, 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.
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.
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.
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.
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.
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.
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.
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.
Do not administer live vaccines or live-attenuated vaccines concurrently with CIMZIA.
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, firstname.lastname@example.org
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.
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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