New Advances In Anti-TNF Therapy For RA

Author: Nicola O’Connell

Golimumab, a new anti-tumour necrosis factor (TNF) treatment, has shown that it is a promising treatment option for different patient groups with rheumatoid arthritis (RA), including patients for whom anti-TNF therapies have previously failed. New findings, presented at the European League Against Rheumatism (EULAR) Annual Congress of Rheumatology in June, indicate that this second-generation, fully human monoclonal antibody is likely to become a key therapy in RA management. Golimumab is currently in the most comprehensive Phase III development programme to date for an anti-TNF alpha biologic therapy. The GOlimumab After Former anti-TNF Therapy Evaluated in RA (GO-AFTER) study, involving 461 patients with active RA, was the first randomised, double-blind study in patients with active RA who had previously received another anti-TNF inhibitor. Findings showed that 35 per cent and 38 per cent of patients receiving every four-week subcutaneous injections of golimumab 50 mg and 100 mg, respectively, achieved the primary endpoint of at least 20 per cent improvement in arthritis symptoms (American College of Rheumatology [ACR] 20) at week 14, compared with 18 per cent of patients receiving placebo. These results were maintained through six months. Interestingly, 58 per cent of patients whose prior anti-TNF-alpha therapy had been discontinued due to lack of efficacy experienced a significant improvement with golimumab. “Our findings show that golimumab holds great promise in various RA patient populations, including those patients who have previously discontinued other TNF inhibitors,” said Josef S. Smolen (left), MD, professor and Chairman, Department of Rheumatology, Medical University of Vienna and lead study investigator. “Golimumab may provide an appropriate treatment option to the many people facing the consequences of this debilitating disease.”

In combination with MTX

Two additional studies presented at EULAR demonstrate that golimumab significantly improves signs and symptoms of RA among methotrexate (MTX)-naïve patients, as well as patients with active RA despite ongoing treatment with MTX. The GOlimumab Before Employing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset (GO-BEFORE) study involved 637 patients who had not previously been treated with disease-modifying antirheumatic drug (DMARD) MTX. Patients treated with golimumab in combination with MTX experienced improvement in signs and symptoms of arthritis as well as in disease activity. In the primary analysis of the combined group of patients receiving either golimumab 50 mg or 100 mg in combination with MTX, 38 per cent achieved at least 50 per cent improvement in signs and symptoms of RA (ACR 50) through week 24, compared with 29 per cent of patients receiving placebo plus MTX.

RA Statistics

• More than 350,000 people in Britain and over 9.7 million people worldwide have rheumatoid arthritis
• According to the World Health Organization, the incidence of RA in Europe is expected to increase over the next decade as the population ages.
• The most common age for the disease to start is between 40 and 50
• RA occurs approximately two to three times more often in women than in men.
• Although the cause of RA is not known, genetic and environmental factors may contribute to the disease.
• As well as inflammation of the joints, swelling, difficulty moving, and pain, symptoms of RA also include loss of appetite, fever, loss of energy, and anaemia.
• If not monitored and treated as early as possible, RA can cause serious joint deformation in 70-80% of patients.
• The joint pain of RA can impact a patient’s ability to perform normal daily activities, limit job opportunities, and make family and household responsibilities a challenge.
• Many RA patients experience some degree of depression, anxiety, and/or feelings of helplessness.

In the GOlimumab FOR subjects With Active RA Despite MTX (GO-FORWARD), study, both the 50 mg and 100 mg doses of golimumab were studied in patients whose disease was active despite ongoing treatment with MTX. The study, which involved 444 patients, found that 55 per cent of patients receiving golimumab 50 mg plus MTX experienced at least 20 per cent improvement in signs and symptoms of RA (ACR 20) at week 14, compared to 33 per cent of patients receiving placebo and MTX. Improvements were seen after the first clinical assessment, which was four weeks after the first golimumab injection, and generally continued to improve over time.

Further development of anti-TNF therapy

It is anticipated that golimumab will be launched in the UK in early 2009, following the March 2008 application to the European Medicines Agency, requesting its approval as a monthly subcutaneous treatment for adults with RA, psoriatic arthritis and ankylosing spondylitis. The drug will join three other anti-TNFs currently available in the UK and approved by NICE to treat RA: etanercept, infliximab and adalimumab. Since the discovery that TNF· plays a role in RA, the introduction of anti-TNF agents has helped to revolutionalise treatment for patients. The agents were discovered by Emeritus Professor Sir Ravinder Maini and Professor Marc Feldmann, of the Kennedy Institute of Rheumatology in London. The researchers found that proinflammatory cytokines were present in inflamed joints, and that a single cytokine – TNF – could drive the disease process. Anti-TNFs represent an important advancement over the older DMARDs, which include MTX, sulfasalazine, leflunomide and azathioprine. While these traditional drugs target broad aspects of the immune disease, aiming to dampen down the immune system, anti-TNFs have a more specific mode of action. The biological therapies work by switching off TNF, which stimulates cells to produce the inflammation response leading to swelling of joints and pain. Anti-TNF therapies have been shown to not only diminish signs and symptoms of the disease, but also prevent joint damage. Randomised, placebo-controlled, multi-centre clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to two years, in addition to their ability to retard joint damage (Feldman, 2001). Most of the patients studied were already using disease-modifying drugs, or had failed to improve on them, but research also suggests that earlier treatment with the agents can be as, if not more, beneficial (Breedveld, 2004; Baumgartner, 2004).

NICE guidance

However, the use of these agents is more restricted in the UK than elsewhere. Comments Paul Emery (right), Professor of Rheumatology and Lead Clinician of Rheumatology at Leeds Teaching Hospitals, lead investigator of the GO-BEFORE study and new President-Elect of EULAR: “The UK has the lowest use of anti-TNFs in Europe and the situation is very unsatisfactory for patients. “These drugs make a huge difference to how patients feel and the opportunity to use them as optimal therapy would make the biggest change in RA management. In the US, the agents are used from the beginning, and much better results are produced.” Currently, the National Institute for Health and Clinical Excellence (NICE) recommends that anti-TNF therapy is prescribed for patients with active RA who have been treated with at least two DMARDs (one should be MTX), which have failed to suitably control the disease, have not sufficiently reduced symptoms or have produced adverse events. By comparison, a recently updated consensus statement on biological treatments, by experts in Europe and the USA, still advises that biological treatments should be considered after the failure of one DMARD in patients with active RA – although active RA is undefined (Furst, 2005). The NICE guidelines state that two pre-assessments of Disease Activity Score (DAS28) should be performed a month apart. In an article published in Rheumatology last year, Smith et al questioned the need for this preassessment protocol, and after performing a retrospective audit of data from six centres to determine the stability of DAS28 between assessments, they found that there is no significant change in the DAS28 over the month waiting to go onto anti-TNF therapy. Therefore, they concluded a single assessment of the DAS28 would suffice to enable patients to go on to anti-TNF treatment (Smith, 2007). NICE has also been criticised for its recent decision – announced at the end of July – advising against allowing patients to use a second anti-TNF treatment for RA if the first is not effective. Ailsa Bosworth, Chief Executive of the National Rheumatoid Arthritis Society, commented: “This decision is another nail in the coffin for the treatment of RA in England and Wales. NICE are re-writing the rules of RA treatment in this country ignoring the clinical effectiveness of drugs and ignoring the views of patients and clinicians.” Anti-TNFs are, without question, a major leap forward in the treatment of RA. For some patients, they have the potential to transform management. As Professor Emery says: “Patients who are more likely to get structural damage would benefit most from anti-TNF therapy with MTX. We can identify these patients and easily model the treatment to those patients.” As it stands, the NICE guidance restricts the use of anti-TNFs in the UK; consequently, not all patients who could benefit from them are benefitting from them. But new evidence, such as the GO-AFTER study, and the introduction of new drugs, like golimumab, may lead to broader recommendations and enable many more patients with RA to benefit from anti-TNF therapies.

References

1. Baumgartner SW, Fleischmann RM, Moreland LW et al. Eternercept (Enbrel) in patients with rheumatoid arthritis with recent onset versus established disease: improvement in disability. J Rheumatol. 2004 31: 1532-1537
2. Breedveld FC, Emery P, Keystone E et al. Infliximab in active early rheumatoid arthritis. Ann Rheum Dis. 2004 63: 149-155
3. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163-96
4. Furst D, Breedveld F, Kalden J et al. Updated consensus statement on biological agents, specifically tumour necrosis factor (TNF·) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases. Ann Rheum Dis. 2005 64:iv2–iv14
5. Smith N, Gadsby K, Butt S, Carruthers D, Deeming A et al. Is pre- assessment for anti-TNF therapy in RA necessary in the UK? Analysis of DAS28 in six centres. Rheumatol 2007;46(10):1557-9