Improved attack

Rheumatoid arthritis (RA) is a chronic auto-immune disease which affects around 1 per cent of the adult population, globally. The disease is three times more common in women than in men, and new-onset disease tends to be diagnosed between 40 and 60 years of age.

RA sufferers experience inflammation and progressive destruction of the joint and joint tissue.

RA is phenotypically characterised by red, swollen, stiff and painful joints, with inflammation triggered by an up-regulated immune response, the cause of which is not currently known.

Certain environmental factors may play a part, and infections may also elicit the observed response. Some specialists believe the disease has a genetic component or basis, as multiple diagnoses have been observed within families.

Treatment of RA is multi-faceted, with patients typically prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, as well as disease-modifying antirheumatic drugs (DMARDs).

NSAIDs and corticosteroids act rapidly to relieve RA symptoms such as swelling, pain and inflammation. DMARDs, in contrast, act to suppress the immune system, improving symptoms in a preventative and longer-term manner. Recently, excitement has been growing in the area of DMARD research signalled by the presence of a new range of biological therapies in drug development pipelines ñ therapies that specifically target and inhibit key cells and messengers within the inflammatory cascade.

The cytokine tumour necrosis factor alpha (TNF-a) plays a central role in the inflammatory process, as it stimulates the production of inflammatory mediators, and increases the flux of immune and inflammatory cells into joint tissue. Inhibition of TNF-a has been shown to improve significantly the condition of patients with RA. In particular, certolizumab pegol has attracted much positive press.

Certolizumab pegol (Cimzia) is an anti-cytokine antibody fragment which binds with high affinity to TNF-a. The drug was originated by UCB, which revealed the results of its RAPID phase III trials at the 2007 European League Against Rheumatism (EULAR) Congress.

The RAPID 1 trial investigated the efficacy of certolizumab pegol in patients with active RA who were receiving concomitant methotrexate. A total of 992 patients were randomised to treatment with certolizumab pegol (200mg or 400mg every two weeks), or placebo.

After 24 weeks, a 20 per cent improvement in the American College of Rheumatology response criteria (ACR20) was achieved by only 14 per cent of placebo recipients, but by 59 per cent and 61 per cent of certolizumab pegol 200mg and 400mg recipients, respectively (primary endpoint; both p<0.001 vs placebo). More stringent response critieria, ie, ACR responses of 50 per cent (ACR50) or 70 per cent (ACR70), were also more common with active treatment than with placebo.

Efficacy data from RAPID 1 were confirmed by the results of RAPID 2. A total of 634 patients were enrolled in this trial, and treatment groups were identical to those in RAPID 1, except that a new liquid subcutaneous formulation of certolizumab pegol was utilised.

At the endpoint of the trial, an ACR20 was achieved by approximately 60 per cent of active treatment recipients, compared with less than 10 per cent of placebo recipients. Besides pure efficacy, RAPID 2 showed that certolizumab pegol improved patients' quality of life in a statistically and clinically significant manner.

The results of the RAPID series will be used to support a US submission for the use of certolizumab pegol in RA. UCB plans to make this submission in H2 2007.

Another TNF-a inhibitor in phase III development is golimumab, a therapy which was borne out of a collaboration between Medarexa and Centocor. Large multinational trials are currently underway, which will compare the efficacy and tolerability of golimumab and methotrexate, either as monotherapies or combination therapy. To date, phase II trial results have revealed that golimumab reduces RA disease activity.

B cells are increasingly viewed as a key player in the pathogenesis of RA. While the diverse roles of B cells have not yet been clearly defined, these cells are known to be involved in the activation
of T cells, the secretion of cytokines and the production of rheumatoid factor antibody.

Researchers have discovered a way to inhibit busy B cells ñ antagonism of the CD20 antigen. The CD20 transmembrane protein acts as a calcium channel and, by inhibiting its activity, B cells are unable to activate, differentiate and proliferate as they usually do.

Ocrelizumab is a CD20 antagonist currently in phase III development with Biogen Idec and Genentech, a subsidiary of Roche. According to Roche's product pipeline, regulatory filings are projected for post-2009, and at the present time it is recruiting patients for a number of large phase III trials.

Ofatumumab, another CD20 antagonist, is in phase II testing in patients with RA. However, Genmab (the originator) and GlaxoSmithKline (the worldwide licensee), are expected to initiate phase III trials in this indication by the end of 2007.

Like TNF-a, interleukin-6 (IL-6) is a cytokine which induces an acute-phase inflammatory response and, like certolizumab pegol and golimumab, tocilizumab is a novel therapy that can inhibit cytokine activity.

Tocilizumab (Actmera) was originated by Chugai Pharmaceutical, and because of this, the drug has already been filed for approval in the Japanese market. Phase III testing continues in the US and European markets, and regulatory filing is expected at some point this year. A wealth of recently published data will likely ease the application process for Chugai. Most significantly in 2007, the results of the OPTION trial (tOcilizumab Pivotal Trial in methotrexate Inadequate respONders) were revealed.

This trial was the first multinational phase III investigation of tocilizumab. In OPTION, 623 patients with moderate-to-severe RA were randomised to receive tocilizumab 4mg or 8 mg/kg, every four weeks, or placebo. All patients continued their baseline methotrexate therapy.

After 24 weeks, an ACR20 response was achieved by 48 per cent and 59 per cent of tocilizumab recipients, respectively, but only 27 per cent of placebo recipients. ACR50 and ACR70 response rates were also greater with tocilizumab, and disease activity was reduced after only two weeks of this treatment (p<0.001 for all comparisons between tocilizumab and placebo).

Tocilizumab improved patients' quality of life in a manner which investigators considered well above generally accepted thresholds for [a] minimal clinically important difference.

As the pathogenesis of RA is elucidated, more and more treatment targets should arise. Physicians with more prescribing options are better equipped to tackle this chronic disease, and patients with more treatment options are more likely to enjoy personalised, effective care. The extension of Hippocrates' wisdom is clear, and can be summed up by another, better-known dictum: knowledge is power.