Novel PEGylated Anti-TNF Drug Cimzia Is First To Demonstrate X-ray Proof Of Significant Early Joint Protection In Rheumatoid Arthritis

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Main Category: Arthritis / Rheumatology
Also Included In: Clinical Trials / Drug Trials
Article Date: 17 Jun 2008 - 0:00 PDT

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The first PEGylated, Fc-free, anti-tumour necrosis factor (TNF) alpha agent Cimzia (certolizumab pegol), in development for rheumatoid arthritis (RA) as an add-on therapy to methotrexate (MTX), has demonstrated X-ray evidence of ability to protect joints from structural damage at an unprecedented early stage (16 weeks). Even more remarkable is that the protective effect was demonstrated in patients apparently not responding to the drug clinically. The finding may have implications for future clinical trial design and treatment evaluation. There is growing recognition that early effective treatment in RA, especially aggressive disease, is vital to achieve remission before irreversible joint damage and loss of physical function occurs. Ideally patients should start treatment within 10 to 12 months of experiencing their first symptoms, say experts.

Data presented at the 9th Annual European Rheumatology Congress (EULAR) meeting in Paris 11-14 June 2008 show that, compared to a placebo/MTX combination, Cimzia added to standard MTX significantly reduced mean modified Total Sharp Score (mTSS) - a measure of bone erosion and joint space narrowing evaluating whether joint destruction is progressing - as early as 16 weeks after commencing treatment. Findings emerged in patients withdrawing from treatment because of apparent lack of response on other measures.

Patients were participating in two randomised double-blind phase III trials, RAPID 1 and RAPID 2, evaluating safety and efficacy of two subcutaneously-administered doses (200 and 400mg) of Cimzia and 10-30mg MTX, against placebo and MTX, at 52 and 24 weeks respectively. RAPID 1 is a year-long trial of 982 patients randomly allocated to receive one of three treatment regimens together with 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. Both formulas are effective.

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 mTSS reflecting progressive damage, at one year. The primary endpoint of RAPID 2 was the ACR20 responder rate at week 24.

Patients not meeting usual ACR20 criteria for clinical response were considered treatment failures and were withdrawn at week 16 so they could switch to an alternative treatment. 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 were then compared against baseline X- rays.

Professor Desiree van der Heijde of Leiden University Medical Centre, Leiden, The Netherlands, said patients withdrawn from the trials showed little change in RA disease activity from baseline but X rays of those randomised to Cimzia/MTX (assessed by 3 blinded independent reviewers) showed significantly lower mTSS measures than those of placebo/MTX-treated patients. The mean mTSS score was even lower compared to placebo for patients who continued Cimzia/MTX for 24 and 52 weeks. For the 400mg dose, there was not only evidence of less progression but of damage reversal and repair. "This supports shorter-term imaging studies in RA," she concluded. This was one of the earliest known time points when treatment effects on joint protection were demonstrable. Normally radiographic assessment of treatment efficacy in preventing structural damage is not performed until six months after starting treatment. However, this may now be possible as early as 12 weeks. "To be able to do this three months earlier than usual is a big advance" she commented. "Early radiographic evidence of benefit depends on how effective a drug is and its speed of onset". Progressive structural damage is linked to impaired physical function and deterioration in ability to work so the finding has important implications.

Benefits appear as early as one week

Other data at EULAR show Cimzia appears to be the fastest anti-TNF in reducing clinical signs and symptoms of RA when added to MTX. "Treatment benefit was observed with Cimzia/MTX as early as within the first week of starting therapy, 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 Karolinska University Hospital, Stockholm, Sweden and colleagues. The earliest reported response for other anti-TNFs is 2 weeks.

As early as week one, patients treated with Cimzia/MTX also saw highly significant improvements in physical function and health-related quality of life 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 with 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 were made using SF-36 scores from week 12 to study end. These showed sustained and clinically meaningful improvements for Cimzia/MTX regimens compared to placebo/MTX (p<0.001), reported Dr Strand's group.

The key factors influencing patients' quality of life are pain and fatigue, 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 in more than one third of cases, he stressed. Patients taking a biologic treatment for their RA are likely to experience less pain, he noted. Patients participating in the two RAPID trials 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 working ability, including the number of extra days patients feel well enough to work, the number of complete, fully productive days they experience whilst at work, or the days they are 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 continued to experience improvement in productivity 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. It means more patients can hold down a job from the start," 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 extra 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.

Safety data for Cimzia show a small but acceptable excess of serious adverse events compared to placebo (7.3 vs 3.2 percent in RAPID 1 and 14.8 vs 12 per cent in RAPID 2) including infections, say researchers. The most common infections reported were urinary tract infections, nasopharyngitis and upper respiratory tract infections.

• Cimzia currently has approval in Switzerland and the US to treat Crohn's disease. UCB, the company developing the drug, 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 in Europe is expected shortly.

-- www.nektar.com/wt/page/cimizia
-- www.cimzia.com/Default2.asp

Written by Olwen Glynn Owen
glynnowen(at)macline.co.uk


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