Study of Sotatercept (ACE-011) in Subjects With Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 3
study groups, that will receive different doses of the study drug, based on when you join
this study. Patients who are already on treatment with ruxolitinib will be assigned to Group
3.

- Group 1 will receive sotatercept 1 time every 3 weeks (at a lower dose).

- Group 2 will receive will receive sotatercept 1 time every 3 weeks (at a higher dose).

- Group 3 will receive sotatercept 1 time every 3 weeks (at a lower dose).

Study Drug Administration:

Each cycle is 21 days.

You will receive sotatercept at the clinic as an injection under the skin on Day 1 of every
cycle. The injections will be given in the upper arm, abdomen, or thigh.

Study Visits:

On Day 1 of every cycle:

- You will have a physical exam, including measurement of your weight and vital signs
(blood pressure, breathing rate, temperature, and heart rate).

- Your spleen and/or liver will be measured by feeling your abdomen.

- You will be asked about any drugs you are taking and about recent blood transfusions you
may have had.

- You will also be asked about any new side effects or medical conditions you may have
experienced.

- Your performance status will be recorded.

- Blood (about 4 teaspoons) will be drawn for routine tests

- Urine will be collected for kidney function tests.

- You will complete a questionnaire that asks you about quality of life (for the first 6
cycles only and then 1 time every 3 cycles). It should take about 10 minutes to complete
the questionnaire.

Weekly during Cycle 1-5 only:

- Blood (about 2 teaspoons) will be drawn for routine tests.

- You will have vital signs measured on Day 1 of Week 3 (around Day 15 of Cycle 1).

On Day 1 of Cycle 6, and then every 6-24 cycles after that if the disease responds to
treatment, a bone marrow biopsy will be performed to check the status of the disease.

On Day 1 of Cycles 1-5, 7, 9, and 11, then every 6 cycles after that:

°Blood (about 2 teaspoons) will be drawn for antibody testing and pharmacokinetic (PK)
testing. Antibodies are created by the immune system and may attack foreign cells or
substances, such as the study drug. PK testing measures the amount of study drug in the body
at different time points.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Treatment Visit:

After your last dose of study drug, you will have an end-of-study visit and the following
tests and procedures will be performed:

- You will have a physical exam, including measurement of your weight and vital signs
(blood pressure, heart rate, breathing rate, and temperature) and your spleen and/or
liver will be measured by feeling your abdomen.

- Your performance status will be recorded.

- Blood (about 4 teaspoons) and urine will be collected for routine tests.

- You will be asked about any drugs you are taking and about recent blood transfusions you
may have had.

- You will also be asked about any new side effects or medical conditions you may have
experienced.

- You will complete the quality of life questionnaire.

Follow-up Visit:

About 1 month after your last dose of study drug, you will receive a telephone call from
someone on the study team. You will be asked about any drugs you are taking, any recent blood
transfusions you may have had, any new side effects or medical conditions you may have
experienced. This phone call should last about 10 minutes.

Inclusion Criteria:

1. MPN-associated myelofibrosis

2. Anemic patient OR RBC-transfusion-dependent patient

3. Equal to or greater than 18 years of age

4. ALT (SGPT) and AST (SGOT) equal to or less than 2.5x upper limit of normal (ULN), or
equal to or less than 4x ULN (if upon judgment of the treating physician, it is
believed to be due to extramedullary hematopoiesis [EMH] related to MF)

5. Direct bilirubin equal to or less than 1.5 x ULN; or equal to or less than 2x ULN (if
upon judgment of the treating physician, it is believed to be due to extramedullary
hematopoiesis related to MF)

6. Creatinine clearance equal to or more than 50 mL/min

7. Treatment-related toxicities from prior therapies must have resolved to Grade equal to
or less than 1

8. Women of childbearing potential and men must agree to using medically approved (i.e.,
mechanical or pharmacological) contraceptive measure for at least 112 days following
the last dose of sotatercept (ACE-011), Males must agree to use a latex condom or
non-latex condom NOT made of natural (animal) membrane during any sexual contact with
females of childbearing potential or a pregnant female while participating in the
study and for at least 112 days following the last dose of sotatercept (ACE-011), even
if he has a vasectomy.

9. For cohort of patients that are already on ruxolitinib therapy: on therapy with
ruxolitinib for at least for 6 months, and on stable dose for last 2 months, before
starting therapy with sotatercept

Exclusion Criteria:

1. Serious medical condition or psychiatric illness that would prevent, (as judged by the
treating physician) the subject from signing the informed consent form or any
condition including the presence of laboratory abnormalities, which places the subject
at unacceptable risk if he/she were to participate in the study or confounds the
ability to interpret data from the study

2. Pregnant or lactating female

3. Known positive for human immunodeficiency virus-1 (HIV-1), or active infection with
hepatitis-B or -C

4. Use of any MPN-associated myelofibrosis-directed therapy within 2 weeks prior to study
Day 1

5. Symptomatic congestive heart failure, unstable angina, or unstable cardiac arrhythmia

6. Prior sotatercept

7. Major surgery within 4 weeks prior to Day 1

8. Severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins
or excipients in the investigational product

9. Uncontrolled hypertension (systolic blood pressure [SBP] equal to or more than 140 or
diastolic blood pressure [DBP] equal to or more than 90).