An adaptive, randomized, double-blind, placebo-controlled, single and multiple ascending dose study to examine the safety, tolerability, pharmacokinetics, pharmacodynamics and food effect of RGH-338 in healthy male volunteers.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that is
typically recognized during the first 2-3 years of life but may not become
fully manifested until social demands exceed limited capacities or may be
masked by learned strategies in later life. The core symptoms of ASD include
impaired socio-communicational and social interaction skills as well as
repetitive behaviour and restricted thinking.

Recent human imaging data in ASD demonstrate reduced GABA-ergic
neurotransmission with preservation normal gamma-aminobutyric acid (GABA)
levels2. This is most likely the functional consequence of reduced GABA
receptor expression despite a seemingly conserved GABA production. Under such
conditions, a positive allosteric modulation (PAM) approach where a molecular
partner (endogenous GABA) is needed for enhancing receptor activation is
expected to boost GABA-ergic neurotransmission, and as a consequence, may
reduce ASD-related symptoms. Specifically, a number of clinical, post mortem,
and preclinical findings suggest that stimulation of the GABAB receptor may be
relevant for treatment of the core symptoms of ASD.

The novel proprietary drug candidate RGH-338 is a potent, orally active and
selective PAM of the GABAB receptor discovered and developed at Gedeon Richter
Plc. for the treatment of ASD. RGH-338 has nanomolar affinity to a PAM binding
site of the human recombinant and rat native GABAB receptors.
RGH-338 showed significant improvement in several endpoints of social behavior
including social play, social approach-avoidance, and social recognition memory
at the dose of 0.05 mg/kg and above in the prenatal valproic acid (VPA) model,
a widely accepted disease model of ASD.

The results of preclinical studies suggest that RGH-338 has the potential to
effectively alleviate the socio-communicational deficits, together with some of
the associated symptoms of individuals with ASD with a satisfactory safety
profile. All these data together support to proceed to investigation of the
compound in humans. Additionally, enhancing GABA receptor function may have
therapeutic benefit in treating other conditions, such as chronic pain.

To investigate the safety and tolerability, and to characterise the
pharmacokinetics (PK) of RGH-338 in healthy subjects

The study will be conducted in three parts in healthy male participants:Part 1
SAD, Part 2 Food Effect, and Part 3 MAD.
Part 1 will evaluate single-ascending doses (SAD) of RGH-338 following an
overnight fast using a single-dose, double-blind, randomized,
placebo-controlled, dose-escalating design.
Part 2 will be an open-label, randomized, two-way crossover study to assess the
effect of food on RGH-338 pharmacokinetics. Part 2 is intended to start
following review of sufficient interim safety, tolerability, pharmacokinetic
and pharmacodynamic data from Part 1. All subjects will receive one dose of RGH
338 after an overnight fast and another dose of RGH 338 after consumption of a
high-fat breakfast, on two different occasions separated by a washout period of
at least 2 weeks (or 5 times the half-life of RGH-338 determined in Part 1,
whichever is longer.).
Part 3 will evaluate multiple-ascending doses of RGH-338 in healthy male
volunteers.

RGH-338 or placebo (oral tablets) , starting dose of 0.05 mg in cohort 1 of
Part 1, subsequent dose levels are to be determined following satisfactory
review of the safety, tolerability, pharmacodynamic and pharmacokinetic data
from previous cohorts.

This phase 1 trial has been designed to mitigate the known risks associated
with GABA potentiators as a class in general and the potential risks based on
the nonclinical toxicity data RGH- 338 in particular. As this trial will be
conducted in healthy male subjects, there is no expected clinical benefit to
trial participants. The principal mitigations for these potential risks include
the maintenance of an appropriate safety margin based on nonclinical study drug
exposure, appropriate selection of the trial population, prespecified safety
monitoring procedures, and the selection of the trial facility, where close
monitoring can be performed and rapid institution of appropriate care canbe
given. The potential risks associated with GABAB receptor potentiators as a
class and the potential risk based on nonclinical toxicity data can be
monitored clinically and/or with laboratory tests and have been considered when
determining the stopping rules for this clinical trial.

In addition to the potential risks associated with study drug administration,
there is minimal risk associated with trial procedures including scheduled,
periodic phlebotomy (limited to < 500 mL), pain tests and non-invasive
procedures including vital sign assessments, electrocardiograms (ECGs), and PD
assessments. Overall, the benefit-risk profile is considered appropriate for
this trial.