizophrenia.

Part 1 (SRD)
Primary:
to evaluate the safety, tolerability and pharmacokinetics of ascending single
doses of ASP2905 in healthy young males
Secondary:
- to obtain pilot data on the central nervous system activity of ASP2905
- if possible, to determine the maximal tolerated dose (MTD)


Part 2 (FE)
Primary:
to determine the effect of food on the pharmacokinetics of single oral doses of
ASP2905 in healthy young male subjects
Secondary:
to evaluate the safety and tolerability of single doses of ASP2905 under fasted
and fed conditions in healthy young male subjects

Part 1 (SRD):
a double-blind, randomized, sequential group, placebo-controlled, single dose
escalating study with six groups of eight healthy male subjects each (six verum
and two placebo) receiving a single oral dose of ASP2905 or placebo;

Part 2 (FE):
an open-label, randomized, two-period crossover study to evaluate the effect of
food on the pharmacokinetics of ASP2905 in one group of twelve healthy male
subjects receiving a single oral dose of ASP2905 or placebo in the fed state in
one period and a single oral dose of ASP2905 or placebo in the fasted state in
the other period

Medicatie: Part 1 (SRD) Group A: a single oral dose of 0.03 mg ASP2905 or placebo as an oral solution in the fasted state Group B: a single oral dose of 0.1 mg ASP2905 or placebo given as tablets in the fasted state Group C: a single oral dose of 0.3 mg ASP2905 or placebo given as tablets in the fasted state Group D: a single oral dose of 1 mg ASP2905 or placebo given as tablets in the fasted state Group E: a single oral dose of 3 mg ASP2905 or placebo given as tablets in the fasted state Group F: a single oral dose of 10 mg ASP2905 or placebo given as tablets in the fasted state Group G: a single oral dose of 20 mg ASP2905 or placebo given as tablets in the fasted state Part 2 (FE) period 1: a single oral dose of 10 mg ASP2905 or placebo given as tablets in the fasted state period 2: a single oral dose of 10 mg ASP2905 or placebo given as tablets in the fed state

Procedures: pain, light bleeding, heamatoma, possibly an infection
Medication: clonic convulsions, muscle weakness and behavioural or mood changes
and increased heart rate