A phase 1, first human exposure, single dose, double-blind, randomized, placebo controlled trial to assess the safety, tolerability, pharmacokinetics and pharmaco-dynamics after oral administration of Org 48775-0 in healthy male volunteers in fasted and fed state, in female healthy volunteers, and in rheumatoid arthritis patients with active disease while on methotrexate treatment.

Activation of the p38 mitogen activated protein kinase (MAPK) pathway plays a
crucial role in the production of the proinflammatory cytokines IL-1β and
TNF-α. Current approaches with biologicals that block the effect of both
cytokines are efficacious in both animal models and in the clinic for
auto-immune diseases.
Another therapeutic option would be the inhibition of MAP-kinase of which four
variants are known among which p38α is considered to be the most relevant
variant involved in inflammatory responses. It plays an important role in the
pro-inflammatory activation of e.g. monocytes and macrophages, lymphocytes,
neutrophils and endothelial cells. Many different stimuli can activate p38α
MAPK, including LPS and other bacterial products, cytokines, growth factors,
and stress signals such as heat shock, hypoxia, and ischemia/reperfusion. The
p38α MAPK positively regulates a variety of genes involved in inflammation. For
its broad pro-inflammatory role in several in vitro systems, inhibition of the
p38α pathway has been advocated as a novel therapeutic strategy for
inflammatory diseases such as RA.
Org 48775-0 is a potent and selective p38 kinase inhibitor that in addition may
be involved in reduction of pain, not solely as a result of reduction of
inflammation but also via direct interference of the mechanistic role of p38
kinase in pain signaling. As the pre-clinical experiments have not raised
safety concerns precluding administration of Org 48775-0 to humans, this
protocol describes the plan for the first study with the compound in humans.
This will concern healthy male volunteers, post-menopausal women and RA
patients who are given single doses, and healthy male volunteers in whom the
effect of food intake will be investigated.

Primary:
To assess the pharmacokinetics and effects of single oral doses of Org 48775-0
in healthy male volunteers, post-menopausal women and RA patients.
Secondary:
To study the influence of Org 48775-0 on the PK of MTX in RA patients
To explore gene expression and proteomics after administration of Org 48775-0
in the 3 populations

Randomised , placebo-controlled, double blind, dose-escalation interventional
trial

Healthy male volunteers: Single oral dose(s) of study drug in an escalating
dose design with randomised placebo
Healthy post-menopausal females: Single oral dose of study drug
Patients: Single oral dose of study drug

MAPkinase is essential in host defense and excessive and long-lasting
inhibition is associated with impaired host defense. In this trail this may
occur, but that is unlikely as the trial is designed such that excessive and
long-lasting inhibition of MAPkinase are unlikely to occur. This was achieved
by using not only classical ways to determine the starting dose but also the
MABEL approach using data on the in-vitro inhibition of the compound assessed
in human blood.
The drug is further potentially associated with phototoxicity and the subjects
are requested to avoid direct exposure to sunlight.
Because of the limits defined for MAPkinase inhibition (that are known to be
well tolerated by healthy subjects and patients) the risks are considered to be
limited. As CHDR is closely linked to LUMC, also in the case that problems
should occur, it is considered that these problems can be adequately managed.