Pfizer Announces Results from XELJANZ® XR (tofacitinib) ORAL Shift Study, The First Phase 3b/4 Study to Evaluate Methotrexate Withdrawal with a JAK Inhibitor

Results to be Presented During a Late-Breaking Oral Session at the
Annual European Congress of Rheumatology (EULAR 2019)

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) announced today positive results from ORAL Shift,
a Phase 3b/4 study in adult patients with moderately to severely active
rheumatoid arthritis (RA). Patients who achieved low disease activity
(LDA) with XELJANZ^® (tofacitinib) extended release (XR) 11 mg
once daily (QD) plus methotrexate (MTX) after a 24-week open-label
run-in period, were randomized to evaluate the efficacy and safety of
XELJANZ XR 11 mg QD as monotherapy after MTX withdrawal compared with
XELJANZ XR with continued MTX. The study demonstrated non-inferiority of
MTX withdrawal with XELJANZ XR 11 mg QD compared to XELJANZ XR 11 mg QD
plus MTX at week 48 as measured by the primary endpoint, the change in
the Disease Activity Score (DAS28-4[ESR]) from randomization at week 24
to the end of the double-blind MTX withdrawal phase at week 48. The
study results will be presented during a late-breaking oral session at
the Annual European Congress of Rheumatology (EULAR 2019) in Madrid,
Spain (15 June).

“The results of ORAL Shift provide important information on the use of
XELJANZ XR as monotherapy after methotrexate withdrawal, which is
significant as some people living with rheumatoid arthritis are unable
or unwilling to use methotrexate,” said Stanley Cohen, MD, Metroplex
Clinical Research Center, Dallas, TX. “From a clinical perspective,
these results give physicians data to help inform the decision to take
appropriate patients off methotrexate.”

Efficacy Results

For the primary efficacy analysis, patients who achieved Clinical
Disease Activity Index (CDAI) low disease activity at week 24 were
randomized into the MTX withdrawal phase resulting in least squares (LS)
mean changes in DAS28-4(ESR) from weeks 24 to 48 of 0.33 and 0.03 in the
XELJANZ XR monotherapy and XELJANZ XR plus MTX groups, respectively [LS
mean difference = 0.3; 95% CI, 0.12-0.48; non-inferiority p<0.0005]. The
primary analysis showed that XELJANZ XR 11 mg QD monotherapy was
non-inferior to XELJANZ XR 11 mg QD with MTX at week 48.

“ORAL Shift exemplifies Pfizer’s commitment to ongoing JAK research with
the goal of meeting the evolving needs of patients living with this
chronic inflammatory condition,” said Michael Corbo, Chief Development
Officer, Inflammation & Immunology, Pfizer Global Product Development.
“We are extremely pleased with the findings from ORAL Shift, which to
date is the only non-inferiority study to evaluate and demonstrate the
efficacy of a JAK inhibitor after methotrexate withdrawal in adults with
moderately to severely active RA who achieved low disease activity after
combination therapy.”

Safety Results

The safety findings in ORAL Shift include the most frequently reported
adverse events (AEs) for each study group in the double-blind treatment
period of nasopharyngitis, upper respiratory tract infection and
bronchitis. Rates of AEs, serious AEs (SAEs) and discontinuations due to
AEs were generally comparable between treatment arms. In the XELJANZ XR
monotherapy group, there were 10 SAEs and 5 discontinuations due to AEs.
In the XELJANZ XR plus MTX group, there were 5 SAEs and 5
discontinuations due to AEs. During the double-blind withdrawal phase of
the study, AEs were reported in 40.5% of patients (n=107) in the XELJANZ
XR monotherapy treatment group and 41.0% of patients (n=109) in the
XELJANZ XR plus MTX treatment group. In addition, SAEs were reported in
3.8% of patients (n=10) in the XELJANZ XR monotherapy treatment group
and 1.9% of patients (n=5) in the XELJANZ XR plus MTX treatment group.
In the double-blind treatment period, there were two deaths reported in
the XELJANZ XR plus MTX treatment group. The full Prescribing
Information for XELJANZ/XELJANZ XR includes a BOXED WARNING for serious
infection and malignancy.

About the Study

ORAL Shift was a 12-month randomized, double-blind, placebo-controlled,
non-inferiority, methotrexate (MTX) withdrawal study in subjects with
moderate to severe rheumatoid arthritis (RA) who were also inadequate
responders to treatment with MTX alone. The study included 694 patients
with moderate to severe RA. During the run-in phase, all patients
received open-label XELJANZ XR 11 mg QD plus MTX using their previously
stabilized MTX dose. At week 24, patients who achieved low disease
activity (LDA) as assessed by CDAI (n=530) were randomized into the
24-week double-blind, placebo-controlled MTX withdrawal phase, for a
total of 48 weeks. The primary efficacy endpoint was the difference
between the two treatment groups in change in DAS28-4(ESR). Change was
measured from the time of randomization, at Week 24, to the end of the
double-blind MTX withdrawal phase at Week 48. In the double-blind phase,
subjects were randomized in a 1:1 ratio to either continue on XELJANZ XR
plus MTX (n=266) or to receive XELJANZ XR monotherapy plus blinded
matching placebo for MTX (n=264).

About XELJANZ^® (tofacitinib)

XELJANZ^® (tofacitinib) is approved in the U.S. for
adult patients in three indications: moderately to severely active
rheumatoid arthritis (RA), active psoriatic arthritis (PsA) and
moderately to severely active ulcerative colitis (UC). Globally, XELJANZ
is approved in more than 130 countries for the treatment of moderately
to severely active RA and has been prescribed to an estimated 205,000
patients.

As the developer of tofacitinib, Pfizer is committed to advancing the
science of JAK inhibition and enhancing understanding of tofacitinib
through robust clinical development programs in the treatment of
immune-mediated inflammatory conditions.

INDICATIONS

Rheumatoid Arthritis

• XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of
  adult patients with moderately to severely active rheumatoid arthritis
  who have had an inadequate response or intolerance to methotrexate. It
  may be used as monotherapy or in combination with methotrexate or
  other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with
  biologic DMARDs or with potent immunosuppressants such as azathioprine
  and cyclosporine is not recommended.

Psoriatic Arthritis

• XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of
  adult patients with active psoriatic arthritis who have had an
  inadequate response or intolerance to methotrexate or other
  disease-modifying antirheumatic drugs (DMARDs).
• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with
  biologic DMARDs or with potent immunosuppressants such as azathioprine
  and cyclosporine is not recommended.

Ulcerative Colitis

• XELJANZ (tofacitinib) is indicated for the treatment of adult patients
  with moderately to severely active ulcerative colitis (UC).
• Limitations of Use: Use of XELJANZ in combination with biologic
  therapies for UC or with potent immunosuppressants such as
  azathioprine and cyclosporine is not recommended.

IMPORTANT SAFETY INFORMATION

SERIOUS INFECTIONS

Patients treated with XELJANZ/XELJANZ XR are at increased risk for
developing serious infections that may lead to hospitalization or death.
Most patients who developed these infections were taking concomitant
immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until
the infection is controlled.

Reported infections include:

• Active tuberculosis, which may present with pulmonary or
  extrapulmonary disease. Patients should be tested for latent
  tuberculosis before XELJANZ/XELJANZ XR use and during therapy.
  Treatment for latent infection should be initiated prior to
  XELJANZ/XELJANZ XR use.
• Invasive fungal infections, including cryptococcosis and
  pneumocystosis. Patients with invasive fungal infections may present
  with disseminated, rather than localized, disease.
• Bacterial, viral, including herpes zoster, and other infections due
  to opportunistic pathogens.

The most common serious infections reported with XELJANZ included
pneumonia, cellulitis, herpes zoster, urinary tract infection,
diverticulitis, and appendicitis. Avoid use of XELJANZ/XELJANZ XR in
patients with an active, serious infection, including localized
infections, or with chronic or recurrent infection.

In the UC population, XELJANZ 10 mg twice daily was associated with
greater risk of serious infections compared to 5 mg twice daily.
Opportunistic herpes zoster infections (including meningoencephalitis,
ophthalmologic, and disseminated cutaneous) were seen in patients who
were treated with XELJANZ 10 mg twice daily.

The risks and benefits of treatment with XELJANZ/XELJANZ XR should be
carefully considered prior to initiating therapy in patients with
chronic or recurrent infection, or those who have lived or traveled
in areas of endemic TB or mycoses. Viral reactivation including herpes
virus and Hepatitis B reactivation have been reported. Screening for
viral hepatitis should be performed in accordance with clinical
guidelines before starting therapy.

Patients should be closely monitored for the development of signs and
symptoms of infection during and after treatment with XELJANZ/XELJANZ
XR, including the possible development of tuberculosis in patients who
tested negative for latent tuberculosis infection prior to initiating
therapy.

Caution is also recommended in patients with a history of chronic lung
disease, or in those who develop interstitial lung disease, as they may
be more prone to infection.

MALIGNANCIES

Lymphoma and other malignancies have been observed in patients
treated with XELJANZ. Epstein Barr Virus-associated post-transplant
lymphoproliferative disorder has been observed at an increased rate in
renal transplant patients treated with XELJANZ and concomitant
immunosuppressive medications.

Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to
initiating therapy in patients with a known malignancy other than a
successfully treated non-melanoma skin cancer (NMSC) or when considering
continuing XELJANZ/XELJANZ XR in patients who develop a malignancy.

Malignancies (including solid cancers and lymphomas) were observed more
often in patients treated with XELJANZ 10 mg twice daily dosing in the
UC long-term extension study.

Other malignancies were observed in clinical studies and the
post-marketing setting including, but not limited to, lung cancer,
breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs
have been reported in patients treated with XELJANZ. In the UC
population, treatment with XELJANZ 10 mg twice daily was associated with
greater risk of NMSC. Periodic skin examination is recommended for
patients who are at increased risk for skin cancer.

GASTROINTESTINAL PERFORATIONS

Gastrointestinal perforations have been reported in XELJANZ clinical
trials, although the role of JAK inhibition is not known. In these
studies, many patients with rheumatoid arthritis were receiving
background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).
There was no discernable difference in frequency of gastrointestinal
perforation between the placebo and the XELJANZ arms in clinical trials
of patients with UC, and many of them were receiving background
corticosteroids. XELJANZ/XELJANZ XR should be used with caution in
patients who may be at increased risk for gastrointestinal perforation
(e.g., patients with a history of diverticulitis or taking NSAIDs).

HYPERSENSITIVITY

Angioedema and urticaria that may reflect drug hypersensitivity have
been observed in patients receiving XELJANZ/XELJANZ XR some events were
serious. If a serious hypersensitivity reaction occurs, promptly
discontinue tofacitinib while evaluating the potential cause or causes
of the reaction.

LABORATORY ABNORMALITIES

Lymphocyte Abnormalities: Treatment with XELJANZ was associated
with initial lymphocytosis at one month of exposure followed by a
gradual decrease in mean lymphocyte counts. Avoid initiation of
XELJANZ/XELJANZ XR treatment in patients with a count less than 500
cells/mm³. In patients who develop a confirmed absolute
lymphocyte count less than 500 cells/mm³, treatment with
XELJANZ/XELJANZ XR is not recommended. Risk of infection may be higher
with increasing degrees of lymphopenia and consideration should be given
to lymphocyte counts when assessing individual patient risk of
infection. Monitor lymphocyte counts at baseline and every 3 months
thereafter.

Neutropenia: Treatment with XELJANZ was associated with an
increased incidence of neutropenia (less than 2000 cells/mm³)
compared to placebo. Avoid initiation of XELJANZ/XELJANZ XR treatment in
patients with an ANC less than 1000 cells/mm³. For patients
who develop a persistent ANC of 500-1000 cells/mm³, interrupt
XELJANZ/XELJANZ XR dosing until ANC is greater than or equal to 1000
cells/mm³. In patients who develop an ANC less than 500
cells/mm³, treatment with XELJANZ/XELJANZ XR is not
recommended. Monitor neutrophil counts at baseline and after 4-8 weeks
of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ/XELJANZ XR treatment in
patients with a hemoglobin level less than 9 g/dL. Treatment with
XELJANZ/XELJANZ XR should be interrupted in patients who develop
hemoglobin levels less than 8 g/dL or whose hemoglobin level drops
greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and
after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated
with an increased incidence of liver enzyme elevation compared to
placebo. Most of these abnormalities occurred in studies with background
DMARD (primarily methotrexate) therapy. If drug-induced liver injury is
suspected, the administration of XELJANZ/XELJANZ XR should be
interrupted until this diagnosis has been excluded. Routine monitoring
of liver tests and prompt investigation of the causes of liver enzyme
elevations is recommended to identify potential cases of drug-induced
liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with
dose-dependent increases in lipid parameters, including total
cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density
lipoprotein (HDL) cholesterol. Maximum effects were generally observed
within 6 weeks. There were no clinically relevant changes in LDL/HDL
cholesterol ratios. Manage patients with hyperlipidemia according to
clinical guidelines. Assessment of lipid parameters should be performed
approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR
therapy.

VACCINATIONS

Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The
interval between live vaccinations and initiation of tofacitinib therapy
should be in accordance with current vaccination guidelines regarding
immunosuppressive agents. Update immunizations in agreement with current
immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy.

PATIENTS WITH GASTROINTESTINAL NARROWING

Caution should be used when administering XELJANZ XR to patients with
pre-existing severe gastrointestinal narrowing. There have been rare
reports of obstructive symptoms in patients with known strictures in
association with the ingestion of other drugs utilizing a non-deformable
extended release formulation.

HEPATIC and RENAL IMPAIRMENT

Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is
not recommended.

For patients with moderate hepatic impairment or with moderate or severe
renal impairment taking XELJANZ 5 mg twice daily, reduce to XELJANZ 5 mg
once daily.

For UC patients with moderate hepatic impairment or with moderate or
severe renal impairment taking XELJANZ 10 mg twice daily, reduce to
XELJANZ 5 mg twice daily.

ADVERSE REACTIONS

The most common serious adverse reactions were serious infections. The
most commonly reported adverse reactions during the first 3 months in
controlled clinical trials in patients with rheumatoid arthritis (RA)
with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in
greater than or equal to 2% of patients treated with XELJANZ with or
without DMARDs) were upper respiratory tract infection, nasopharyngitis,
diarrhea, headache, and hypertension. The safety profile observed in
patients with active psoriatic arthritis treated with XELJANZ was
consistent with the safety profile observed in RA patients.

Adverse reactions reported in ≥5% of patients treated with either 5 mg
or 10 mg twice daily of XELJANZ and ≥1% greater than reported in
patients receiving placebo in either the induction or maintenance
clinical trials for ulcerative colitis were: nasopharyngitis, elevated
cholesterol levels, headache, upper respiratory tract infection,
increased blood creatine phosphokinase, rash, diarrhea, and herpes
zoster.

USE IN PREGNANCY

Available data with XELJANZ/XELJANZ XR use in pregnant women are
insufficient to establish a drug-associated risk of major birth defects,
miscarriage or adverse maternal or fetal outcomes. There are risks to
the mother and the fetus associated with rheumatoid arthritis and UC in
pregnancy. In animal studies, tofacitinib at 6.3 times the maximum
recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal
findings. The relevance of these findings to women of childbearing
potential is uncertain. Consider pregnancy planning and prevention for
females of reproductive potential.

Please see full Prescribing Information, including BOXED WARNING for
XELJANZ/XELJANZ XR available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=959.

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DISCLOSURE NOTICE: The information contained in this release is as of
June 12, 2019. Pfizer assumes no obligation to update forward-looking
statements contained in this release as the result of new information or
future events or developments.

This release contains forward-looking information about XELJANZ
(tofacitinib) and XELJANZ (tofacitinib) extended release (XR) that
involves substantial risks and uncertainties that could cause actual
results to differ materially from those expressed or implied by such
statements. Risks and uncertainties include, among other things, the
uncertainties inherent in research and development, including the
ability to meet anticipated clinical endpoints, commencement and/or
completion dates for our clinical trials, as well as the possibility of
unfavorable new clinical data and further analyses of existing clinical
data; risks associated with interim data; the risk that clinical trial
data are subject to differing interpretations and assessments by
regulatory authorities; whether regulatory authorities will be satisfied
with the design of and results from our clinical studies; uncertainties
regarding the commercial success of XELJANZ and XELJANZ XR;
uncertainties regarding the commercial impact of the results of the ORAL
Shift trial; uncertainties regarding the commercial impact of actions by
regulatory authorities based on analysis of clinical trial A3921133 or
other data, which will depend, in part, on labeling determinations;
whether and when any applications that may be pending or filed for any
potential indications for XELJANZ or XELJANZ XR in any jurisdictions may
be approved by regulatory authorities, which will depend on myriad
factors, including making a determination as to whether the product’s
benefits outweigh its known risks and determination of the product’s
efficacy, and, if approved, whether they will be commercially
successful; decisions by regulatory authorities impacting labeling,
safety, manufacturing processes and/or other matters that could affect
the availability or commercial potential of XELJANZ and XELJANZ XR; and
competitive developments.

A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended December
31, 2018 and in its subsequent reports on Form 10-Q, including in the
sections thereof captioned “Risk Factors” and “Forward-Looking
Information and Factors That May Affect Future Results”, as well as in
its subsequent reports on Form 8-K, all of which are filed with the U.S.
Securities and Exchange Commission and available at www.sec.gov
and www.pfizer.com.

Contacts

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