Cimzia for adult patients with moderate to severely active rheumatoid arthritis.
UCB's Cimzia (certolizumab pegol), Shows Rapid and Sustained Clinical Response in Adult Patients Living with Moderate to Severe Rheumatoid Arthritis
UCB today announced data that showed rapid and sustained improvements in ACR20, physical function, pain and fatigue of rheumatoid arthritis (RA) as early as the first week, and inhibition of progression of structural joint damage (seen at week 24) following treatment with Cimzia® (certolizumab pegol), together with methotrexate (MTX), was sustained up to 100 weeks. Cimzia® is approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis. Cimzia® can be dosed at 400 mg initially and at weeks 2 and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered.
Also presented at the Annual Scientific Meeting of the American College of Rheumatology (ACR) in Philadelphia data from a post hoc analysis showed the speed of developing a clinical response to treatment with 200 mg Cimzia® and MTX, was important in improving long-term outcomes for patients living with active RA. The analysis found most patients achieved early control at Week 6. These patients had significantly better control of symptoms and significantly better improvements in pain and physical function at one year, compared to patients who achieved a later response at Week 12.
"These recently published data have shown Cimzia® to work rapidly, and demonstrate that an early response to treatment is associated with greater improvements in long-term outcomes," said lead investigator Edward Keystone, M.D., at The Rebecca MacDonald Center for Arthritis, Mount Sinai Hospital, The University of Toronto. "The data also confirm the rapid and sustained effect of Cimzia® in providing effective and clinically meaningful relief of rheumatoid arthritis, and reducing disease progression," he added. "This highlights the importance of getting the disease under control quickly in this debilitating condition which helps improve overall quality of life."
The post hoc analysis presented at the meeting investigated the relationship between the kinetics of response and long-term outcomes in patients who responded to treatment with 200 mg Cimzia® every 2 weeks and MTX, as measured by ACR20 response or change in DAS28 of greater than or equal to 1.2 from baseline.
Early Week 6 responders had significantly higher ACR20, ACR50 and ACR70 responses at Week 52, compared to the later Week 12 responders [ACR20 83.1% versus 66.7%; ACR50 66.7% versus 34.5%; and ACR70 39.0% versus 16.1%, respectively (p < 0.001)]. Patients with an early ACR20 response at Week 6 also experienced significantly greater improvements in physical function (HAQ-DI) and pain relief (VAS), compared to later Week 12 responders, and early Week 6 Disease Activity Score (DAS28) responders reported significantly greater pain relief (p < 0.001).
Radiographic data presented from the RAPID 1open-label extension study found the inhibition of progression of structural joint damage observed from baseline to Week 24 and Week 52 was maintained out to Week 100 in patients who completed treatment with Cimzia® and MTX. The mean change from baseline in modified total Sharp score (mTSS)(b) for the combined Cimzia® dose groups at Week 100 was 0.59.
In the same study rapid improvements in ACR(a) scores were sustained up to 100 weeks in patients maintained on open-label treatment with 400 mg Cimzia® every 2 weeks and MTX in the RAPID 1. ACR20 response rates at Week 100, in patients who completed treatment with Cimzia® were 68.2% and 69.5% for patients who originally received Cimzia® 200 mg or 400 mg every 2 weeks plus MTX, respectively. ACR50 response rates were 55.2% and 51.5% respectively. Similar results were also observed for DAS28, and patient reported outcomes such as physical function and health-related quality of life.
These and other Cimzia® data are available on display during the 2009 Annual Scientific Meeting of the American College of Rheumatology in Philadelphia, Oct. 17 - 21.
Serious and sometimes fatal side effects have been reported with Cimzia®, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens. In pre-marketing controlled trials of all patient populations combined the most common adverse reactions (greater than or equal to 8%) were upper respiratory infections (18%), rash (9%) and urinary tract infections (8%).
*About RAPID 1
RAPID 1 is a Phase III double-blind placebo-controlled trial, involving 982 adults, that was designed to establish the efficacy and tolerability of certolizumab pegol together with MTX, in the treatment of active RA in patients who did not adequately respond to conventional treatment. Patients were randomly allocated to receive one of three treatment regimens: 393 patients received certolizumab pegol 400 mg and at Weeks 0, 2 and 4, then 200 mg every two weeks; 390 patients received certolizumab pegol 400 mg every 2 weeks; 199 patients received placebo every 2 weeks. RAPID 1 met co-primary endpoints: ACR20 response rate at Week 24 and change from baseline in mTSS at Week 52. Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p less than or equal to 0.001); rates at Week 24 were 58.8%, 60.8%, and 13.6%, respectively, and remained significant at Week 52 (p less than or equal to 0.001). Certolizumab pegol 200 mg and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at Week 52 were 0.4 and 0.2, respectively, versus 2.8 for placebo (rank analysis p less than or equal to 0.001). Certolizumab pegol treated patients reported rapid, significant and clinically meaningful improvements in physical function versus placebo (p less than or equal to 0.001).
(+) Post hoc analysis of RAPID 1
The post hoc analysis of the RAPID 1 study aimed to determine if a more rapid response to certolizumab pegol, together with MTX, was associated with better long-term improvements in physical function, and relief of pain and fatigue, in the treatment of active RA in patients who did not respond to conventional treatment. Patients who responded to treatment with certolizumab pegol 200 mg every two weeks by Week 12 were divided into two subgroups: The earlier Week 6 responders and later Week 12 responders based on responder definitions: ACR20 response or DAS28 change of greater than or equal to 1.2 from baseline. The early Week 6 DAS and ACR20 responders had a higher probability of achieving ACR20/50/70 scores at Week 52 (p < 0.001). By ACR20 definition, 83.1% of the early Week 6 responders maintained an ACR20 response at Week 52 compared to 66.7% of the later Week 12 responders (p < 0.001).
(++) Open label extension study to RAPID 1(028)
The Phase III, open-label extension (OLE) study to RAPID 1 is investigating the long-term efficacy and safety of subcutaneous certolizumab pegol (400 mg every 2 weeks) together with methotrexate in the treatment of signs and symptoms and in the prevention of joint damage in patients with active RA. Patients completing RAPID 1 through 52 weeks (completers), or who were ACR20 non-responders at Week 12 (confirmed at Week 14) and were to be withdrawn from the study at Week 16 (with-drawers), could continue in the 028 study. The open-label extension study continued to evaluate the effects of certolizumab pegol ( ) over two years. This analysis was performed in completers (n= 508) with 100 weeks of exposure from RAPID 1 baseline. 95.8% of completers entered open-label treatment, and of these, 91.1% continued in the study after 100 Weeks. ACR response rates in these patients were sustained throughout the study. At Week 100, ACR20 response rates were 68.2% and 69.5% in patients who originally received certolizumab pegol 200 mg or 400 mg plus MTX, respectively. ACR50 response rates were 55.2% and 51.5 % respectively. At Week 100, 72.4% and 77.3% of certolizumab pegol 200 mg or 400 mg completers respectively, were mTSS non-progressors, as defined by a change from RAPID 1 baseline in mTSS of less than or equal to 0.05.
(a)ACR (American College of Rheumatology) response scores measure improvement in the tender and swollen joint count and also include assessment of the following five parameters: patient's global assessment, physician's global assessment, patient's assessment of pain, degree of disability, and level of acute-phase reactant. ACR20 is achieved when there is 20% improvement in the tender and swollen joint count as well as a 20% improvement in at least three of the five parameters. ACR50 and ACR70 are an extension of these criteria corresponding to a 50% and 70% improvement respectively.
(b)The modified total Sharp score (mTSS) is a measurement used to assess changes in bone erosion and joint-space narrowing measured by X-ray. A smaller change in mTSS reflects less progression of joint damage.
Cimzia® is the only PEGylated anti-TNF (Tumor Necrosis Factor). Cimzia® has a high affinity for human TNF-alpha, selectively neutralizing the pathophysiological effects of TNF-alpha. Over the past decade, TNF-alpha has emerged as a major target of basic research and clinical investigation. This cytokine plays a key role in mediating pathological inflammation, and excess TNF-alpha production has been directly implicated in a wide variety of diseases. The U.S. Food and Drug Administration (FDA) has approved Cimzia® for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderate to severe active disease who have had an inadequate response to conventional therapy and for the treatment of adults with moderate to severely active rheumatoid arthritis. Cimzia® was approved in Switzerland for induction of a clinical response and for the maintenance of a clinical response and remission in patients with active Crohn's disease who have not responded adequately to conventional treatment in September 2007. UCB is also developing Cimzia® in other autoimmune disease indications. Cimzia® is a registered trademark of UCB PHARMA S.A.
IMPORTANT SAFETY INFORMATION
Risk of Serious Infections
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 immuno-suppressants 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 extra-pulmonary 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.
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.
Serious and sometimes fatal infection due to bacterial, mycobacterial, invasive fungal, viral or other opportunistic pathogens has been reported in patients receiving TNF-blocking agents. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most common. 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 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 anti-fungal 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 Mycosis 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.
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. If such reactions occur, discontinue further administration of Cimzia ® and institute appropriate therapy.
Hepatitis B Reactivation
Use of TNF blockers, including Cimzia ® , may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. Some cases have been fatal. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating Cimzia ® therapy. 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 demyelinating disease. 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, abatcept, 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 auto-antibodies 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 attenuated vaccines concurrently with Cimzia ® .
In controlled Crohn's clinical trials, the most common adverse events that occurred in greater than or equal to 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 greater than or equal to 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 ® , 1% 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 ® 400mg as monotherapy every 4 weeks in RA controlled clinical trials had similar adverse reactions to those patients receiving Cimzia ® 200mg 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.
Please see full prescribing information at www.cimzia.com/rheumatoidarthritis/pdf/Prescribing_Information.pdf
UCB, Brussels, Belgium www.ucb.com is a biopharmaceutical company dedicated to the research, development and commercialization of innovative medicines with a focus on the fields of central nervous system and immunology disorders. Employing approximately 10,000 people in over 40 countries, UCB generated revenue of EUR 3.6 billion in 2008. UCB is listed on Euronext Brussels (symbol: UCB).