A Randomized, Double-blind, Placebo- and Active-controlled, Multicenter, Phase 3 Study to Assess the Efficacy and Safety of Filgotinib Administered for 52 weeks in Combination with Methotrexate to Subjects with Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that
affects approximately 1.3 million adults in the United States (US) {Helmick et
al 2008}. Rheumatoid arthritis manifests principally as an attack on peripheral
joints and may lead to marked destruction and deformity of joints, with
considerable disability and impact on quality of life. It is characterized by
the production of autoantibodies, synovial inflammation with formation of
pannus tissue, and erosion of underlying cartilage and bone. Although people of
any age can be affected, the onset of RA is most frequent between the ages of
40 and 50 years, and women are affected 3 times more often than men. While the
cause of RA is still not completely understood, aberrant B-cell activation,
T-cell co-stimulation, osteoclast differentiation, and cytokine release all
have been implicated in its pathogenesis.

Treatment of RA is dependent on severity, the patient*s co*morbidities and
initial response to therapy. Methotrexate (MTX) is a conventional disease
modifying anti-rheumatic drug (DMARD) and continues to be the cornerstone of RA
therapy {Singh et al 2012}. Patients with an inadequate response to
conventional DMARD(s) are often treated with biologic therapies such as tumor
necrosis factor inhibitors (TNFi) as an initial second line therapy. However,
approximately 28% to 58% of RA patients with inadequate response to MTX fail
TNFi as reviewed in {Redlich et al 2003}. In this setting, treatment guidelines
recommend either switching to another TNFi, alternate biologic, or to a small
molecule drug {Singh et al 2012}. Despite significant advances in disease
management in recent years, there remains a need for new treatments, since not
all patients respond adequately to current therapies, have co-morbidities and
some patients experience toxicities and/or intolerance that limit the use of
approved therapies.

In November 2012, tofacitinib (Xeljanz®) became the first Janus kinase (JAK)
inhibitor to receive Food and Drug Administration (FDA) approval for the
treatment of adult patients with RA. Tofacitinib is a small molecule, has
strong binding affinity for JAK1 and JAK3, and weaker affinity for JAK2. The
extensive pre-clinical and clinical development programs demonstrated its
mechanisms of action via anti-inflammatory and immunosuppressive effects. The
drug proved to be efficacious in treating the signs and symptoms of RA.
However, the observed side-effects and risk profile of tofacitinib are similar
to those of several existing anti-rheumatic agents with cytopenias, elevated
levels of liver function enzymes, increased total cholesterol levels, with
increase in LDL typically exceeding those for HDL, and increased risk for
infections including serious and opportunistic infections. At higher doses,
tofacitinib treatment was associated with anemia, which is thought to be linked
to inhibition of JAK2.

While the pan JAK inhibitor tofacitinib has shown an early onset of action and
long-term efficacy in RA as mono therapy and in combination with background
conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs)
therapy, dose levels were limited by side effects potentially mediated by its
effect on JAK 2 and JAK 3. This highlights the need for more selective and
targeted therapies with improved immunomodulatory and hematologic effects.

JAK1 is thought to be an integral part of RA pathogenesis due its role in
transmitting inflammatory cytokine signaling. Hence, targeted inhibition of
JAK1 has great potential for the treatment of RA with an improved safety and
side effect profile.

The primary objective of this study is:

* To evaluate the effects of filgotinib versus placebo for the treatment of
signs and symptoms of rheumatoid arthritis (RA) as measured by the proportion
of subjects achieving an American College of Rheumatology 20% improvement
response (ACR20) at Week 12

The secondary objectives of this study include:

* To evaluate the effects of filgotinib versus placebo as measured by the
proportion of subjects achieving Disease Activity Score for 28 joint count
using c-reactive protein (DAS28[CRP]) *3.2 at Week 12
* To evaluate the effect of filgotinib versus placebo on physical function as
measured by change from Baseline in the Health Assessment Questionnaire
Disability Index (HAQ-DI) score at Week 12
* Toevaluate the effects of filgotinib versus placebo for the treatment of
signs and symptoms of RA as measured by the proportion of subjects achieving
DAS28 (CRP)<2.6 at Week 24
* To evaluate the effects of filgotinib versus placebo on preservation of joint
structure as measured by change from Baseline in the van der Heijde modified
Total Sharp Score (mTSS) at Week 24
* To evaluate the effects of filgotinib versus adalimumab for the treatment of
signs and symptoms of RA as measured by the proportion of subjects achieving
DAS28 (CRP) * 3.2 at Week 12
* To evaluate the safety and tolerability of filgotinib
* To evaluate the effects of filgotinib on work productivity, fatigue, and
general quality of life as measured by SF-36, FACIT-Fatigue, EQ-5D and WPAI-RA

The exploratory objectives of this study include:

* To characterize the pharmacokinetics (PK) of filgotinib and its metabolite
(GS-829845, formerly G254445)
* To characterize the association of host genetics and other markers with
disease severity, disease progression and treatment response to filgotinib in
subjects with RA
* To evaluate the effects of filgotinib on healthcare resource utilization and
other patient reported outcomes

This is a randomized, double-blind, placebo- and active-controlled, Phase 3
study in adult male and female subjects with active RA who have an inadequate
response to MTX (MTX-IR). The study is designed to evaluate the efficacy,
safety, and tolerability of filgotinib as well as its effect on work
productivity, fatigue, and quality of life.

Approximately 1650 subjects will be randomized in a 3:3:2:3 ratio to filgotinib
200 mg, filgotinib 100 mg, active comparator (adalimumab), or placebo to match
(PTM) administered for up to 52 weeks, all in the context of a weekly stable
dose of MTX:

* Filgotinib 200 mg group: filgotinib (200 mg q.d.) + PTM filgotinib 100 mg
(PTM q.d.) + PTM adalimumab (PTM s.c. injection q2w) (N=450)
* Filgotinib 100 mg group: filgotinib (100 mg q.d.) + PTM filgotinib 200 mg
(PTM q.d.) + PTM adalimumab (PTM s.c. injection q2w) (N=450)
* Active comparator group: PTM filgotinib 200 mg (PTM q.d.) + PTM filgotinib
100 mg (PTM q.d.) + adalimumab (40 mg s.c. injection q2w) (N=300)
* Placebo control group: PTM filgotinib 200 mg (PTM q.d.) + PTM filgotinib 100
mg (PTM q.d.) + PTM adalimumab (PTM s.c. injection q2w) (N=450)

At Week 14, subjects who have not achieved at least 20% improvement from Day 1
in both swollen joint count (SJC) and tender joint count (TJC) will discontinue
investigational study drug dosing but will continue with study visits and
assessments per protocol. All subjects meeting this criterion who discontinue
from investigational therapy are to receive standard of care treatment for
their RA as determined by the investigator.

At Week 24, all subjects assigned to placebo + MTX will be reassigned 1:1 to
either filgotinib 100 mg q.d. or 200 mg q.d. in addition to MTX in a blinded
fashion and will continue in the study per protocol up to Week 52.

All subjects who continue on study drug will be evaluated for loss of
therapeutic response from Week 30 through Week 52. Subjects failing to maintain
at least a 20% improvement from Day 1 in TJC and SJC, (which is confirmed at 2
consecutive visits), will discontinue from investigational study drug therapy
but will continue with study visits and assessments per protocol. All subjects
meeting this criterion who discontinue from investigational study drug dosing
are to receive standard of care treatment for their RA as determined by the
investigator.

All subjects who have received at least one dose of study drug and exit the
study early will complete an early termination (ET) visit at the time of study
discontinuation, with a follow up visit four weeks after the last dose of study
drug (Post Treatment Week 4), regardless of dosing duration.

At completion of the 52-week dosing period, subjects who have not discontinued
assigned study drug dosing, will be provided the option to enroll into a
separate Long Term Extension (LTE) study
(GS-US-417-0304).

* Filgotinib 200 mg group: filgotinib (200 mg q.d.) + PTM filgotinib 100 mg
(PTM q.d.) + PTM adalimumab (PTM s.c. injection q2w) (N=450)
* Filgotinib 100 mg group: filgotinib (100 mg q.d.) + PTM filgotinib 200 mg
(PTM q.d.) + PTM adalimumab (PTM s.c. injection q2w) (N=450)
* Active comparator group: PTM filgotinib 200 mg (PTM q.d.) + PTM filgotinib
100 mg (PTM q.d.) + adalimumab (40 mg s.c. injection q2w) (N=300)
* Placebo control group: PTM filgotinib 200 mg (PTM q.d.) + PTM filgotinib 100
mg (PTM q.d.) + PTM adalimumab (PTM s.c. injection q2w) (N=450)

FILGOTINIB COMMON ADVERSE EVENTS
INFECTIONS
Drugs that affect your immune system can lower your body*s ability to fight off
infections. There is a possibility that your ability to fight off infections
will be weakened while taking filgotinib. In studies of patients with RA and
CD, there have been more infections in people who took filgotinib compared to
those who took a placebo. Pneumonia (lung infection) has been identified as a
side effect of filgotinib based on studies in people with RA and CD. Serious
infections leading to hospitalization and, in 3 cases, death have been
reported. Overall, less than 3% of patients taking filgotinib developed a
serious infection of any type.

Neutrophils are a type of blood cell that helps to fight infections. The number
of neutrophils was lower in the blood of patients with RA who were given
filgotinib, but only approximately 1.5% of these patients had a severe decrease
in neutrophils. Other types of infection fighting cells in the blood were not
affected.

MALE INFERTILITY
Filgotinib caused damage to the testes (testicles) of male rats and dogs. In
these animals, filgotinib caused deterioration and loss of cells that make
sperm, resulting in less sperm, or no sperm being produced. As a result,
filgotinib caused male rats to be infertile (unable to get a female rat
pregnant).

Damage to the testes in rats and dogs was observed at doses slightly higher
than the doses that are planned to be given to people in this study. At these
doses, while sperm counts in rats and dogs increased after filgotinib was
stopped, they stayed low overall and did not return to normal. At the highest
doses tested in male rats and dogs, these side effects did not go away. These
side effects were not seen in the testes of rats and dogs when a dose was given
that was similar to the 200 mg daily dose in humans.

Based on the results in male rats and dogs, there is a risk that men treated
with filgotinib may have reduced sperm production, and may become temporarily
or permanently infertile (unable to get a woman pregnant). An additional study
will be done in men with RA to measure the effect of filgotinib on sperm
production. Until results from that study are available, the long term effect
of filgotinib on sperm production in humans is unknown. Do not enroll in this
study unless you understand and accept the risk that you may have reduced
fertility (a lower chance of getting a woman pregnant) or infertility (unable
to get a woman pregnant), and that this side effect may not go away after you
leave the study; it could be permanent.

BIRTH DEFECTS
Filgotinib treatment caused malformations (birth defects) of the bone and
internal organs in the fetuses (unborn babies) of pregnant rats and rabbits.
These birth defects happened at doses of filgotinib similar to those planned to
be given to humans. Other effects were also seen, including increased pregnancy
loss and decreased fetal body weights.

Based on this animal data, filgotinib may cause birth defects in humans. Do not
enroll in this study unless you understand and accept this risk and are willing
to take appropriate measures to avoid pregnancy. To be in this study, highly
effective birth control is required for both men and women. Birth control
should also be considered for female partners of male participants; your study
doctor can provide details on recommended types of birth control. If you are
planning to become pregnant in the future, you should discuss this with your
study doctor before entering the study.

OTHER EFFECTS
Increases in cholesterol, including certain types of both good and bad
cholesterols, have been seen in people taking filgotinib, but the importance of
these findings is not yet known. A small increase in creatinine (which is a
measure of how well the kidney is working) was seen in studies with RA
patients. The creatinine levels overall, however, stayed within normal limits.

As with any drug, there are unknown risks involved, since only a limited number
of people have taken this drug and not all side effects and risks of taking
this drug are known. In the future, more serious and/or long term side effects
could happen, including allergic reactions. Also, the risks or discomforts
described here could happen more often or be more severe than what has been
seen before. Your health will be checked at each visit during the study by your
study doctor, and you will be asked to report any changes or problems you may
have noticed. If you or your partner becomes pregnant during the study, you
should let your study doctor know right away. If you have any changes in your
health or if you have any health problems, you should let your study doctor
know right away.