A double-blind randomized placebo-controlled single and multiple ascending doses study of the safety and tolerability, pharmacokinetics (including bioavailability comparison and food effect) and pharmacodynamics of oral BMS-986251 administration in healthy subjects, with efficacy assessment of multiple doses in patients with moderate-to-severe psoriasis

BMS-986251 is a new compound that may eventually be used for the treatment of
psoriasis and other (auto)immune disorders. In this type of disorder the immune
system is overactive. BMS-986251 binds within cells in the body to a protein
called ROR-gamma-t. This protein plays an important role in activating immune
reactions. One part of these immune reactions is an increased production of
specific signaling proteins such as interleukins. By binding to ROR-gamma-t,
BMS-986251 is able to counteract the effects of this protein. By doing so
BMS-986251 may decrease the production of interleukins (among others).
Experience with antibodies against interleukins have shown that by interfering
with these interleukins a good clinical result can be obtained in immune
disorders such as psoriasis and rheumatoid arthritis. BMS-986251 can be taken
by mouth, which is an important advantage over other treatments for the same
diseases.

The purpose of Part A of this study is to investigate how safe the new compound
BMS 986251 is when it is administered as a single dose to healthy subjects.

The purpose of Part B of this study is to investigate how safe the new compound
BMS 986251 is when it is administered as multiple doses to healthy subjects.

BMS 986251 has not been administered to humans before.

It will also be investigated how quickly and to what extent BMS-986251 is
absorbed and eliminated from the body (this is called pharmacokinetics). In one
of the groups of Part A, it will also be investigated what the pharmacokinetics
of BMS 986251 are when it is administered in another dosage form and whether
this will be influenced by food. In addition, in all parts of the study, the
effect of BMS 986251 on the body will be investigated (this is called
pharmacodynamics).

The effects of BMS-986251 will be compared to the effects of a placebo.

Part A:

For Groups A1-A6
The actual study will consist of 1 period during which the volunteer will stay
in the research center in Groningen (location Martini Hospital) for 8 days (7
nights). Day 1 is the (first) day of administration of the study compound. The
volunteer is expected at the research center at 14:00 h in the afternoon prior
to the day of administration of the study compound. The volunteer will leave
the research center on Day 7 of the study. This will be followed by 2 days
during which you will visit the research center for a short visit. These short
visits will take place on Day 9 and Day 11, between 9 and 12 AM.

For Group A7
The actual study will consist of 3 periods during which the volunteer will stay
in the research center in Groningen (location Martini Hospital) for 8 days (7
nights). Day 1 of each period is the day of administration of the study
compound. The volunteer is expected at the research center at 14:00 h in the
afternoon prior to the day of administration of the study compound. In each
period, the volunteer will leave the research center on Day 7 of the study.
This will be followed by 2 days during which the volunteer will visit the
research center for a short visit. These short visits will take place on Day 9
and Day 11 of each period, between 9 and 12 AM. There will be at least 2 weeks
between each of the 3 study drug administrations.

Part B:

The actual study will consist of 1 period during which the volunteer will stay
in the research center in Groningen (location Martini Hospital) for 17 days (16
nights). Day 1 is the first day of administration of the study compound. The
volunteer is expected at the research center at 14:00 h in the afternoon prior
to the day of first administration of the study compound. The volunteer will
leave the research center on Day 16 of the study. This will be followed by 3
days during which the volunteer will visit the research center for a short
visit. These short visits will take place on Days 18, 20 and 24, between 9 and
12 AM.

Part A:

If the volunteer participate in Groups A1 to A6, the volunteer will be given
BMS-986251 or placebo once as a drink with a small volume (maximally
approximately 6 mL). After administration of the study compound, the volunteer
is required to drink a glass of water (240 mL).

If the volunteer participate in Group A7 (see below), the volunteer will be
given BMS-986251 3 times (once in each period). In this group all subjects will
receive BMS 986251 in all 3 periods (no placebo). Only if the volunteer
participate in Group A7 the volunteer will receive during the study 2 different
types of drinks, one of which is a clear solution (Period 1) and one of which
is a suspension (Period 2 and Period 3). After administration of the study
compound, the volunteer is required to drink a glass of water (240 mL).

All volunteers in Group A7 will receive the study compound once with a
standardized high-fat breakfast (Period 3) and twice after an overnight fast of
at least 10 hours as described above (Period 1 and Period 2). In Period 3 the
volunteer will receive a high-fat breakfast which has to be eaten at a specific
time and will have to be finished within 20 minutes. The entire breakfast must
be consumed

Group Day Period Treatment How often Condition
A1 1 1 BMS-986251 2 mg or placebo once fasting
A2 1 1 BMS-986251 6 mg or placebo once fasting
A3 1 1 BMS-986251 15 mg or placebo once fasting
A4 1 1 BMS-986251 30 mg or placebo once fasting
A5 1 1 BMS-986251 60 mg or placebo once fasting
A6 1 1 BMS-986251 120 mg or placebo once fasting
A7 1 1 BMS-986251 30 or 60 mg or placebo once fasting
1 2 BMS-986251 30 or 60 mg or placebo once fasting
1 3 BMS-986251 30 or 60 mg or placebo once high-fat breakfast

Part B:

The volunteer will be given BMS 986251 or placebo as a drink with a small
volume (maximally approximately 6 mL) on Days 1 to 14 of the study. After
administration of the study compound, he/she is required to drink a glass of
water (240 mL).

Group Days Treatment How often Condition
B1 1-14 BMS-986251 6 mg or placebo once daily fasting
B2 1-14 BMS-986251 x mg or placebo once daily fasting
B3 1-14 BMS-986251 y mg or placebo once daily fasting
B4 1-14 BMS-986251 60 mg or placebo once daily fasting

As BMS-986251 will be administered to humans for the first time in this study,
side effects of BMS-986251 in humans have not been reported to date. However,
BMS-986251 has been studied in animals. There were no findings related to
BMS-986251 in monkeys treated with oral doses up to 8 mg/kg/day for 2 weeks and
in rats treated with oral doses up to 150 mg/kg/day for 2 weeks, which were the
highest dose tested. In the animal studies in monkeys and rats, large intestine
inflammation was seen. However, the findings were minimal, in general fully
reversible and not associated with clinical signs. In the rat the large
intestine inflammation was persistent only in the highest dose group (150
mg/kg). This is a much higher dose than will be administered to humans.

Based on the mechanism of action of BMS-986251 and its possible effects on the
immune system, it is possible that the volunteer may be more susceptible to
infections during participation in the study. You will be closely monitored for
any signs and symptoms of infection.

Procedures: pain, minor bleeding, bruising, possible infection