Pfizer Inc. (NYSE: PFE) announced today co-primary endpoint
results from a recently completed post-marketing required safety
study, ORAL Surveillance (A3921133; NCT02092467). The primary
objective of this study was to evaluate the safety of tofacitinib
at two doses (5 mg twice daily and 10 mg twice daily) versus a TNF
inhibitor (TNFi) in subjects with rheumatoid arthritis (RA) who
were 50 years of age or older and had at least one additional
cardiovascular (CV) risk factor.
The co-primary endpoints of this study were non-inferiority of
tofacitinib compared to TNFi in regard to major adverse
cardiovascular events (MACE) and malignancies (excluding
non-melanoma skin cancer (NMSC)). Results showed that for these
co-primary endpoints, the prespecified non-inferiority criteria
were not met for the primary comparison of the combined tofacitinib
doses to TNFi. Based on the prespecified secondary comparisons,
there was no evidence of a difference in the primary endpoints
between the two tofacitinib treatment groups.
The study included 4,362 subjects who received study treatments.
The primary analyses included 135 subjects with MACE and 164
subjects with malignancies (excluding NMSC). For tofacitinib, the
most frequently reported MACE was myocardial infarction and the
most frequently reported malignancy (excluding NMSC) was lung
cancer. In those subjects with a higher prevalence of known risk
factors for MACE and malignancy (e.g., older age, smoking), a
higher occurrence of events was seen across all treatment
groups.
Adjudicated MACE*
Tofacitinib
5 mg BID
Tofacitinib
10 mg BID**
Tofacitinib Doses
Combined
TNFi
Total number of subjects
1455
1456
2911
1451
Number of subjects with first event within
the risk period*** (%)
47 (3.23)
51 (3.50)
98 (3.37)
37 (2.55)
Person-years
5166.32
4871.96
10038.28
5045.27
IR (95% CI) (number of subjects with
event/100 person-years)
0.91 (0.67, 1.21)
1.05 (0.78, 1.38)
0.98 (0.79, 1.19)
0.73 (0.52, 1.01)
HR (95% CI) for
tofacitinib vs TNFi
1.24 (0.81, 1.91)
1.43 (0.94, 2.18)
1.33 (0.91, 1.94)****
BID=twice daily; CI=confidence interval; HR=hazard ratio;
IR=incidence rate; MACE=major adverse cardiovascular event;
TNFi=Tumor Necrosis Factor inhibitor. (*) Based on Cox proportional
hazard model (**)The 10 mg BID treatment group includes patients
that were switched from 10 mg BID to 5 mg BID as a result of a
study modification in February 2019. (***) The risk period was from
start of therapy up to 60 days past last dose. (****) The
non-inferiority criterion was not met for the primary comparison of
the combined tofacitinib doses to TNFi since the upper limit of the
95% CI exceeded the pre-specified non-inferiority criterion of 1.8,
ie, 1.94 >1.8.
Adjudicated Malignancies Excluding NMSC*
Tofacitinib 5 mg BID
Tofacitinib 10 mg
BID**
Tofacitinib Doses
Combined
TNFi
Total number of subjects
1455
1456
2911
1451
Number of subjects with first event within
the risk period*** (%)
62 (4.26)
60 (4.12)
122 (4.19)
42 (2.89)
Person-years
5491.48
5311.71
10803.19
5482.30
IR (95% CI) (number of subjects with
event/100 person-years)
1.13 (0.87, 1.45)
1.13 (0.86, 1.45)
1.13 (0.94, 1.35)
0.77 (0.55, 1.04)
HR (95% CI) for
tofacitinib vs TNFi
1.47 (1.00, 2.18)
1.48 (1.00, 2.19)
1.48 (1.04, 2.09)****
BID=twice daily; CI=confidence interval; HR=hazard ratio;
IR=incidence rate; NMSC=non-melanoma skin cancer; TNFi=Tumor
Necrosis Factor inhibitor. (*) Based on Cox proportional hazard
model (**)The 10 mg BID treatment group includes patients that were
switched from 10 mg BID to 5 mg BID as a result of a study
modification in February 2019. (***) The risk period included all
available follow-up regardless of treatment exposure. (****) The
non-inferiority criterion was not met for the primary comparison of
the combined tofacitinib doses to TNFi since the upper limit of the
95% CI exceeded the pre-specified non-inferiority criterion of 1.8,
ie, 2.09 >1.8.
“Providing information on the safe and effective use of our
medicines is imperative,” said Tamas Koncz, M.D., Ph.D., Chief
Medical Officer, Inflammation and Immunology, Pfizer. “We believe
that extensive additional analyses of these study data, and
communicating them as soon as possible, will further clarify the
benefit and risk profile of tofacitinib to help inform medical
decision making and patient care.”
Full study results, beyond the co-primary endpoints (including,
but not limited to, secondary endpoints such as pulmonary embolism
and mortality as well as efficacy data), are not yet available.
Pfizer is working with the U.S. Food and Drug Administration (FDA)
and other regulatory agencies to review the full results and
analyses as they become available.
About the Study
In contrast to previous tofacitinib studies, ORAL Surveillance
was specifically designed to assess the risk of CV events and
malignancies, and therefore subjects were required to be 50 years
of age or older and have at least one additional CV risk factor at
screening. All subjects in this study were also required to be
treated with background methotrexate to be eligible for
enrollment.
About XELJANZ® (tofacitinib)
XELJANZ® (tofacitinib) is approved in the U.S. in four
indications: adults with moderately to severely active rheumatoid
arthritis (RA) after methotrexate failure, adults with active
psoriatic arthritis (PsA) after disease modifying antirheumatic
drug (DMARD) failure, adults with moderately to severely active
ulcerative colitis (UC) after tumor necrosis factor inhibitor
(TNFi) failure, and patients 2 years of age or older with active
polyarticular course juvenile idiopathic arthritis (pcJIA). XELJANZ
has been studied in more than 50 clinical trials worldwide and
prescribed to over 208,000 adult patients (the majority of whom
were RA patients) worldwide in the last eight years.1,2,3
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.
- 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 is indicated for the treatment of adult patients with
moderately to severely active ulcerative colitis (UC), who have had
an inadequate response or who are intolerant to TNF blockers.
- Limitations of Use: Use of XELJANZ in combination with
biological therapies for UC or with potent immunosuppressants such
as azathioprine and cyclosporine is not recommended.
Polyarticular Course Juvenile Idiopathic Arthritis
- XELJANZ/XELJANZ Oral Solution is indicated for the treatment of
active polyarticular course juvenile idiopathic arthritis (pcJIA)
in patients 2 years of age and older.
- Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in
combination with biologic DMARDs or potent immunosuppressants such
as azathioprine and cyclosporine is not recommended.
IMPORTANT SAFETY INFORMATION
SERIOUS INFECTIONS
Patients treated with XELJANZ* 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 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 use and during therapy. Treatment for
latent infection should be initiated prior to XELJANZ 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
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 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, 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.
MORTALITY
Rheumatoid arthritis (RA) patients 50 years of age and older
with at least one cardiovascular (CV) risk factor treated with
XELJANZ 10 mg twice a day had a higher rate of all-cause mortality,
including sudden CV death, compared to those treated with XELJANZ 5
mg given twice daily or TNF blockers in a large, ongoing,
postmarketing safety study. XELJANZ 10 mg twice daily or
XELJANZ XR 22 mg once daily is not recommended for the treatment of
RA or PsA. For UC, use XELJANZ at the lowest effective dose and for
the shortest duration needed to achieve/maintain therapeutic
response.
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 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 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.
THROMBOSIS
Thrombosis, including pulmonary embolism, deep venous
thrombosis, and arterial thrombosis, have occurred in patients
treated with XELJANZ and other Janus kinase inhibitors used to
treat inflammatory conditions. RA patients who were 50 years of age
and older with at least one CV risk factor treated with XELJANZ 10
mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers
in a large, ongoing postmarketing safety study had an observed
increase in incidence of these events. Many of these events were
serious and some resulted in death. Avoid XELJANZ in patients at
risk. Discontinue XELJANZ and promptly evaluate patients with
symptoms of thrombosis. For patients with UC, use XELJANZ at the
lowest effective dose and for the shortest duration needed to
achieve/maintain therapeutic response. XELJANZ 10 mg twice
daily or XELJANZ XR 22 mg once daily is not recommended for the
treatment of RA or PsA. In a long-term extension study in UC, four
cases of pulmonary embolism were reported in patients taking
XELJANZ 10 mg twice daily, including one death in a patient with
advanced 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 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 and 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 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 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 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
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 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 treatment in patients
with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ
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 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 therapy.
VACCINATIONS
Avoid use of live vaccines concurrently with XELJANZ. 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 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 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 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 PsA 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 UC 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 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.
* Unless otherwise stated, “XELJANZ” in the Important Safety
Information refers to XELJANZ, XELJANZ XR, and XELJANZ Oral
Solution.
Please see full Prescribing Information, including BOXED WARNING
available at: www.xeljanzpi.com.
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DISCLOSURE NOTICE: The information contained in this release is
as of January 27, 2021. 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) 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, regulatory submission dates, regulatory approval dates
and/or launch dates, as well as the possibility of unfavorable new
clinical data and further analyses of existing clinical 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; 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; uncertainties regarding the commercial
impact of or the results of clinical trial A3921133 or any
potential actions by regulatory authorities based on analysis of
clinical trial A3921133 or other data, which will depend, in part,
on labeling determinations; decisions by regulatory authorities
impacting labeling, manufacturing processes, safety and/or other
matters that could affect the availability or commercial potential
of XELJANZ and XELJANZ XR; uncertainties regarding the impact of
COVID-19 on our business, operations and financial results; 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, 2019 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.
###
1 Pfizer Data on File. XELJANZ Worldwide Registration Status. 2
ClinicalTrials.gov. Tofacitinib RA Studies. Accessed June 25, 2020.
3 Pfizer. Data on File. Tofa Counts. April 2019
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