NEW YORK--(BUSINESS WIRE)--
Pfizer Inc. announced a positive outcome from today’s U.S. Food and Drug
Administration (FDA) Gastrointestinal Drugs Advisory Committee (GIDAC)
meeting. The GIDAC met to discuss Pfizer’s supplemental New Drug
Application (sNDA) for XELJANZ® (tofacitinib), which
is currently under review by the FDA, for the treatment of adult
patients with moderately to severely active ulcerative colitis (UC).
“Today’s discussion underscored the significant unmet need that exists
for people living with ulcerative colitis, a disease that is often
debilitating and difficult to control. We are encouraged about the
positive outcome of today’s GIDAC meeting,” said Michael Corbo, Chief
Development Officer, Inflammation & Immunology, Pfizer Global Product
Development. “If approved, tofacitinib will be the first Janus kinase
inhibitor and the first oral therapy for adults living with moderately
to severely active ulcerative colitis. We look forward to working with
the FDA as it completes the review of our pending application.”
The GIDAC voted on two dosing questions related to the use of the 10 mg
twice-daily (BID) dose beyond the eight week induction period. First,
the Committee voted unanimously (15-0) in favor of the extension of the
use of tofacitinib 10 mg BID from eight to 16 weeks of induction in
adult patients who have not achieved adequate therapeutic benefit by
Week 8. Second, the Committee voted unanimously (15-0) in favor of 10 mg
BID as continuous maintenance treatment for adult patients with an
inadequate response, loss of response or intolerance to tumor necrosis
factor (TNF) blocker therapy.
The submitted sNDA for adult patients with moderately to severely active
UC included a proposed dosing regimen of tofacitinib 10 mg BID for eight
weeks of induction, followed by tofacitinib 5 mg BID for maintenance. It
also included the proposed option to extend the induction period by an
additional eight weeks (for a total of 16 weeks), as well as proposed
consideration for the use of tofacitinib 10 mg BID for maintenance
therapy in patients with an inadequate response, loss of response, or
intolerance to TNF blocker therapy.
The third question the Committee voted on related to a post-marketing
efficacy study comparing a tofacitinib 10 mg BID continuous dosing
regimen versus a regimen of tofacitinib 10 mg BID induction and 5 mg BID
as maintenance in this patient population. The Committee voted 8-7
against conducting this study.
The role of the GIDAC is to provide recommendations to the FDA; however,
the recommendations are not binding. FDA’s decision on whether or not to
approve tofacitinib for UC is expected by the Prescription Drug User Fee
Act (PDUFA) date in June 2018.
About Ulcerative Colitis
UC is a chronic and often debilitating inflammatory bowel disease that
affects millions of people worldwide.1,2 Symptoms of UC can
include chronic diarrhea with blood and mucus, abdominal pain and
cramping, and weight loss.3 While the exact cause of UC is
unknown, it is believed to be the result of complex interactions between
multiple factors that include genetic predisposition and an exaggerated
immune response to a microbial trigger.4 UC can have a
significant effect on work, family and social activities.5
About Tofacitinib
Tofacitinib is a Janus kinase (JAK) inhibitor. It is not currently
approved for the treatment of UC. Applications for tofacitinib for the
treatment of moderately to severely active UC are currently under review
by the U.S. FDA and the European Medicines Agency (EMA).
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 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.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: SERIOUS INFECTIONS AND MALIGNANCY
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 risks and benefits of treatment with XELJANZ/XELJANZ XR should be
carefully considered prior to initiating therapy in patients with
chronic or recurrent infection.
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.
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.
WARNINGS AND PRECAUTIONS
SERIOUS INFECTIONS
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. Consider the risks and benefits of treatment before
initiating XELJANZ/XELJANZ XR in patients:
-
with chronic or recurrent infection;
-
who have been exposed to tuberculosis (TB);
-
with a history of a serious or an opportunistic infection;
-
who have lived or traveled in areas of endemic TB or mycoses; or
-
with underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and
symptoms of infection during and after treatment with XELJANZ/XELJANZ
XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a
serious infection, an opportunistic infection, or sepsis.
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.
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.
Tuberculosis
Evaluate and test patients for latent or active infection prior to and
per applicable guidelines during administration of XELJANZ/XELJANZ XR.
Consider anti-TB therapy prior to administration of XELJANZ/XELJANZ XR
in patients with a past history of latent or active TB in whom an
adequate course of treatment cannot be confirmed, and for patients with
a negative test for latent TB but who have risk factors for TB
infection. Treat patients with latent TB with standard therapy before
administering XELJANZ/XELJANZ XR.
Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (eg,
herpes zoster), was observed in clinical studies with XELJANZ. Screening
for viral hepatitis should be performed in accordance with clinical
guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of
herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR
and appears to be higher in patients treated with XELJANZ in Japan and
Korea.
MALIGNANCY and LYMPHOPROLIFERATIVE DISORDERS
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.
In the 7 controlled rheumatoid arthritis clinical studies, 11 solid
cancers and 1 lymphoma were diagnosed in 3328 patients receiving XELJANZ
with or without DMARD, compared to 0 solid cancers and 0 lymphomas in
809 patients in the placebo with or without DMARD group during the first
12 months of exposure. Lymphomas and solid cancers have also been
observed in the long-term extension studies in rheumatoid arthritis
patients treated with XELJANZ.
In the 2 controlled Phase 3 clinical trials in patients with active
psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474
patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months
exposure) compared with 0 malignancies in 236 patients in the placebo
plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in
106 patients in the adalimumab plus nonbiologic DMARD group (12 months
exposure). No lymphomas were reported. Malignancies have also been
observed in the long-term extension study in psoriatic arthritis
patients treated with XELJANZ.
In Phase 2B controlled dose-ranging trials in de-novo renal transplant
patients, all of whom received induction therapy with basiliximab,
high-dose corticosteroids, and mycophenolic acid products, Epstein Barr
Virus-associated post-transplant lymphoproliferative disorder was
observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared
to 0 out of 111 patients treated with cyclosporine.
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.
Non-Melanoma Skin Cancer
Non-melanoma skin cancers (NMSCs) have been reported in patients treated
with XELJANZ. 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.
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).
LABORATORY ABNORMALITIES
Lymphocyte Abnormalities
Treatment with XELJANZ was associated with initial lymphocytosis at 1
month of exposure followed by a gradual decrease in mean lymphocyte
counts of approximately 10% during 12 months of therapy. Counts less
than 500 cells/mm3 were associated with an increased incidence of
treated and serious infections. 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. 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.
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. If drug-induced liver injury is suspected,
the administration of XELJANZ/XELJANZ XR should be interrupted until
this diagnosis has been excluded.
Lipid Elevations
Treatment with XELJANZ was associated with 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.
Assess lipid parameters approximately 4-8 weeks following initiation of
XELJANZ/XELJANZ XR therapy, and manage patients according to clinical
guidelines for the management of hyperlipidemia.
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. A varicella virus naïve patient experienced
dissemination of the vaccine strain of varicella zoster virus 16 days
after vaccination with live attenuated virus vaccine which was 2 days
after 5mg twice daily treatment with tofacitinib. The patient recovered
after discontinuation of tofacitinib and treatment with antiviral
medication. Update immunizations in agreement with current immunization
guidelines prior to initiating XELJANZ/XELJANZ XR therapy.
GENERAL
Specific to XELJANZ XR
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.
The recommended dose in patients with moderate hepatic impairment or
with moderate or severe renal impairment is XELJANZ 5 mg once 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 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 infections (4.5%, 3.3%), headache (4.3%, 2.1%), diarrhea (4.0%,
2.3%), and nasopharyngitis (3.8%, 2.8%).
USE IN PREGNANCY
There are no adequate and well-controlled studies in pregnant women and
the estimated background risks of major birth defects and miscarriage
for the indicated population is unknown. Based on animal studies,
tofacitinib has the potential to affect a developing fetus. Women of
reproductive potential should be advised to use effective contraception.
Please see full Prescribing Information for XELJANZ/XELJANZ XR available
at: http://labeling.pfizer.com/showlabeling.aspx?id=959
Pfizer Inc.: Working together for a healthier world®
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to people that extend and significantly improve their lives. We strive
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DISCLOSURE NOTICE: The information contained in this release is as of
March 8, 2018. 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 a potential new
indication for XELJANZ for the treatment of adult patients with
moderately to severely active UC (the “potential indication”), including
its 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 trial
commencement and completion dates and regulatory submission dates, as
well as the possibility of unfavorable clinical trial results, including
unfavorable new clinical data and additional analyses of existing
clinical data; the risk that clinical trial data are subject to
differing interpretations, and, even when we view data as sufficient to
support the safety and/or effectiveness of a product candidate,
regulatory authorities may not share our views and may require
additional data or may deny approval altogether; 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 the
potential indication may be filed with regulatory authorities in any
additional jurisdictions; whether and when the FDA and the EMA will
approve the applications pending for the potential indication and
whether and when regulatory authorities in any other jurisdictions may
approve any such other applications and/or any other applications that
are pending or may be filed for XELJANZ or XELJANZ XR, which will depend
on the assessment by such regulatory authorities of the benefit-risk
profile suggested by the totality of the efficacy and safety information
submitted; decisions by regulatory authorities regarding labeling and
other matters that could affect the availability or commercial potential
of XELJANZ and XELJANZ XR, including the potential indication; 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, 2017 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 Loftus E. Clinical Epidemiology of Inflammatory Bowel
Disease: Incidence, Prevalence, and Environmental Influences. Gastroenterology.
2004;126:1504–1517.
2 Kappelman MD, et al. Recent trends
in the prevalence of Crohn’s disease and ulcerative colitis in a
commercially insured US population. Digestive Diseases and Sciences.
2013;58:519–525.
3 Hanauer SB. Inflammatory bowel
disease. The New England Journal of Medicine. 1996;334(13):841-8.
4
Sartor RB. Mechanisms of Disease: pathogenesis of Crohn's disease and
ulcerative colitis. Nature Clinical Practice Gastroenterology &
Hepatology. 2006;3:390-407.
5 Irvine EJ. Quality of
Life of Patients with Ulcerative Colitis: Past, Present, and Future.
Inflammatory Bowel Diseases. 2008;14(4):554-563.
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Source: Pfizer Inc.