ATLANTA, May 5, 2014 /PRNewswire/ -- UCB announced
today results from the PRECiSE 3 7-year open label extension
clinical trial of Cimzia® (certolizumab pegol), the
longest continuous trial of an anti-TNF therapy evaluating
long-term safety in Crohn's disease. Remission was also assessed
over the trial period. Results were presented at Digestive Disease
Week (DDW), taking place in Chicago from May
3-6.
"The breadth of the PRECiSE 3 study offers opportunities to
examine baseline factors that provide insights into the likelihood
of long-term remission in moderate to severe Crohn's disease
patients," said William Sandborn,
MD, investigator and Chief, Division of Gastroenterology,
University of California San Diego.
"These data provide insight to the impact of prior anti-TNF use on
long-term outcomes among adult patients receiving
Cimzia® and its use as a first-line biologic treatment
option for Crohn's disease after conventional therapy."
In total, 595 patients enrolled in PRECiSE 3 following the
completion of the PRECiSE 1 and 2 pivotal studies (354 enrolled
from PRECiSE 1 and 241 enrolled from PRECiSE 2) and received
certolizumab pegol (CZP) 400 mg every four weeks for up to seven
years. No new safety signals were identified during the study.
However, patients treated with Cimzia® are at an
increased risk for developing serious infections that may lead to
hospitalization or death.
In the observed case analysis of the study, annual remission
rates ranged from 68% (269 out of 394 patients still in the study)
to 76% (78 out of 103 patients still in the study) from year one to
year seven, as defined by a Harvey Bradshaw Index score of less
than four. The remission rates analyzed by last observation carried
forward and non-responder imputation methods were 58% (347 out of
594 patients) and 45% (266 out of 594 patients) at year one, 56%
(331 out of 594 patients) and 26% (152 out of 594 patients) at year
three, and 55% (325 out of 594 patients) and 13% (78 out of 594
patients) at year seven, respectively.
Open-label extension studies may have limitations, including
potential enrichment of the study population with responders, lack
of placebo control, and patient dropout rates due to tolerability
issues.
A separate post-hoc analysis of the PRECiSE 3 data evaluated
long-term outcomes in Crohn's disease, stratified by patients with
prior anti-TNF exposure (N=119) versus bio-naive patients (N=475).
Results from the analysis suggested that the mean duration of
remission was shorter among patients with prior anti-TNF exposure
compared to bio-naive patients (1.5 years vs. 2.3 years,
respectively), as was the mean duration of treatment response (2.5
years vs. 3.14 years, respectively).
"Long-term assessments of safety and efficacy are critically
important for managing Crohn's disease patients, who suffer a
tremendous disease burden," said Professor Dr. Iris Loew-Friedrich, Chief Medical Officer and
Executive Vice President UCB. "UCB is committed to conducting
research that aids clinicians in making the most informed treatment
decisions for their patients living with Crohn's disease."
In the U.S., Cimzia® is approved for reducing signs
and symptoms of Crohn's disease and maintaining clinical response
in adult patients with moderately to severely active disease who
have had an inadequate response to conventional therapy. Please see
the important safety information at the end of this press
release.
About the PRECiSE Clinical Trial Program
PRECiSE (PEGylated antibody fragment evaluation in Crohn's
disease: safety and efficacy), one of the largest, most
comprehensive development programs for an anti-TNF for moderate to
severe Crohn's disease, is composed of two placebo-controlled
studies (PRECiSE 1 and 2) and two open-label safety follow-up
studies. In these pivotal clinical trials, the primary
efficacy endpoints of clinical response were evaluated using the
Crohn's Disease Activity Index (CDAI) and defined as a decrease in
CDAI score of > 100 points. CDAI is a weighted,
composite index of eight items, which requires daily completion of
a diary card and calculation of various weighting factors for one
week. In 2007, the two former studies were published in the
New England Journal of Medicine (NEJM). The studies
demonstrated that patients with moderate to severe Crohn's disease
achieved and maintained clinical response with Cimzia®
for up to 6 months, compared to placebo. In a follow-up
open-label extension study (PRECiSE 3), patients continued to
receive Cimzia® every 4 weeks for up to 7 years.
The Harvey-Bradshaw Index (HBI), which only requires scoring from
the day before the study visit and involves a lower number of
components, was used to evaluate Crohn's disease activity in
PRECiSE 3.1,2,3,4,5,6
IMPORTANT SAFETY INFORMATION ABOUT CIMZIA® IN THE
US1
Risk of Serious Infections and Malignancy
Patients treated with CIMZIA are at an 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. CIMZIA should be discontinued if a patient
develops a serious infection or sepsis. Reported infections
include:
- Active tuberculosis, including reactivation of latent
tuberculosis. Patients with tuberculosis have frequently presented
with disseminated or extrapulmonary disease. Patients should be
tested for latent tuberculosis before CIMZIA use and during
therapy. Treatment for latent infection should be initiated prior
to CIMZIA use.
- Invasive fungal infections, including histoplasmosis,
coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and
pneumocystosis. Patients with histoplasmosis or other invasive
fungal infections may present with disseminated, rather than
localized disease. Antigen and antibody testing for histoplasmosis
may be negative in some patients with active infection. Empiric
anti-fungal therapy should be considered in patients at risk for
invasive fungal infections who develop severe systemic
illness.
- Bacterial, viral and other infections due to opportunistic
pathogens, including Legionella and Listeria.
The risks and benefits of treatment with CIMZIA 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 CIMZIA, including the possible
development of tuberculosis in patients who tested negative for
latent tuberculosis infection prior to initiating therapy.
Lymphoma and other malignancies, some fatal, have been
reported in children and adolescent patients treated with TNF
blockers, of which CIMZIA is a member. CIMZIA is not indicated for
use in pediatric patients.
Patients treated with CIMZIA are at an increased risk for
developing serious infections involving various organ systems and
sites that may lead to hospitalization or death. Opportunistic
infections due to bacterial, mycobacterial, invasive fungal, viral,
parasitic, or other opportunistic pathogens including
aspergillosis, blastomycosis, candidiasis, coccidioidomycosis,
histoplasmosis, legionellosis, listeriosis, pneumocystosis and
tuberculosis have been reported with TNF blockers. Patients have
frequently presented with disseminated rather than localized
disease.
Treatment with CIMZIA should not be initiated in patients
with an active infection, including clinically important localized
infections. CIMZIA should be discontinued if a patient develops a
serious infection or sepsis. Patients greater than 65 years of age,
patients with co-morbid conditions, and/or patients taking
concomitant immunosuppressants (e.g., corticosteroids or
methotrexate) may be at a greater risk of infection. Patients who
develop a new infection during treatment with CIMZIA should be
closely monitored, undergo a prompt and complete diagnostic workup
appropriate for immunocompromised patients, and appropriate
antimicrobial therapy should be initiated. Appropriate empiric
antifungal therapy should also be considered while a diagnostic
workup is performed for patients who develop a serious systemic
illness and reside or travel in regions where mycoses are
endemic.
Malignancies
During controlled and open-labeled portions of CIMZIA studies
of Crohn's disease and other diseases, malignancies (excluding
non-melanoma skin cancer) were observed at a rate of 0.5 per 100
patient-years among 4,650 CIMZIA-treated patients versus a rate of
0.6 per 100 patient-years among 1,319 placebo-treated patients. In
studies of CIMZIA for Crohn's disease and other investigational
uses, there was one case of lymphoma among 2,657 CIMZIA-treated
patients and one case of Hodgkin lymphoma among 1,319
placebo-treated patients. In CIMZIA RA clinical trials
(placebo-controlled and open label), a total of three cases of
lymphoma were observed among 2,367 patients. This is approximately
2-fold higher than expected in the general population. Patients
with RA, particularly those with highly active disease, are at a
higher risk for the development of lymphoma. The potential role of
TNF blocker therapy in the development of malignancies is not
known.
Malignancies, some fatal, have been reported among children,
adolescents, and young adults who received treatment with
TNF-blocking agents (initiation of therapy <18 years of age), of
which CIMZIA is a member. Approximately half of the cases were
lymphoma (including Hodgkin's and non-Hodgkin's lymphoma), while
the other cases represented a variety of different malignancies and
included rare malignancies associated with immunosuppression and
malignancies not usually observed in children and adolescents. Most
of the patients were receiving concomitant
immunosuppressants.
Cases of acute and chronic leukemia have been reported with
TNF-blocker use. Even in the absence of TNF-blocker therapy,
patients with RA may be at a higher risk (approximately 2-fold)
than the general population for developing leukemia.
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL),
a rare type of T-cell lymphoma that has a very aggressive disease
course and is usually fatal, have been reported in patients treated
with TNF blockers, including CIMZIA. The majority of reported
TNF blocker cases occurred in adolescent and young adult males with
Crohn's disease or ulcerative colitis. Almost all of these
patients had received treatment with the immunosuppressants
azathioprine and/or 6-mercaptopurine (6-MP) concomitantly with a
TNF blocker at or prior to diagnosis. Carefully assess the
risks and benefits of treatment with CIMZIA, especially in these
patient types.
Periodic skin examinations are recommended for all patients,
particularly those with risk factors for skin cancer.
Heart Failure
Cases of worsening congestive heart failure (CHF) and new
onset CHF have been reported with TNF blockers. CIMZIA has not been
formally studied in patients with CHF. Exercise caution when using
CIMZIA in patients who have heart failure and monitor them
carefully.
Hypersensitivity
Symptoms compatible with hypersensitivity reactions,
including angioedema, dyspnea, hypotension, rash, serum sickness,
and urticaria, have been reported rarely following CIMZIA
administration. Some of these reactions occurred after the
first administration of CIMZIA. If such reactions occur,
discontinue further administration of CIMZIA and institute
appropriate therapy.
Hepatitis B Reactivation
Use of TNF blockers, including CIMZIA, has been associated
with reactivation of hepatitis B virus (HBV) in patients who are
chronic carriers of this virus. Some cases have been fatal. Test
patients for HBV infection before initiating treatment with CIMZIA.
Exercise caution in prescribing CIMZIA for patients identified as
carriers of HBV, with careful evaluation and monitoring prior to
and during treatment. In patients who develop HBV reactivation,
discontinue CIMZIA and initiate effective anti-viral therapy with
appropriate supportive treatment.
Neurologic Reactions
Use of TNF blockers, including CIMZIA, has been associated
with rare cases of new onset or exacerbation of clinical symptoms
and/or radiographic evidence of central nervous system
demyelinating disease, including multiple sclerosis, and with
peripheral demyelinating disease, including Guillain-Barré
syndrome. Rare cases of neurological disorders, including seizure
disorder, optic neuritis, and peripheral neuropathy have been
reported in patients treated with CIMZIA. Exercise caution in
considering the use of CIMZIA in patients with these
disorders.
Hematologic Reactions
Rare reports of pancytopenia, including aplastic anemia, have
been reported with TNF blockers. Medically significant cytopenia
(e.g., leukopenia, pancytopenia, thrombocytopenia) has been
infrequently reported with CIMZIA. Advise all patients to seek
immediate medical attention if they develop signs and symptoms
suggestive of blood dyscrasias or infection (e.g., persistent
fever, bruising, bleeding, pallor) while on CIMZIA. Consider
discontinuation of CIMZIA therapy in patients with confirmed
significant hematologic abnormalities.
Drug Interactions
An increased risk of serious infections has been seen in
clinical trials of other TNF blocking agents used in combination
with anakinra or abatacept. Formal drug interaction studies have
not been performed with rituximab or natalizumab; however, because
of the nature of the adverse events seen with these combinations
with TNF blocker therapy, similar toxicities may also result from
the use of CIMZIA in these combinations. Therefore, the combination
of CIMZIA with anakinra, abatacept, rituximab, or natalizumab is
not recommended. Interference with certain coagulation assays has
been detected in patients treated with CIMZIA. There is no evidence
that CIMZIA therapy has an effect on in vivo coagulation. CIMZIA
may cause erroneously elevated aPTT assay results in patients
without coagulation abnormalities.
Autoimmunity
Treatment with CIMZIA may result in the formation of
autoantibodies and, rarely, in the development of a lupus-like
syndrome. Discontinue treatment if symptoms of lupus-like syndrome
develop.
Immunizations
Do not administer live vaccines or live-attenuated vaccines
concurrently with CIMZIA.
Adverse Reactions
In controlled Crohn's clinical trials, the most common
adverse events that occurred in >5% of CIMZIA patients (n=620)
and more frequently than with placebo (n=614) were upper
respiratory infection (20% CIMZIA, 13% placebo), urinary tract
infection (7% CIMZIA, 6% placebo), and arthralgia (6% CIMZIA, 4%
placebo). The proportion of patients who discontinued treatment due
to adverse reactions in the controlled clinical studies was 8% for
CIMZIA and 7% for placebo.
In controlled RA clinical trials, the most common adverse
events that occurred in >3% of patients taking CIMZIA 200 mg
every other week with concomitant methotrexate (n=640) and more
frequently than with placebo with concomitant methotrexate (n=324)
were upper respiratory tract infection (6% CIMZIA, 2% placebo),
headache (5% CIMZIA, 4% placebo), hypertension (5% CIMZIA, 2%
placebo), nasopharyngitis (5% CIMZIA, 1% placebo), back pain (4%
CIMZIA, 1% placebo), pyrexia (3% CIMZIA, 2% placebo), pharyngitis
(3% CIMZIA, 1% placebo), rash (3% CIMZIA, 1% placebo), acute
bronchitis (3% CIMZIA, 1% placebo), fatigue (3% CIMZIA, 2%
placebo). Hypertensive adverse reactions were observed more
frequently in patients receiving CIMZIA than in controls. These
adverse reactions occurred more frequently among patients with a
baseline history of hypertension and among patients receiving
concomitant corticosteroids and non-steroidal anti-inflammatory
drugs. Patients receiving CIMZIA 400 mg as monotherapy every 4
weeks in RA controlled clinical trials had similar adverse
reactions to those patients receiving CIMZIA 200 mg every other
week. The proportion of patients who discontinued treatment due to
adverse reactions in the controlled clinical studies was 5% for
CIMZIA and 2.5% for placebo.
The safety profile for patients with Psoriatic Arthritis
(PsA) treated with CIMZIA was similar to the safety profile seen in
patients with RA and previous experience with CIMZIA.
The safety profile for AS patients treated with CIMZIA was
similar to the safety profile seen in patients with RA.
For full prescribing information, please visit
www.cimzia.com
For further information
- Andrea Levin Christopher,
Associate Director, Public Relations & Communications, UCB,
Inc. T +1 770 970 8352, andrea.levin@ucb.com
References
1. Sandborn WJ,
Feagan BG, Stoinov S,et al. Certolizumab pegol for the treatment of
Crohn's disease. N Engl J Med. 2007;357:228-38.
2. Schreiber S, Khaliq-Kareemi M, Lawrence
IC, et al. Maintenance therapy with certolizumab pegol for Crohn's
disease. N Engl J Med. 2007;357:239-250.
3. Data on file. UCB, Inc; Smyrna, GA, 2010.
4. Lichtenstein GR, Thomsen OO, Schreiber
S, et al. Clin Gastroenterol Hepatol. 2010;8(7):600-609.
5. Vermeire S, Schreiber S, Sandborn WJ,
Dubois C, Rutgeerts P. Clin Gastroenterol Hepatol.
2010;8(4):357-363.
6. Harvey RF, Bradshaw JM. Lancet.
1980;1(8167):514.
About UCB
UCB, Brussels, Belgium
(www.ucb.com) is a global biopharmaceutical company focused on the
discovery and development of innovative medicines and solutions to
transform the lives of people living with severe diseases of the
immune system or of the central nervous system. With more than 8500
people in approximately 40 countries, the company generated revenue
of € 3.4 billion in 2013. UCB is listed on Euronext Brussels
(symbol: UCB). Follow us on Twitter: @UCB_news
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