Actemra - Biological Therapy for Rheumatoid Arthritis (RA)

The European Commission has approved Roche Pharmaceuticals' Actemra (tocilizumab), known as Actemra outside the EU, to treat patients with rheumatoid arthritis (RA), in late January 2009.

A combination of Actemra and methotrexate (MTX) can be used for the treatment of adult patients with moderate to severe RA who failed to respond to, or were intolerant to, previous therapy with one or more tumour necrosis factor (TNF) antagonists or disease modifying anti-rheumatic drugs (DMARDs).

Actemra is therefore appropriate where continued MTX treatment is not beneficial or to patients who are MTX intolerant. It can be given as monotherapy where Actemra is the interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody.

Roche conducted five multinational Phase III studies as part of its clinical development of Actemra, which demonstrated that treatment with Actemra as a monotherapy or a combination with MTX or other DMARDs, reduced signs and symptoms of RA compared with other therapies.

Actemra approved in Japan

Actemra was first deployed in Japan when Chugai (part of the Roche Group) filed for approval for its use as a treatment for RA in adult patients and for children with systemic onset Juvenile Idiopathic Arthritis (sJIA), a particularly serious form of arthritis.

Filing was based on phase III data from trials conducted in Japanese patients that showed first-line use of Actemra significantly improved signs and symptoms of RA while also reducing disease progression.

In April 2008, the company received the green light from the Japanese authorities to market the drug for RA. Actemra has also been approved in Japan for the treatment of Castleman's disease, a rare condition that causes severe lymph node enlargement.

Approval in Japan hinted at success in other countries. Submissions were made to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) in November 2007. The filings were based on a substantial body of trial data which showed that Actemra significantly reduced signs and symptoms of RA when use either alone or in combination with standard treatments.

Worldwide Actemra approval status

Actemra is currently approved in the EU, Japan, Switzerland, India, Brazil, Kuwait, Peru, Moldova and Liechtenstein. It is now awaiting regulatory nod in the US and other countries worldwide.

Phase III trials support clinical efficacy

Data from phase III trials conducted in Japan have shown that Actemra is an effective therapy for RA and sJIA. In the pivotal Japanese trials in adult patients with RA, in which Actemra was compared with established DMARDs, patients in the Actemra arm of the study achieved significantly greater improvement in signs and symptoms of RA as well as significantly less radiographic joint destruction (p=0.001).

Similar positive results have now been reported from pivotal phase III trials conducted outside Japan. These trials include OPTION (TOcilizumab Pivotal Trial in Methotrexate Inadequate responders), a three-arm, randomised, double-blind, controlled study designed to compare the safety and efficacy of Actemra plus methotrexate with methotrexate plus placebo in RA patients who had an inadequate response to methotrexate alone, and RADIATE (RheumAtoiD ArthritIs Study in Anti-TNF FailurEs) among others.

Actemra was generally well tolerated by patients enrolled in the Japanese and international clinical trials programme.

Marketing commentary

RA is a chronic, progressive autoimmune disease for which patients often require long-term therapy. Biological response modifiers offer the prospect of not only providing symptom relief but also the potential to stop disease progression, the ultimate goal of therapy.

In addition to Actemra, Roche has also been exploring the potential of its targeted B-cell therapy MabThera / Rituxan (rituximab) as a treatment for RA. MabThera / Rituxan (rituximab) is currently marketed for the treatment of B-cell lymphomas.

In March 2006, Roche secured FDA approval for use of MabThera / Rituxan (rituximab) in adult patients with RA unresponsive to current biological therapies, among the most difficult group of RA patients to treat.

Roche in rheumatoid arthritis

Roche is currently working on a pipeline of potential drug candidates for the treatment of RA using several approaches. It is exploring MabThera, the selective B-cell therapy for RA, which provides a fundamentally different treatment approach targeting B-cells.

Actemra is a humanised monoclonal antibody to the IL-6 receptor, inhibiting the activity of IL-6, a protein that plays a key role in the RA inflammation process. Roche has begun Phase III development of Ocrelizumab, a humanised anti-CD20 antibody, for RA.

Pro-inflammatory cytokines as therapeutic targets

Biological response modifiers, which target inflammatory mediators of RA, represent a relatively new approach to the treatment of RA and, indeed, of other autoimmune diseases.

Medications targeting tumour necrosis factor alpha (TNF-a), a pro-inflammatory cytokine implicated in the pathogenesis of RA, were among the first to be developed and approved for the treatment of RA. Several anti-TNF-a medications are currently marketed for the treatment of RA.

Actemra (tocilizumab) differs from currently marketed biological response modifiers in targeting interleukin-6 (IL-6), a cytokine that is over-produced in the joints of RA patients.

Il-6 is believed to contribute to inflammation, swelling and joint damage and possibly thrombocytosis in RA. It is also elevated in the serum of patients with sJIA and believed to contribute to clinical signs and symptoms of this disease.

sJIA affects about 10-20% of children with juvenile inflammatory arthritis.

Actemra is a humanised anti-human IL-6 receptor monoclonal antibody that works by competitively blocking the binding of IL-6 to its receptor. Thus, it inhibits the proliferative effects of IL-6, which lead to synovial thickening and pannus formation in RA.

Unmet clinical need in RA

Rheumatoid arthritis is a relatively common autoimmune disease, estimated to affect about 1% of the world's population. The disease is characterised by aberrant immune mechanisms that lead to joint inflammation and swelling with progressive destruction of joints. In addition to affecting the joints, RA can also affect connective tissue in the skin and organs of the body.

Traditional approaches to the treatment of RA include the use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), COX-2 inhibitors, and so-called Disease-Modifying Anti-Rheumatic Drugs (DMARDs) such as methotrexate.

None of these traditional approaches to treatment is however ideal, especially in long-term use. Although treatment has advanced with the recent introduction of biological response modifiers, RA remains a disease for which there is still significant unmet clinical need.