New Data Showed Cimzia(R) Provided Rapid And Sustained Clinical Response, And Reinforces Need For Rapid-acting Treatments For RA

Main Category: Arthritis / Rheumatology
Article Date: 12 Jun 2009 - 3:00 PDT

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UCB today announced data that showed rapid and sustained improvements in symptoms of RA, as early as the first week, and inhibition of progression of structural joint damage (seen at week 24) following treatment with certolizumab pegol, together with methotrexate (MTX), was sustained for two years. The results from an open-label extension study*** to RAPID 1*, were presented at the European League Against Rheumatism (EULAR) meeting in Copenhagen.

New data from a post hoc** analysis, also presented at EULAR, showed the speed of developing a clinical response to treatment with 200 mg certolizumab pegol and MTX, is important in improving long-term outcomes for patients living with active RA. The analysis found most patients responded by Week 6. Patients who achieved control early at Week 6 had significantly better control of symptoms and quality of life at one year, compared to patients who achieved a later response at Week 12.

"These data confirm the rapid and sustained effect of Cimzia® in providing effective and clinically meaningful relief of rheumatoid arthritis, and reducing disease progression," said lead investigator Edward Keystone, M.D., The Rebecca MacDonald Center for Arthritis, Mount Sinai Hospital, The University of Toronto. "Recently published clinical data have shown Cimzia® to work rapidly, demonstrating an early response to treatment is associated with greater improvements in long-term outcomes, such as pain relief and physical function. This highlights the importance of using rapid-acting treatments to control inflammation in this debilitating condition."

The RAPID 1 extension study*** showed that rapid improvements in ACR[a] scores were sustained for two years in patients maintained on open-label treatment with 400 mg certolizumab pegol every 2 weeks and MTX. In the study, ACR20 response rates at Week 100, in patients who completed treatment with certolizumab pegol for two years, were 68.2% and 69.5% for patients who originally received certolizumab pegol 200 mg or 400 mg every 2 weeks plus MTX, respectively. ACR50 response rates were 55.2% and 51.5% respectively. Additionally, similar results were observed for Disease Activity Score (DAS28), and patient reported outcomes such as physical function and health-related quality of life.

Radiographic data presented in the same study, found the inhibition of progression of structural joint damage observed in RAPID 1* at 24 and 52 weeks in patients who completed treatment with certolizumab pegol and MTX, compared to MTX alone (p<0.001), was maintained at 100 Weeks. The mean change from baseline in modified total Sharp score (mTSS)[b] for the combined certolizumab pegol dose groups was 0.59.

A fast clinical response leads to better long-term outcomes

The separate 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 certolizumab pegol every 2 weeks and MTX, as measured by ACR20 response or change in DAS28 of >=1.2 from baseline.

Patients who had a rapid clinical response to certolizumab pegol early at Week 6 had a higher probability of improved quality of life and significantly better symptom control compared to the later responders at Week 12.

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 DAS28 responders reported significantly greater pain relief (p<0.001).

A comprehensive clinical development programme, involving more than 2 300 patients with RA and over 4 000 patient-years experience, and including four multi-centre placebo-controlled phase III clinical trials, have established the efficacy and tolerability of certolizumab pegol in the treatment of RA.

In the pivotal clinical trials, reported serious adverse reactions included infections (including tuberculosis) and malignancies (including lymphoma). The most commonly occurring adverse events were upper respiratory tract infections, rash and urinary tract infections. A pooled analysis of the safety data showed there was a low incidence of injection site pain (1.5%) and a low level of discontinuations due to adverse events (5%). Certolizumab pegol demonstrated a favorable risk-benefit profile in patients with at least up to two years of drug exposure.

The U.S. Food and Drug Administration (FDA) recently approved Cimzia® for the treatment of adult patients with moderately to severely active RA. Per the U.S. label, Cimzia® can be dosed as monotherapy or in combination with disease-modifying anti-rheumatic drugs (DMARDs) at 400 mg initially (given as two subcutaneous injections of 200mg) initially and at Weeks 2 and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every four weeks can be considered.

UCB submitted a Marketing Authorisation Application to the European Medicines Agency in June 2008 requesting the approval of Cimzia® (certolizumab pegol) in combination with MTX, for the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to DMARDs including MTX, has been inadequate.

*About RAPID 1

The Phase III double-blind placebo-controlled trial, involving 982 adults, 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<= 0.001); rates at Week 24 were 58.8%, 60.8%, and 13.6%, respectively, and remained significant at Week 52 (p<= 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<= 0.001). Certolizumab pegol treated patients reported rapid, significant and clinically meaningful improvements in physical function versus placebo (p<= 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 >=1.2 from baseline. 78% (200/257) of patients who responded at ACR20 by Week 12 achieved a change in DAS28 by Week 6. 67% (178/265) of patients achieved an ACR20 response by Week 6. 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 nonresponders at Week 12 (confirmed at Week 14) and were to be withdrawn from the study at Week 16 (withdrawers), 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= 345) 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 <=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.

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Cimzia