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