A phase 1, open-label, non-randomized, 2-period, fixed sequence study to investigate the absorption, distribution, metabolism and excretion of 14C-PF-06651600 and to assess the absolute bioavailability and fraction absorbed of PF-06651600 in healthy male participants using a 14C-microtracer approach

PF-06651600 is an investigational compound because it is not approved for use
as a medication. PF-06651600 is a compound that may eventually be used for the
treatment of autoimmune and inflammatory diseases. In these diseases the immune
system (your body*s system that protects the body from foreign substances,
cells, and tissues) is dysregulated and attacks healthy cells in the body. This
overactive immune system can also result in inflammation (a part of the body
becomes reddened, swollen, hot, and often painful).

PF-06651600 is a, so called, Janus kinase 3 (JAK3) inhibitor. JAK3 is a protein
involved in the immune response. It is thought that by suppressing this kinase,
PF-06651600 will specifically target the inflammatory mechanisms involved in
inflammatory diseases such as ulcerative colitis, alopecia areata, rheumatoid
arthritis and vitiligo, while maintaining normal immune responses.

The purpose of this study is to investigate how quickly and to what extent
PF-06651600 is absorbed and eliminated from the body (this is called
pharmacokinetics). In this study doses of PF-06651600 labeled with very low
doses radioactive (14C) will be used. In this way PF-06651600 can be traced in
blood, urine, and feces.

This study will also investigate how safe the compound PF-06651600 is and how
well it is tolerated when it is administered to healthy volunteers. PF-06651600
has been administered to humans before. In addition, the taste of the oral
solution of PF-06651600 will be assessed.

The volunteer will be admitted to the research center 1 day before the
administration of study compound (Day -1). The actual study will consist of 2
periods. During Period 1 the volunteer will stay in the research center for a
minimum of 5 days (4 nights) and maximum of 15 days (14 nights). The second
period will start 16 days after administration of the study compound in the
first period, and the volunteer will stay in the research center for a maximum
of 8 days (7 nights).

In the Period 1 on Day 1 the volunteer will be given PF-06651600 with the
radioactive label as a drink of 240 mL. The volunteer will have to fill out a
taste assessment questionnaire immediately after drinking the solution with the
study compound, and again after 5, 10 and 20 minutes.

In Period 2 on Day 1 the volunteer will be given PF-06651600 without the
radioactive label as a drink of 240 mL, similar as in Period 1. About 30
minutes after the drink, the volunteer will receive PF-06651600 with
radioactive label as an intravenous infusion of 10 mL (solution of the compound
that will be administered directly in a blood vessel). The infusion will last
about 5 minutes.

In the Period 1 on Day 1 the volunteer will be given PF-06651600 with the
radioactive label as a drink of 240 mL. The volunteer will have to fill out a
taste assessment questionnaire immediately after drinking the solution with the
study compound, and again after 5, 10 and 20 minutes.

In Period 2 on Day 1 the volunteer will be given PF-06651600 without the
radioactive label as a drink of 240 mL, similar as in Period 1. About 30
minutes after the drink, the volunteer will receive PF-06651600 with
radioactive label as an intravenous infusion of 10 mL (solution of the compound
that will be administered directly in a blood vessel). The infusion will last
about 5 minutes.


Period 1 Washout
Day -1 Day 1 Between Day 5* and 14 16 days between Day 1 of Period 1
and Day 1 of Period 2
Entry into the research center PF-06651600 with label Discharge
(200 mg oral)

Period 2
Day -1 Day 1 Between Day 7
Entry into the research center PF-06651600 without label Discharge
(200 mg, oral)
+
labeled PF-06651600 (60 µg, intravenous.)

1. Frequently Reported Negative Effects
PF-06651600 has been studied in healthy volunteers (in single doses up to 800
mg and multiple doses up to 400 mg daily), subjects with rheumatoid arthritis
(inflammation in joints causing pain, stiffness, swelling, and sometimes
destruction of joints) (at the dose of 200 mg daily), and subjects with
alopecia areata (spot baldness) (at an induction dose of 200 mg daily for 4
weeks, followed by maintenance dosing of 50 mg daily). In all those human
studies, PF-06651600 was generally safe and well tolerated. There are also
ongoing studies of PF­06651600 in subjects with ulcerative colitis
(inflammation and ulcers of the colon and rectum) and subjects with Crohn*s
disease. The negative effects that were reported in more than 1 in 20 subjects
with alopecia areata receiving PF-06651600 for up to 24 weeks were headache,
infections of upper respiratory tract, acne, diarrhea, nausea, and skin
infections.

2. Reactivation of viruses
Certain viruses can be stored in the body and they may reactivate (wake up) and
cause negative effects. In studies with PF-06651600 or other similar
medications, reactivation of the chicken pox virus (herpes zoster) has caused
shingles (a painful or burning skin condition), and reactivation of the herpes
simplex virus has caused cold sores or fever blisters in the mouth or genital
ulcers. We don*t know if PF-06651600 or other similar medications could lead to
the reactivation of hepatitis viruses. The volunteer will not be allowed to
participate in the study if his blood tests show that the volunteer has had
hepatitis types B or C viruses. During the study, the volunteer has to call his
study doctor right away if the volunteer think the volunteer may have shingles,
ulcers in the genital area, or cold sores.

3. Serious or Unusual Infections
PF-06651600 is a study drug that affects the immune system. It can lower the
ability of your body to fight infections, leading to more serious infections or
infections that usually don*t occur in people with a normal immune system. Some
people have had serious infections or unusual infections while taking
PF-06651600 or other similar medications. The volunteer should not start taking
PF-06651600 if the volunteer have any kind of infection. After starting PF­
06651600, the volunteer has to call his study doctor right away if the
volunteer has any symptoms of an infection. Symptoms of an infection could
include fever, weight loss or excessive tiredness or other symptoms specific to
the site of infection, such as a persistent cough. PF-06651600 can make the
volunteer more likely to get infections or make worse any infection that the
volunteer may already have.

4. Cancer
PF-06651600 may increase the risk of certain cancers by changing the way your
immune system defends against cancer. Lymphoma and other cancers, including
skin cancers, have been reported in patients taking medications that work in a
similar way to PF-06651600. Most people with a history of cancer will not be
eligible for this study, except for those who have had successfully treated
skin cancers that were not the melanoma type and those who have had
successfully treated local cancer of the cervix (the lower part of the uterus).
Talk to your study doctor if the volunteer have had any type of cancer.

5. Changes in certain laboratory test results
Your study doctor will do blood tests before the volunteer start taking
PF-06651600 and while the volunteer take PF-06651600. Some changes in blood
tests that have occurred in earlier studies with PF-06651600 are described
below. The volunteer will have these blood tests at every visit and the
volunteer will be discontinued from the study if your blood counts drop to a
level which would cause concern for your continued participation in the study.

• Decreases in lymphocyte counts. Lymphocytes are white blood cells that help
the body fight off infections. If your lymphocytes are low, the volunteer might
be more likely to have an infection.
• Changes in neutrophil counts. Neutrophils are white blood cells that help the
body fight off infections. If your neutrophils are low, the volunteer might be
more likely to have an infection.
• Decreases in platelet counts. Platelets are blood cells that help blood to
clot. If the platelets are low, the volunteer might be more likely to bruise or
bleed. Although bleeding or bruising related to low platelets has not been seen
in previous studies with PF-06651600, there is still a potential risk that this
could happen.
• Changes in other laboratory tests, such as the blood cholesterol or
hemoglobin (red blood cells) levels, may also be seen. Those tests and others
will be checked on a regular basis through the study.

6. Skin Effects
Occurrences of rash and acne have been observed in studies with PF-06651600.
The majority of events were reported as mild or moderate. It is not known if
PF-06651600 causes these skin effects. During the study, the volunteer should
inform the study doctor if the volunteer notice any changes on his skin. In
some cases the doctor may take a skin biopsy (a small sample of skin that is
cut and removed) to investigate a rash. Photographs of a rash may also be taken.

7. Other Effects
Studies have been conducted in animals to identify risks that may occur in
people that are given PF-06651600. In studies with dogs, microscopic changes
(changes so small as to be seen only with a microscope) in nerves were seen
after 9 months of taking doses more than 14 times higher than the highest dose
that will be used long term in this study (50 mg daily). After 7 months, at
even higher doses (more than 30 times higher than the 50 mg dose), a few dogs
had hearing loss. All the microscopic changes and hearing loss got better after
stopping the drug. Because the dog findings occurred only at doses much higher
than will be used in this study, it is unlikely that there are related human
risks from PF-06651600 at the doses used in this study. However, hearing will
be tested in this study. Additionally, if the volunteer develop any changes
related to the nervous system, the volunteer should inform the study doctor.
The volunteer may be referred for additional evaluation by a doctor
specializing in diseases of the nervous system. There may be rare and unknown
side effects with taking PF-06651600. Some of these side effects may be life
threatening. It is important that the volunteer report all side effects that
the volunteer experience as soon as they occur, regardless of whether or not
the volunteer believe they are caused by the study drug.

8. Pregnancy Related Risks/Use of Birth Control
In animals, PF-06651600 was associated with changes in bones and some internal
organs, and lower fetal body weights. It is not known whether PF-06651600 can
affect male or female fertility or whether PF-06651600 is secreted into human
milk. Because of the investigational nature of PF-06651600, it should not be
administered to pregnant women, breastfeeding women, or fertile women of
childbearing potential who are unwilling or unable to use contraception as
defined in the study protocol. PF-06651600 is not likely to transfer to a
partner through semen at pharmacologically relevant levels; however, men in the
study are required to use birth control.

This study involves using radioactive markers. The additional radiation the
volunteer will be exposed to in this study is about 0.0104 mSv (Sv = Sievert
[unit used to measure radiation]). This amount is negligible, as it is less
than the natural background radiation during 1 month. To compare: the
background radiation in the Netherlands is ~2.0 mSv per year.

Procedures: pain, minor bleeding, bruising, possible infection