A double-blind, placebo-controlled, randomized, single and multiple ascending dose study (including food effect, pH effect, and Japanese bridging Study) of the safety, pharmacokinetics, and exploratory pharmacodynamics of oral BMS-986278 administration in healthy participants

BMS-986278 is a new compound that may eventually be used for the treatment of
idiopathic pulmonary fibrosis (IPF). IPF is a chronic and fatal lung disease
with an unknown cause (idiopathic). It is characterized by worsening shortness
of breath and loss of lung function caused by scarring in the lungs. The
scarring and loss of long function get worse over time and most patients die of
respiratory failure.
There are two approved drugs that slow down this decline in some patients.
However, in addition to not being very effective, these drugs are not tolerated
well.
Abnormal wound healing is thought to contribute to fibrotic lung diseases like
IPF. Fibrosis is similar to scarring, but in case of fibrosis an excess scar
tissue is formed. The so-called lysophosphatidic acid (LPA) is involved in many
functions that regulate wound healing. LPA can regulate the transition from
normal scar tissue to abnormal wound repair (fibrosis).
BMS-986278 targets the LPA1 receptor, and blocks LPA from stimulating the
formation of fibrotic tissue. It is therefore expected that BMS-986278 will
help treating patients with IPF.

The purpose of this study is to investigate how safe the new compound
BMS-986278 is when it is administered as a single dose to healthy subjects.
BMS-986278 has not been administered to humans before. It has been previously
tested in the laboratory and on animals. BMS-986278 will be tested at various
dose levels.

It will also be investigated how quickly and to what extent BMS-986278 is
absorbed and eliminated from the body (this is called pharmacokinetics).
Additionally, it will also be investigated what the effect is of a high-fat
meal on the pharmacokinetics of BMS-986278.
The effect of famotidine on the pharmacokinetics of BMS-986278 will be
investigated when it is given shortly before BMS-986278. Famotidine is already
being used for the treatment of heartburn.

In addition, the effect of BMS-986278 on biomarkers will be investigated (this
is called pharmacodynamics). Biomarkers are substances in the body that can be
used as a sign of a specific disease, or condition or as a method to predict
how you respond to or tolerate treatment with BMS-986278.

The effects of BMS-986278 will be compared to the effects of a placebo. A
placebo is a medicine without any active ingredient. It is a *fake* medicine.

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 Martini Hospital for 6 days (5 nights).
This will be followed by 2 short visits which will take place on Day 7 and 11
between 10.00 and 12.00 hour.

For Group A7:
The actual study will consist of 3 periods during which you will stay in the
research center in Groningen Martini Hospital for 6 days (5 nights) each
period. After Period 1 and Period 2 there will also be a one short visit on Day
7. After Period 3 there will be short visits on Day 7 and Day 11. For the short
visits, you are expected at the research center between 10:00 and 12:00 hour.

Part B:
The actual study will consist of 1 period during which the volunteer will stay
in the research center in Groningen Martini Hospital for 19 days (18 nights).
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 Days
20 and 24 between 10.00 and 12.00 hour.

Part A:
BMS-986278 or placebo will be given in the morning as a suspension with a
volume between 6 mL and 50 mL. After administration of the study compound, the
vial will be rinsed three times with 5 or 10 mL, taken from 240 mL of
(tap)water, which the volunteer will also be required to drink. Then the
volunteer will be given the remainder of the 240 mL of water which he/she will
also have to drink.

For Groups A1 to A6
If the volunteer participate in Groups A1 to A6 (see below), he/she will be
given BMS-986278 or placebo once.
When BMS-986278 or placebo is administered, the volunteer should have fasted
for at least 10 hours (no eating and drinking). Also after administration of
the study compound, the volunteer will be required to fast for 4 additional
hours on Day 1. Then he/she will be served lunch. The volunteer will receive
dinner approximately 10 hours after administration of the study drug. All meals
on this day must be consumed entirely. On this day the volunteer is not allowed
to eat or drink between lunch and dinner. During fasting the volunteer is
allowed to drink water, exception during 2 hours before and 1 hour after
administration of the study compound.

For group A7:
If the volunteeer participate in Group A7 he/she will be given BMS-986278 3
times (once in each period). In Period 1 the volunteer will receive BMS-986278
without breakfast. In Period 2 the volunteer will receive famotidine 2 hours
before receiving BMS-986278, again without breakfast. Famotidine will be given
as a tablet with 240 mL of water. In Period 3 the volunteer will receive a high
fat breakfast 30 minutes before dosing with BMS-986278. This standardized high
fat breakfast has to be started exactly on time and will have to be finished
within 20 minutes.

Part B:
BMS-986278 or placebo will be given in the morning as a suspension with a
volume between 6 mL and 50 mL for 14 consecutive days. After administration of
the study compound, the vial will be rinsed three times with 5 or 10 mL, taken
from 240 mL of (tap)water, which the volunteer will also be required to drink.
Then the volunteer will be given the remainder of the 240 mL of water which
he/she will also have to drink.

BMS-986278 has been administered to humans for the first time in this study.
Single doses of BMS-986278 up to a dose level of 150 mg have been administered
to volunteers in previous cohorts in the current study. BMS-986278 was well
tolerated. Several volunteers had a transient lowering of blood pressure,
however they did not experience any symptoms. To study this further, if you
participate in Cohort A6, additional blood pressure measurements (while you are
standing up) will be included.
In addition, BMS-986278 has been studied in animals. In the studies performed
in animals few abnormalities have been observed. After multiple administrations
of high doses in monkeys mild elevations in some liver enzymes in the blood
were observed; and after very high doses given to rats an increase in the
weight of the liver and inflammation of the lining of the stomach were seen.
Abnormalities in bone formation were observed in monkeys after repeated dosing,
however this was only observed in monkeys that still had growing bones.

The study compound may also have adverse effects that are still unknown.

Procedures: pain, minor bleeding, bruising, possible infection

Group A7:
Side effects which might occur after use of the heart burn medicine famotidine
are given below. As this will be given only once in this study the chances on
the mentioned effects are judged to be minimal.

Common side effects are (occurring in less than 1 in 10 users): Headache,
dizziness, constipation, diarrhea.

Uncommon side effects are (occurring in less than 1 in 100 users): Dry mouth,
nausea, vomiting, abdominal discomforts or distension, flatulence, lack of
appetite, taste disorder, rash, itching (pruritus), fatigue.

Rare side effects (occurring in less in 1 in 1000 users):
Hypersensitivity reactions (anaphylaxis (allergic reactions), angioneurotic
edema (swelling of face and throat), bronchospasm (trouble breathing), liver
enzyme abnormalities, hepatitis cholestatic jaundice, urticaria (hives),
arthralgia (joint pain), increase in laboratory values (transaminases, gamma
GT, alkaline phosphatase, bilirubin).

Very rare side effects (occurring in less than 1 in 10,000 users):
Changes in blood: reduction in different type of blood cells (pancytopenia,
leucopenia, agranulocytosis) or platelets (thrombocytopenia), which can lead to
weakness, fatigue, sudden fever, sore throat, nose bleed, bruises. Reversible
psychological disturbances (including hallucinations, disorientation,
confusion, anxiety, disorders, agitation, depression, insomnia), reduced
libido, impotence, paraesthesia, drowsiness, convulsions, grand mal seizures
(particularly in patients with impaired renal function), alopecia,
Stevens-Johnson
Syndrome/toxic epidermal necrolysis, muscle cramps, chest tightness.