New generation anti-TNF drug Cimzia (certolizumab pegol) may offer faster control of RA

Certolizumab pegol (Cimzia) is a PEGylated Fc-free anti-TNF alpha agent, administered subcutaneously, and currently licensed in the US and Switzerland for treatment of Crohn’s Disease. By not having the Fc region present in conventional anti-TNFs, Cimzia retains the potency of anti-TNFs without the possible cytotoxicity mediated by Fc. In vitro, Fc activates the complement pathway and can cause cell-dependent or antibody dependent cell-mediated cytotoxicity (ADCC). Like other anti-TNF drugs, Cimzia has shown a small excess of serious adverse events, including infections and malignancies, over placebo but the safety profile is acceptable given the outcome of inadequately-controlled RA, say researchers.

Cimzia is now being extensively evaluated in rheumatoid arthritis (RA) and other auto-immune disease indications including psoriasis. The safety and efficacy of Cimzia in RA in combination with standard methotrexate (MTX) therapy has been explored in two double-blind phase III trials, RAPID 1 and RAPID 2. RAPID 1 is a year-long trial of 982 patients randomly allocated to receive one of three treatment regimens together with methotrexate (MTX) 10-30mg. In arm 1, 393 patients were randomised to the lyophilised formula of Cimzia 400mg at baseline and at weeks 2 and 4, followed by 200mg every other week. In arm 2, 390 patients received Cimzia 400mg every other week. In the remaining arm, 199 patients were randomised to placebo every two weeks. RAPID 2 is a six-month trial in which 619 patients were randomised to the liquid formula of Cimzia in three treatment arms as in RAPID 1 – 246 to each of arms 1 and 2 and 127 to placebo.

Co-primary endpoints for RAPID 1 were the American College of Rheumatology 20 (ACR20) score which looks for a 20 per cent improvement on a range of subjective and objective measures at week 24, and the change from baseline in the modified Total Sharp Score (mTSS) – a composite of bone erosion and joint space narrowing measurements reflecting progressive damage – at one year. The primary endpoint of RAPID 2 was the ACR20 responder rate at week 24.

The goal of treatment for RA is to achieve remission, ie, to suppress inflammatory disease activity completely or to such a low level that it has minimal impact on joint structures and physical function. It is now acknowledged that there is a “window of opportunity” when patients exhibit symptoms of RA, before the disease has caused structural damage to joints, when clinicians can intervene to arrest disease and prevent later deformity and disability. The strategy has been described as “the oncological model” because it draws parallels with the success that effective interventions can achieve at an early stage of cancer, preventing metastasis and death, whereas treatments instigated later in the disease process produce only modest benefits. RA treatments are initially evaluated on the basis of standard measures such as the ACR20 or the Disease Activity Score 28 (DAS28) a measure of disease activity in 28 swollen and tender joints. The cumulative effects of inflammation on joint cartilage and bone and the impact of treatment on preventing structural changes over a longer time period is measured radiologically, comparing X rays taken before and several months after starting therapy. Changes are assessed using the mTSS. Assessing the impact of treatment on physical function, quality of life or on ability to hold down a job or complete household tasks is carried out by validated patient questionnaires. All these parameters were explored in patients participating in RAPID 1 and RAPID 2.

Structural damage-limitation by Cimzia starts early
New data analyses from the two studies featured in 11 presentations at EULAR. Of these, one of the most interesting concerned 16-week radiographic data of patients from both RAPID trials who appeared not to be responding clinically to the drug. Patients not meeting the ACR20 criteria for clinical response to either of the two Cimzia/MTX regimens, or to placebo/MTX, were regarded as treatment failures and were withdrawn at week 16. Around 20 per cent of Cimzia/MTX-treated subjects withdrew from each trial compared to 61 per cent of placebo/MTX patients in RAPID 1 and 80 per cent in RAPID 2. Radiographic assessments of these patients’ joints were then compared against baseline X rays.

Describing the findings at EULAR, Professor Desiree van der Heijde of Leiden University Medical Centre, Leiden, The Netherlands, said it was considered unethical to leave patients on treatments to which they were not responding beyond 16 weeks. The trial design therefore included an ‘escape’ point at week 16 when non-responders could be offered an alternative open-label treatment. The withdrawn 276 patients in RAPID 1 and 207 in RAPID 2 had shown little change in RA disease activity from baseline but X rays of patients randomised to Cimzia/MTX showed significantly lower mTSS measures than those of placebo/MTX-treated patients,” she reported. Assessment scores were calculated by three ‘blinded’ independent reviewers. Data presented in oral session showed that, compared to placebo, Cimzia had significantly reduced the mean change in mTSS score from baseline. Mean change in mTSS scores were 1.0 for placebo/MTX but only 0.2 for Cimzia/MTX-treated patients withdrawn from RAPID 1 and were 0.8 vs 0.2 respectively for patients withdrawn from RAPID 2.

Mean TSS score change from baseline compared to placebo/MTX was even better for Cimzia/MTX-treated patients in RAPID 1 and 2 who completed 52 and 24 weeks prior to final assessment, she noted. In patients receiving the higher 400mg dose plus MTX in RAPID 2 not only was less radiographic progression seen but reversal of changes and repair was evident. Results were irrespective of the baseline dose of MTX that patients were using. “This demonstrates that radiographic assessment is sufficiently sensitive to pick up effects on structural preservation as early as 16 weeks and supports shorter-term imaging studies in RA,” she concluded. Assessment at 12 weeks may even be feasible, she added. Normally a 24-week time point is the earliest used to assess effects on joint protection. “To be able to do this three months earlier is a big advance,” she commented.

Treatment response by week one

New data also suggest the drug may be the fastest TNF alpha inhibitor in reducing clinical signs and symptoms of RA. “Treatment benefit was observed with Cimzia and MTX as early as the first week in the two RAPID trials, with around 50 per cent of patients either achieving an ACR20 response or at least an average of 20 per cent improvement in ACR core set measures at this time point”, reported Professor Ronald van Vollenhoven of the Karolinska University Hospital, Stockholm, Sweden and colleagues. Commenting on the results Professor Arthur Kavanaugh of University of California said: “Patients feel so much better so quickly. Combination treatment is the gold standard but even with Cimzia monotherapy, a very clinically significant response is seen. making this an option for patients who choose not to go on MTX.”

As early as week one, patients treated with Cimzia/MTX also saw highly significant improvements in physical function compared to patients treated with placebo/MTX according to Health Assessment Questionnaire – Disability Index (HAQ-DI) scores which were sustained through to the end of the trials (p<0.001), reported Dr Vibeke Strand of Stanford University, California, USA, and colleagues. The proportion of patients remaining on active treatment at either Cimzia dose in RAPID 1 and 2, who experienced clinically meaningful improvements (MCID >0.22 points) in the HAQ-DI at week one was between 40 and 46 per cent. By the end of the studies the proportions had risen to between 83 and 86 per cent in RAPID 1 and between 79 and 90 per cent in RAPID 2. Health-related quality of life (HTQoL) assessments using SF-36 scores from week 12 to study end also showed sustained and clinically meaningful improvements for Cimzia/MTX regimens compared to placebo/MTX (p<0.001), reported Dr Strand’s group.

Pain and fatigue are key factors influencing patients’ quality of life, reported Dr Peter Taylor on behalf of the steering committee for DESIGN, a study of 756 patients’ and 501 physicians’ perceptions of RA. Pain control in RA is an unmet need because despite treatment with currently available DMARDS and biologic drugs, RA patients’ pain levels remain unacceptably high for more than one third, he emphasised. Patients taking a biologic treatment for their RA experience less pain, he noted, and patients participating in RAPID saw a significant reduction in pain and fatigue with both doses of Cimzia/MTX, especially those receiving treatment for one year in RAPID 1.

A new area of study in RA is the impact of treatment on the number of extra days patients feel well enough to attend work, have fully productive days whilst at work, or feel able to cope with household tasks. Patients in RAPID 1 and 2 were questioned about work performance using a novel RA-specific Work Productivity Survey, reported Professor Johanna Mieke Hazes of Erasmus University, Rotterdam, The Netherlands. Results showed patients randomised to Cimzia and MTX gained at least one work day per month by week 4, increasing to a monthly average gain of 1.5 to 3 days by week 24. This compared to less than 2 days by week 4 and less than half a day by week 24 reported by patients receiving placebo/MTX. In both trials patients treated with Cimzia/MTX reported an increase in productivity whilst at work of between 2 and 3.8 days per month, and continuing improvement over six months to 4.6 to 6.6 days by week 24. . This compared to a less than one-day increase or a worsening in placebo/MTX treated patients. ‘”This is a very responsive questionnaire,” commented Professor Hazes. “It would give a patient treated with Cimzia/MTX around 70 more productive days per year. Improvement is seen within a month and that’s important for recently diagnosed patients wanting to hold down a job,” she remarked. Productivity in home-based activities for the 60 per cent of patients unable to work also improved gaining them between 50 and 92 days of productive activity, she added. “Work outside and inside the home is an important outcome in RA. It should be measured in trials and be a focus of routine clinical practice. It can make a difference,” she concluded.

UCB, the manufacturers of Cimzia, filed a Biologics License Application for Cimzia to treat adult RA with the US FDA in February 2008. A Marketing Authorisation Application to the European Medicines Agency for Cimzia to treat RA is expected shortly.