Extended Access of Momelotinib for Subjects with Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)

Myeloproliferative neoplasm (MPN) is classified by the World Health
Organization (WHO) into seven categories that include polycythemia vera (PV),
essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic
myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic
eosinophilic leukemia, and MPN unclassifiable {Arber 2016}. Clonal
hematopoiesis is a shared feature of the MPNs, with CML characterized by the
presence of the Philadelphia chromosome, the product of a reciprocal
translocation between the long arms of chromosomes 9 and 22. This translocation
results in the formation of the BCR-ABL1 oncogene, the molecular pathogenetic
event of CML {Quintas-Cardama 2009}. Subsequently, a single acquired point
mutation in the Janus kinase (JAK) 2 gene at codon 617, resulting in the
substitution of valine for phenylalanine (JAK2V617F), was identified in
patients with PV (~96%), ET (~50%), and myelofibrosis (~50%) {Baxter 2005,
Hasselbalch 2012, James 2005, Kralovics 2005}. Positivity for the JAK2V617F
mutation results in constitutive activation of the downstream Signal Transducer
and Activator of Transcription (STAT), cytokine hypersensitivity, and formation
of erythropoietin-independent erythroid colonies {Bogani 2013}.

Since the discovery of the JAK2V617F mutation in patients with MPN, additional
mutations have been identified including signaling mutations that activate the
thrombopoietin receptor (MPL). Somatic mutations of CALR, the gene encoding
calreticulin, have also been identified in patients with wild type JAK2, as
well as mutations in epigenetic regulators of DNA methylation and chromatin
structure {Nangalia 2013}.

Myelofibrosis is associated with a characteristic marrow stroma pattern,
leukoerythroblastosis, and elevated levels of inflammatory cytokines. Patients
may experience anemia, leukopenia or leukocytosis, thrombocytopenia or
thrombocytosis, constitutional symptoms, and extramedullary hematopoiesis
resulting in hepatosplenomegaly{Harrison 2012}. In a proportion of patients,
myelofibrosis may transform into acute leukemia {Abdel-Wahab 2010}. Treatment
for PMF, and the phenotypically similar post-PV/ET MF, are principally focused
on symptom palliation, with allogeneic stem cell transplantation offering a
potential cure for select patients {Patriarca 2008}.

Momelotinib (MMB) is a small molecule JAK1 and JAK2 inhibitor, with good
selectivity over other JAK family kinases (JAK3, TYK2) and excellent
selectivity over other tyrosine and serine/threonine kinases. MMB also potently
inhibits bone morphogenic protein activin A receptor, type 1 (ACRV1) * mediated
hepcidin expression that stimulates erythropoiesis {Asshoff 2017}.

The primary objective of this study is to provide extended access to
momelotinib (MMB) and assess long-term safety in 4 cohorts of subjects who are
currently receiving treatment with MMB and have not experienced progression of
disease:

* Cohort 1: Study GS-US-352-0101, subjects with primary myelofibrosis (PMF) or
post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF)
* Cohort 2: Study GS-US-352-1214, subjects with PMF or post-PV/ET MF
* Cohort 3: Study GS-US-352-1154, subjects with PMF or post-PV/ET MF
* Cohort 4: Study SRA-MMB-301, subjects with PMF or post-PV/ET MF

The secondary objective is to assess overall survival (OS) and leukemia-free
survival (LFS) in all subjects

This is an open-label, extended-access, long-term safety and survival study for
subjects with PMF, post-PV MF, or post-ET MF whose disease has not progressed
and who have tolerated MMB treatment while enrolled in a previous MMB clinical
trial. Subjects in all cohorts continuing MMB treatment will discontinue MMB
tablets from the previous study and initiate MMB tablets in this study at the
same dose they were receiving in the previous study.

After the last dose of study drug, follow-up for assessment for survival and
leukemic transformation will be every 12 weeks for all subjects up to
approximately 7 years after the first dose in a prior study or until the study
ends, unless the subject dies, withdraws consent, or is lost to follow-up.

Additional subjects who discontinued treatment in study SRA-MMB-301 may enroll
for survival follow-up only.

MMB 100 mg, 150 mg, or 200 mg tablet orally self-administered once-daily.

MOMELOTINIB (MMB) COMMON ADVERSE EVENTS
Momelotinib is an experimental drug that is being studied in people with
myelofibrosis.
There are risks involved with taking MMB.
The information below is based on the reported side effects of momelotinib
which occurred in at least 5 out of 100 people during the first 24 weeks of
three randomized clinical trials involving approximately 450 people with
myelofibrosis.

Side effects and frequency in 448 patients:
* Infections (all types; including COVID-19) (40%)
* Diarrhea (23%)
* Low platelet count in the blood (21%)
* Nausea (17%)
* Low red blood cells (14%)
* Headache (13%)
* Dizziness (13%)
* Fatigue (tiredness) (12%)
* Abdominal pain (11%)
* Weakness (11%)
* Constipation (10%)
* Cough (10%)
* Nerve damage (numbness, tingling, pain, weakness) (9%)
* Fever (9%)
* Shortness of breath (9%)
* Itchy skin (9%)
* Vomiting (8%)
* Joint pain (8%)
* Weight loss (7%)
* Swelling in arm or leg (7%)
* Prickling or burning sensation (7%)
* Low white blood cell count (6%)
* Low blood pressure (6%)
* Bruising (6%)
* Decreased appetite (6%)
* Elevation of blood uric acid (6%)
* Elevation of blood creatinine (6%)
* Pain in hands or feet (5%)
* Nosebleed (5%)
* High blood pressure (5%)
* Some subjects have reported a feeling of dizziness or light-headedness,
flushing (reddening of the face), low blood pressure, nausea, or headache when
they take the very first dose of momelotinib (6.5% of subjects experienced this
adverse event in one randomized trial). This can occur up to 3 hours after the
first dose of study medication, and in most subjects resolves by the second day.
* Momelotinib may increase the likelihood of contracting COVID-19. Two of the
patients who got COVID-19 and died were in this extended access study and six
who died were in a different momelotinib trial that is ongoing. These subjects
contracted COVID-19 before COVID-19 vaccines were available. It is important
that patients follow their doctor*s advice on COVID-19 vaccination and
treatment.

If patients experience any of the following conditions (which occurred in
previous momelotinib study subjects at the frequency indicated below) they
should contact their study doctor immediately.
* High blood pressure (9%)
* Heart failure (i.e., the pumping chambers of the heart can not pump blood
efficiently throughout the body (<2%). Symptoms patients might feel if this
were to happen include: shortness of breath, swelling in their legs, feeling
tired or weak, feeling that their heart is beating fast, wheezing, and/or
coughing which could include white or pink blood-tinged phlegm.
* Jaundice (yellowing of the skin and eyes) or if patient contracts viral
hepatitis infection. In patients who have ever been infected with hepatitis B
virus, there is a risk that the virus can flare up during treatment with drugs
that affect the immune system, such as momelotinib. This could lead to liver
failure or even death.
* Pleural effusion (build-up of fluid between the layers of tissue that line
the lungs and chest cavity) (<1%). Symptoms patients might feel if this were to
happen include: chest pain, dry cough, fever, difficulty breathing when lying
down, shortness of breath, and/or difficulty taking deep breaths.
* Awkward, uncoordinated walking, double vision, and/or confusion.

Possibility of interaction with other medications:
Momelotinib may affect patient's body*s reaction to other medicines. In
particular, momelotinib may block the ability of a protein called BCRP (Breast
Cancer Resistance Protein) to transport some other medicines into and out of
cells.

Other drugs may affect the body of the patient's reaction to momelotinib. In
particular, medicines that are called CYP3A inducers could lead to lower blood
levels of momelotinib, and this can decrease the potential benefit to the
patient.

The patient's study doctor will inform him/her of any medications that he/she
should not be taking while they are taking the study drug.

UNKNOWN/UNEXPECTED RISKS AND DISCOMFORTS
There are adverse events that are not known or happen rarely when subjects take
this study drug. The patients will be told of any new information that might
cause them to change their mind about continuing to take part in this study.

As with any new drug, extra care has to be taken to monitor the side effects
that are not always obvious. If patient's feel any side effects or unusual
symptoms, they should notify their study doctor as soon as possible at the
phone number listed in the ICF.

PREGNANCY AND BREAST-FEEDING
Female participants:

Because the effects of the momelotinib on an unborn baby or a nursing infant
are not known, any female who is pregnant or breast feeding an infant will not
be enrolled in this study for treatment with momelotinib. Information from
animal studies suggests that momelotinib taken at doses resulting in similar or
higher exposures than the doses in this study may cause fetal death or reduced
body weight, or possible death to the baby through exposure to momelotinib
through breast milk. The female patient should not nurse a baby while taking
study treatment and for 30 days after the last dose of study drug because of
the risk that the baby might be exposed to momelotinib that comes out of her
body into the breast milk.

If a female patient becomes pregnant or suspects that she has become pregnant
while she is taking the study drug or within 30 days after the last dose of
study drug, she must stop taking the study drug and notify her study doctor
immediately. She will be discontinued from the study. The study doctor will
request to track her pregnancy and will report the pregnancy to the study
sponsor.

In addition, it is important to prevent pregnancy during the study. For this
study, a woman is considered to be of childbearing potential unless she meets
certain criteria that will be reviewed by the study doctor. If the patient is a
sexually active female of childbearing potential, it is required that she uses
highly effective contraceptive measures from the screening visit, while she is
taking the study drug, and for at least 30 days after the last dose of study
drug.

Highly effective contraceptive measures in this study are:
Complete abstinence from intercourse of reproductive potential. Abstinence is
an acceptable method of contraception only when it is in line with the
subject*s preferred and usual lifestyle; OR
* intrauterine devices (IUD) with a failure rate of < 1% per year
* tubal sterilization
* intrauterine hormone-releasing system (IUS) with a failure rate of <1% per
year
* vasectomy in the male partner (provided that the partner is the sole sexual
partner and had confirmation of surgical success 3 months after the procedure
* one barrier method [diaphragm with spermicide or cervical cap with
spermicide or male condom (with or without spermicide)] combined with one
hormonal method [oral contraceptive pill (estrogen and progesterone or
progesterone only) or transdermal contraceptive patch or injectable
progesterone or implants of levonorgestrel or contraceptive vaginal ring]
* Female subjects must also refrain from egg donation and in vitro
fertilization during treatment and until at least 30 days after the end of
relevant systemic exposure.

Other not yet identified adverse events could occur to the female patient, her
embryo or fetus should she become pregnant during the time she participates in
the study or after she has completed the study.

Information from animal studies suggests that MMB at doses that result in blood
levels approximately 40 fold higher than the recommended human dose causes
decreased female fertility.

Male participants:

Male participants should share this information with the their partner if it is
appropriate.

The effects of momelotinib are not known on the developing fetus (unborn baby)
in humans. It is very important that the patient does not cause others to
become pregnant and avoid sperm donation while he is taking the study drug and
for at least 90 days after the last dose of study drug. Not having sex is the
only certain way to prevent pregnancy.

If a male patient chooses to have sex with a female partner of childbearing
potential, he must use condoms during treatment and until 90 days following
discontinuation of the study drug. Additional contraception recommendations
should also be considered if the female partner is not pregnant. Male
participants should speak with their study doctor to determine the best method
of birth control for them and their female partner during this study.

If a male patient causes his female sex partner to become pregnant while he is
taking the study drug or within 90 days after his last dose of study drug, the
study drug may harm an unborn baby. If a male patient has a female partner who
becomes pregnant or suspects that she has become pregnant while he is in the
study or within 90 days after his last dose of study drug, the male patient
will be required to notify his study doctor immediately. As the risk to his
partner and unborn baby is not known, it is recommended for his female partner
to receive appropriate prenatal care. Upon agreement, the female partner will
be asked to sign a consent form to allow disclosure of medical information
related to pregnancy. The male patient's study doctor may need to disclose to
the female partner details of this study and him taking part in it. The study
sponsor and the study doctor will not be responsible for the costs related to
the pregnancy, delivery, or care of the child.

Information from animal studies also suggests that momelotinib at doses that
result in blood levels approximately 50 fold higher than the recommended human
dose causes reduced male fertility, sperm counts, and sperm movement.

WHAT ARE THE POSSIBLE BENEFITS OF THIS STUDY?
There is no guarantee that the patient will receive personal benefit from
taking part in this study. The study drugs are not expected to cure the
patient's Myelofibrosis. However, clinical research study such as this is a way
for doctors to provide extended access of MMB for patient who have not
experienced recurrence of disease while receiving treatment with MMB.