A randomized, double-blinded, placebo-controlled, single and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BMS-986259 in healthy participants

BMS-986259 is a new compound that may eventually be used for the treatment of
heart failure. Heart failure is characterized by the inability of the heart to
deliver a sufficient supply of blood and oxygen to the organs in the body.
Signs and symptoms may include shortness of breath, tiredness, a limited
ability to exercise, and leg swelling. Patients with heart failure may have a
history of high blood pressure and suffer from chronic kidney
disease. BMS-986259 mimics the hormone H2-relaxin which improves kidney
function and possibly decreases cardiac fibrosis (thickening of heart valves),
and could make BMS-986259 an attractive candidate as a long-term therapy for
patients with heart failure.

The purpose of this study is to investigate how safe the new compound
BMS-986259 is and how well it is tolerated when it is administered as single or
multiple doses to healthy volunteers. BMS-986259 has not been administered to
humans before. It has been previously tested in the laboratory and on animals.
BMS-986259 will be tested at various dose levels.

This study will be performed in approximately 132 healthy male and female
volunteers. The study will be performed in 3 parts: Part A and Part B in
healthy non-Japanese volunteers, and Part C in healthy Japanese volunteers.

It will also be investigated how quickly and to what extent BMS-986259 is
absorbed and eliminated from the body. In addition, the effect of BMS-986259 on
the body will be investigated.

The effects of BMS-986259 will be compared to the effects of a placebo.

Part A:
The study will consist of 1 period during which the volunteer will stay in the
research center for 6 days (5 nights) for Groups A1-A2, and 7 days (6 nights)
for Groups A3-A5.
Day 1 is the day of administration of the study compound. If the volunteers are
in Group A1 or A2, they are expected at the research center at 14:00 h in the
afternoon prior to the day of administration of the study compound. If the
volunteers are in Group A3, A4, or A5, they are expected at the research center
at 14:00 h in the afternoon of Day -2, which is 2 days prior to the
administration of the study compound. The volunteer will leave the research
center on Day 5 of the study. If the volunteers are in Group A6, they are
expected at the research center at 11:00 h in the morning of Day -2, which is 2
days prior to the administration of the study compound. The volunteer will
leave the research center on Day 7 of the study. If the volunteers are in Group
A7, they are expected at the research center at 11:00 h in the morning of Day
-2, which is 2 days prior to the administration of the study compound. The
volunteer will leave the research center on Day 5 of the study.

BMS-986259 or placebo will be given as an injection under the skin
(subcutaneous) of the belly. The number of injections may count up to 6 per
dosing, depending on the dose level.

Part B:
The actual study will consist of 1 period during which you will stay in the
research center for 21 days (20 nights).
Day 1 is the day of administration of the study compound. The volunteers are
expected at the research center at 14:00 h in the afternoon on Day -3, which is
3 days prior to the administration of the study compound. The volunteers will
leave the research center on Day 18 of the study.

BMS-986259 or placebo will be given as an injection under the skin
(subcutaneous) of the belly. The number of injections may count up to 6 per
dosing, depending on the dose level.

Part A:

BMS-986259 or placebo will be given as an injection under the skin
(subcutaneous) of the belly. The number of injections may count up to 6 per
dosing, depending on the dose level.

Whether the volunteer will receive BMS-986259 or placebo will be determined by
chance. Per group, 6 volunteers will receive BMS-986259 and 2 volunteers will
receive placebo. Neither the volunteer, nor the responsible doctor knows if
BMS-986259 or placebo will be administered.

For safety reasons, initially 2 volunteers will receive the study compound in
each group. One volunteer will receive BMS-986259, and 1 will receive placebo.
After administration, the safety and tolerability of the study compound in
these 2 volunteers will be closely monitored. If there are no concerns about
the safety and tolerability 48 hours after administration, then the remaining 6
volunteers (5 will receive BMS-986259 and 1 will receive placebo) in each group
will receive the study compound.

In Groups A3-A7, all volunteers will also receive p-aminohippurate as an
intravenous infusion (solution of the compound that will be administered
directly in a blood vessel) with a duration of 2 hours. P-aminohippurate is a
registered diagnostic agent that is given to investigate whether BMS-986259
affects renal blood flow.

Please refer to the table below to see the planned dose levels for each group.
The doses of Groups A2 to A7 can be adjusted based on the results of the
previous group(s).* However, the dose will not be higher than 30 mg. The dose
for the next group will only be increased if the lower dose of the previous
group was found to be well tolerated and in case of no objection by the Medical
Research Ethics Committee. The study will be discontinued if, in the opinion of
the investigator, unacceptable side effects appear.

Group Day Treatment * Formulation Number of injections How often

A1 1 BMS-986259 0.3 mg or placebo subcutaneous injection 1 once
A2 1 BMS-986259 1 mg or placebo subcutaneous injection 1 once
A3 -1,1 p-aminohippurate ** intravenous infusion once daily
1 BMS-986259 3 mg or placebo subcutaneous injection 1 once
A4 -1.1 p-aminohippurate ** intravenous infusion once daily
1 BMS-986259 5 mg or placebo subcutaneous injection 1 once
A5 -1.1 p-aminohippurate ** intravenous infusion once daily
1 BMS-986259 15 mg or placebo subcutaneous injection 3 once
A6 -1.1 p-aminohippurate ** intravenous infusion once daily
1 BMS-986259 30 mg or placebo subcutaneous injection 6 once
A7 -1.1 p-aminohippurate ** intravenous infusion once daily
1 BMS-986259 0.3 mg or placebo subcutaneous injection 1 once

* In case the dose level will be lower or higher than planned, the volunteer
will be informed verbally.
** The actual dose will depend on the volunteers body weight.

Part B:

BMS-986259 or placebo will be given as an injection under the skin
(subcutaneous) of the belly. The number of injections may count up to 6 per
dosing, depending on the dose level.

Whether the volunteer will receive BMS-986259 or placebo will be determined by
chance. Per group, 10 volunteers will receive BMS-986259 and 3 volunteers will
receive placebo. Neither the volunteer, nor the responsible doctor knows if
BMS-986259 or placebo will be administered.

Please refer to the table below to see the planned dose levels for each group.
The volunteer will receive BMS-986259 or placebo once daily from Day 1 up to
Day 14. Part B of the study will start after completion of Group A4. The doses
of Groups B1 to B4 can be adjusted based on the results of Part A and the
previous group(s).* However, the dose will not be higher than 30 mg. The dose
for the next group will only be increased if the lower dose of the previous
group was found to be well tolerated and in case of no objection by the Medical
Research Ethics Committee. The study will be discontinued if, in the opinion of
the investigator, unacceptable side effects appear.

All volunteers in Part B will also receive p-aminohippurate on Days -1, 1, and
13 as an intravenous infusion (solution of the compound that will be
administered directly in a blood vessel) with a duration of 2 hours.
P-aminohippurate is a registered diagnostic agent that is given to investigate
whether BMS-986259 affects renal blood flow.

All volunteers will also receive iohexol on Days -1, 2, and 12 as an
intravenous injection. Iohexol is a registered diagnostic agent that is given
before BMS-986259 administration to investigate whether BMS-986259 affects
renal function.

The planned dose levels for Part B are as follows:

Group Day Treatment* Formulation Number of injections How often

B1 -1, 1 p-aminohippurate** intravenous solution once daily
-1, 2, 12 iohexol, 5 mL containing 3.236 grams intravenous
solution once daily
13 p-aminohippurate** intravenous solution twice daily
1-14 BMS-986259 1 mg or placebo subcutaneous injection 1
once daily

B2 -1, 1 p-aminohippurate** intravenous solution once daily
-1, 2, 12 iohexol, 5 mL containing 3.236 grams intravenous
solution once daily
13 p-aminohippurate** intravenous solution twice daily
1-14 BMS-986259 3 mg or placebo subcutaneous injection 1
once daily

B3 -1, 1 p-aminohippurate** intravenous solution once daily
-1, 2, 12 iohexol, 5 mL containing 3.236 grams intravenous
solution once daily
13 p-aminohippurate** intravenous solution twice daily
1-14 BMS-986259 10 mg or placebo subcutaneous injection 2
once daily

B4 -1, 1 p-aminohippurate** intravenous solution once daily
-1, 2, 12 iohexol, 5 mL containing 3.236 grams intravenous
solution once daily
13 p-aminohippurate** intravenous solution twice daily
1-14 BMS-986259 30 mg or placebo subcutaneous injection 6
once daily

* In case the dose level will be lower or higher than planned, the volunteer
will be informed verbally.
** The actual dose will depend on the volunteers body weight.

As BMS-986259 will be administered to man for the first time in this study,
side effects of BMS-986259 in man have not been reported to date. However,
BMS-986259 has been studied extensively in the laboratory and in animals.

The dose which can be given first and the dose-increase regimen was calculated
based on the doses that did not cause side effects in various animal studies.

Throughout the study the volunteer will be under careful medical observation.
Any change in your state of health is monitored, evaluated and documented, and
any medically necessary action can be taken immediately. All adverse events
(including changes in laboratory values) are recorded until they return to
normal, are stable, or can be explained by other causes (concomitant illness or
medication) and the doctor no longer considers further examination necessary.
If necessary, your investigator will refer you to other diagnostic procedures
or treatments. The next higher dose will only be used if the previous dose was
tolerated well and there are no medically noticeable symptoms or changes in
medical parameters.

To date, only experience from animal studies on the risks of BMS-986259 is
available. However, another similar peptide H2-relaxin, serelaxin (Novartis),
was administered to healthy participants and over 4000 patients with heart
failure with no concerning safety findings or no clinical significant abnormal
laboratory findings. Most commonly observed was a drop in blood pressure
(hypotension) which were mostly asymptomatic (> 95%), and resolved
spontaneously without treatment (> 85%).

BMS-986259 was well tolerated in rats and monkeys using single and repeated
doses, which were considerably higher compared to the present study. Although a
mild change of an ECG parameter (QTc) was observed in monkeys at higher doses,
no signs of cardiovascular toxicity were observed at lower doses and the
volunteer will be closely monitored by ECG during treatment.

While BMS-986259 is considered to have a low risk of producing drug-induced
liver injury (DILI), there was no evidence of hepatotoxicity (toxic damage to
the liver) in any of the nonclinical studies so far. Due to its properties to
widen blood vessels, drop in blood pressure (hypotension) is an expected
adverse event.

Following treatment with BMS-986259 antibodies against BMS-986259 (anti-drug
antibodies, ADAs) may form. They may also respond to the endogenous hormone
relaxin, which circulates at higher levels during pregnancy. Although it is not
currently known whether ADAs will be formed, women of childbearing potential
are excluded from participation in the present study to avoid any risk to
future pregnancies.

This is the first time that the investigational product BMS-986259 is been used
in humans and therefore unexpected adverse events can also occur.
If new findings from this or other studies, including animal studies, emerge
that could potentially influence the decision of the volunteer to participate
in this study, the volunteer will be informed immediately.

As with other medicines, allergic reactions may occur after taking BMS-986259.
These can manifest themselves in skin redness, itching, fever, breathing
difficulties, circulatory problems and even life-threatening shock (massive
heart failure). Suitable medicines and equipment are available to treat these
symptoms. If the volunteer is allergic to medication or suffer from allergic
asthma, he/she is not allowed to participate in this study.

P-aminohippurate
To measure kidney blood flow, small doses of a substance called
p-aminohippurate are used. P-aminohippurate was previously approved by the FDA
and has been used to conduct studies of blood flow through the kidneys for over
60 years. As the prior manufacturer no longer produces p-aminohippurate, the
researchers have obtained permission from the FDA to use p-aminohippurate as an
investigational product in this study. Allergic reactions to p-aminohippurate
are rare but have been observed in people (itchy rash and/or breathing
problems). This reaction is usually not serious and can be easily reversed with
antihistamine medications. If the volunteer develop such symptoms, the study
will be discontinued, and he/she will be treated. Other side effects which the
volunteer may experience occur rarely (in less than 1 out 100 persons):
Abnormal heartbeat, chest pain, low blood pressure, dizziness, lightheadedness,
pain, blurred vision, headache, and bad taste in your mouth. In addition, the
volunteer may have a sensation of warmth, tingling or the desire to pee during
or shortly after receiving p-aminohippurate. For measurement of renal blood
flow, small doses of p-aminohippurate are used which minimize these risks of
these reactions.

Iohexol
Iohexol is a substance used to measure kidney blood flow. Allergic reactions to
iohexol have been observed in people allergic to iodine (itchy rash and/or
breathing problems). This reaction is usually not serious and can be easily
reversed with antihistamine medications. Nevertheless, we recommend that the
volunteer will not receive iohexol if he/she is known to be allergic to iodine
containing compounds used during X-ray examinations. Participants with
shellfish or iodine allergy will not be allowed to participate in this study
due to their higher risk of an allergic reaction. Other side effects which the
volunteer may experience occur rarely (in less than 1 out 100 persons):
Abnormal heartbeat, chest pain, low blood pressure, dizziness, lightheadedness,
pain, blurred vision, headache, and bad taste in the mouth.

Possible discomforts due to procedures
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising.

In total, we will take about 500 mL of blood from the volunteer.

To make a heart tracing, electrodes will be pasted at specific locations on the
arms, chest and legs. To monitor the heart rate, electrodes will be pasted at
specific locations on the chest and abdomen. Prolonged use of these electrodes
can cause skin irritation (rash and itching).

A sample for the coronavirus test will be taken from the back of the nose and
throat using a swab. Taking the sample only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
the throat may cause the volunteer to gag. When the sample is taken from the
back of the nose, the volunteer may experience a stinging sensation and your
eyes may become watery.