- Trial demonstrates cumulative incidence of death or respiratory
failure through day 28 was 18.1% (26 of 144) with tofacitinib
compared to 29.0% (42 of 145) with placebo, in hospitalized
patients with COVID-19 pneumonia
- Multi-center, randomized, double-blind, placebo-controlled
trial conducted across 15 sites in Brazil
- Tofacitinib is not approved or authorized for the treatment of
COVID-19 patients. Tofacitinib should not be used in patients with
an active serious infection
Pfizer Inc. (NYSE: PFE) and The Academic Research Organization
(ARO) from the Hospital Israelita Albert Einstein today announced
that the New England Journal of Medicine has published positive
findings from the STOP-COVID study (NCT04469114) evaluating the
efficacy and safety of oral Janus kinase (JAK) inhibitor
tofacitinib in 289 hospitalized adult patients with COVID-19
pneumonia who were not on ventilation.
The trial was a research collaboration between Pfizer and the
ARO from the Hospital Israelita Albert Einstein in Sao Paulo,
Brazil, which was the trial coordinating center. It is important to
note that tofacitinib has not been approved or authorized for use
by any regulatory authority worldwide for the treatment of COVID-19
and tofacitinib should not be used in patients with an active
serious infection.
The trial demonstrated a lower cumulative incidence of death or
respiratory failure through day 28 – the primary outcome of the
study – with tofacitinib (18.1%) compared to placebo (29.0%) (risk
ratio 0.63; 95% confidence interval [CI], 0.41 to 0.97; p=0.04).
Death from any cause through day 28 occurred in 2.8% of patients in
the tofacitinib group and in 5.5% in the placebo group (hazard
ratio 0.49; 95% CI, 0.15 to 1.63).
Serious adverse events occurred in 20 patients (14.1%) in the
tofacitinib group and 17 (12.0%) in the placebo group. Among
protocol-specified adverse events of special interest, deep vein
thrombosis, acute myocardial infarction, ventricular tachycardia,
and myocarditis occurred in one patient each in the tofacitinib
group; hemorrhagic stroke and cardiogenic shock occurred in one
patient each in the placebo group. The incidence of serious
infection was 3.5% in the tofacitinib group and 4.2% in the placebo
group.
“We are encouraged by the initial findings of our randomized
trial of tofacitinib in patients hospitalized with COVID-19
pneumonia. These results provide new information which indicates
that the use of tofacitinib when added to standard of care, which
includes glucocorticoids, may further reduce the risk of death or
respiratory failure in this patient population,” said Otavio
Berwanger, M.D., Ph.D., Director of the Academic Research
Organization, Hospital Israelita Albert Einstein. “The study builds
on the hypothesis that JAK inhibition could mitigate systemic and
alveolar inflammation in patients with COVID-19-related
pneumonia.”
“To effectively combat the COVID-19 pandemic, there remains a
critical need for multiple therapeutic options to treat patients
who have contracted the virus,” said Tamas Koncz, M.D., Ph.D.,
Chief Medical Officer, Pfizer Inflammation & Immunology. “As
outlined in Pfizer’s five-point plan at the onset of the COVID-19
pandemic, we are keenly focused on working across the healthcare
ecosystem with partners like Hospital Israelita Albert Einstein. We
look forward to our continued collaboration as we analyze the full
dataset from this study and assess next steps.”
The multi-center, randomized, double-blind, placebo-controlled
trial included adult patients hospitalized with COVID-19 pneumonia
receiving standard of care. Patients were randomized in a 1:1 ratio
to receive either tofacitinib 10 mg twice daily plus standard of
care or placebo twice daily plus standard of care for up to 14 days
or until hospital discharge. Overall, 89.3% used glucocorticoids
during hospitalization, predominantly dexamethasone.
For additional information about the study (NCT04469114), please
visit https://www.clinicaltrials.gov.
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). See
Limitations of Use below.
XELJANZ has been studied in more than 50 clinical trials
worldwide, including more than 20 trials in RA patients, and
prescribed to over 300,000 adult patients (the majority of whom
were RA patients) worldwide since 2012.i,ii,iii 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.
Pfizer recently communicated an increased rate of major adverse
cardiovascular events (MACE) and malignancies (excluding
non-melanoma skin cancer (NMSC)) for XELJANZ relative to anti-TNF
therapy in RA patients who were 50 years of age or older and had at
least one additional cardiovascular (CV) risk factor. Pfizer is
continuing to work with the U.S. Food and Drug Administration
(FDA), European Medicines Agency (EMA), and other regulatory
agencies to review the full results and analysis.
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.
It is important to note that a dosage of Xeljanz 10 mg twice
daily is not recommended for the treatment of rheumatoid arthritis,
psoriatic arthritis, or polyarticular course juvenile idiopathic
arthritis.
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.
†UC = ulcerative colitis. XELJANZ/XELJANZ XR is indicated for
the treatment of adult patients with moderately to severely active
UC, who have had an inadequate response or who are intolerant to
TNF blockers. Limitations of Use: Use of XELJANZ/XELJANZ XR in
combination with biological therapies for UC or with potent
immunosuppressants such as azathioprine and cyclosporine is not
recommended.
‡RA = rheumatoid arthritis. XELJANZ/XELJANZ XR 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. XELJANZ 10 mg twice daily is not approved for
use in RA.
§PsA = psoriatic arthritis. XELJANZ/XELJANZ XR 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. XELJANZ 10 mg twice daily is
not approved for use in PsA.
Please see full Prescribing Information, including BOXED WARNING
for XELJANZ/XELJANZ XR available at: www.xeljanzpi.com.
Pfizer Inc.: Breakthroughs that change patients’
lives®
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
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Pfizer colleagues work across developed and emerging markets to
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DISCLOSURE NOTICE: The information contained in this release is
as of June 16, 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) and a study evaluating the efficacy and safety of
tofacitinib in hospitalized adult patients with COVID-19 pneumonia,
including their potential benefits, 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 for tofacitinib for
hospitalized patients with COVID-19 pneumonia will be filed in any
jurisdictions and whether and when any applications for tofacitinib
for any other indications may be filed in any jurisdictions;
whether and when any applications that may be pending or filed for
any potential indications for tofacitinib 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, 2020 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.
________________________________ i Pfizer Data on File. XELJANZ
Worldwide Registration Status. ii ClinicalTrials.gov. Tofacitinib
RA Studies. Accessed June 2021.
https://clinicaltrials.gov/ct2/results?term=tofacitinib%2C+rheumatoid+arthritis%2C+ORAL&type=&rslt=&recr=&age_v=&gndr=&cond=Rheumatoid+Arthritis&intr=&titles=&outc=&spons=&lead=&id=&state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&rcv_s=&rcv_e=&lup_s=&lup_e=
iii Pfizer. Data on File. June 2021
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