A first-in-human, randomized, double-blind, placebo-controlled, single ascending dose and multiple ascending dose study to investigate the safety, tolerability, pharmacokinetics (including food effect), pharmacodynamics and proof of concept of CKD-506 in healthy subjects and inflammatory bowel disease patients

CKD-506 is a new investigational compound that may eventually be used for the
treatment of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA),
both inflammatory diseases. IBD is a chronic inflammatory disorder of the
gastrointestinal tract of which 2 main forms can be distinguished, namely
Crohn*s disease (CD) and ulcerative colitis (UC). Rheumatoid arthritis is a
long-lasting auto-immune disorder that primarily affects the joints.
Inflammation is characterized by increased blood supply and activation of
defense mechanisms, resulting in redness, swelling, heat and pain. The study
compound that will be researched in this study, CKD-506, inhibits a protein
(HDAC6) that is involved in abnormal immune responses seen in this type of
conditions. This is the first time that CKD-506 is being given to humans.

The purpose of the study is to investigate how safe CKD-506 is and how well
CKD-506 is tolerated (all study parts). It will also be investigated how
quickly and to what extent CKD-506 is absorbed by and eliminated from the body
(this is called pharmacokinetics) (all study parts). Further, the effect of
food on CKD-506 pharmacokinetics will be investigated (FE part only). In
addition, the effect of the compound on certain proteins in your blood will be
investigated (this is called pharmacodynamics) (all study parts).

SAD Part: (Groups 1, 2, 3, 5 and 6):
The study will consist of 1 period during which the volunteer will stay in the
clinical research center for 4 days (3 nights).
The volunteer will receive a single dose of CKD-506 or placebo as oral capsules
on Day 1 with 340 milliliters of water.

SAD + FE Part: (Group 4):
The study will consist of 2 periods during which the volunteer will stay in the
clinical research center for 4 days (3 nights) each period.
The volunteer will receive a single dose of CKD-506 or placebo as oral capsules
on Day 1 with 340 milliliters of water.

MAD Part: (Groups 7, 8 en 9):
The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center for 17 days (16 nights).
On Days 1 to 14, every day the volunteer will receive a dose of CKD-506 or
placebo as oral capsules with 340 milliliters of water.

Groups 1, 2, 3, 4 (only the first period), 5 and 6:
The SAD part of the study will consist of 1 study period (except for Group 4,
see below) during which you will receive either CKD-506 or placebo once under
fasted conditions. CKD-506 and placebo will be given in the form of oral
capsules.

Group 4 (only the second period):
When the volunteer is participating in Group 4, he/she are also participating
in the FE study part and will therefore participate in 2 study periods. In the
first period the volunteer will receive CKD-506 or placebo under fasted
conditions, whereas in the second period the volunteer will receive CKD-506 or
placebo after a breakfast. When the volunteer receives CKD-506 in the first
period, he/she will also receive CKD-506 in the second period. Likewise, when
the volunteer receives placebo in the first period, he/she will also receive
placebo in the second period.

Groups 7, 8 and 9:
The MAD part of the study will consist of 1 study period during which the
volunteer will receive either CKD-506 or placebo once every day for a period of
14 days. CKD-506 and placebo will be given in the form of oral capsules.

All potential drugs cause adverse effects; the extent to which this occurs
differs. As CKD-506 will be administered to man for the first time in this
study, adverse effects of CKD-506 in man have not been reported to date.

Animal studies have previously been conducted with CKD-506. Myelosuppression
was observed in monkeys that received CKD-506 at a very high dose of 70
milligrams per kilogram body weight per day every day for 4 weeks.
Myelosuppression means that bone marrow activity is decreased, which results in
decreased numbers of red and white blood cells and platelets. Lymphoid atrophy
(decrease of thymus weight and lymph follicles of the spleen and mesenteric
lymph nodes) was also observed in monkeys at the same dose of CKD-506. Further,
decreased values were seen in blood for total cholesterol, high-density
lipoprotein, low-density lipoprotein, protein and albumin. Also the coagulation
parameter activated partial thromboplastin time was prolonged; this may result
in bleeding.

With very high doses of 200 milligrams CKD-506 per kilogram body weight per day
every day for 4 weeks in rats, also myelosuppression was observed. Further,
anemia, lymphoid atrophy, degeneration and decrease in immature sperm cells,
decreased protein in blood, and decreased body weight gain and food consumption
was observed at this CKD-506 dose level in rats.

In animals, no effects were observed on the respiratory system or central
nervous system (up to 1000 milligrams CKD-506 per kilogram per day in rats), or
the cardiovascular system (up to 200 milligrams CKD-506 per kilogram per day in
monkeys.

Clinical studies have been conducted with other compounds that inhibit the same
family of proteins (HDAC proteins). These studies show that these compounds are
well tolerated. The side effects observed were nausea, vomiting and fatigue.
Also, transient and reversible low levels of platelets and neutrophils (a type
of white blood cell) were noted as well as anemia, and changes in liver enzymes.

Clinical studies have also been conducted with Ricolinostat, which is a HDAC6
inhibitor, similar to CKD-506. The most common side effects were mild cases of
fatigue, diarrhea and low levels of neutrophils.

Procedures: pain, minor bleeding, possible infection