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PRIORITY PRESS - 10th Annual European Congress of Rheumatology (EULAR)

Copenhagen, Denmark / June 10-13, 2009

Four published international, randomized, 24-week, phase III studies (AMBITION, RADIATE, OPTION and TOWARD) have demonstrated the efficacy of the interleukin 6 (IL-6) inhibitor tocilizumab (TCZ). From these studies, a total of 2583 patients participated in two long-term extension-phase studies for up to 2.5 years in which TCZ was administered intravenously (i.v.) at a dose of 8 mg/kg once every four weeks. Patients on background disease-modifying antirheumatic drugs (DMARDs) continued their treatment, and those previously in a placebo arm were transitioned to TCZ.

Prof. Josef Smolen, Chair of Rheumatology, University of Vienna, Austria, reported on an interim efficacy analysis. Response to TCZ 8 mg/kg therapy was calculated for three groups: patients on monotherapy in the AMBITION study; inadequate responders to anti-tumour necrosis factor (TNF) agents (anti-TNF-IR) in RADIATE; and inadequate responders to DMARDs (DMARD-IR) in TOWARD and OPTION.

According to investigators, ACR response rates were increased in all patient populations who were treated with TCZ 8 mg/kg once every four weeks. More specifically, at week 108, 16.7% of patients in the TCZ monotherapy group, 10.9% of the anti-TNF-IR group and 16.9% in the DMARD-IR group who had previously achieved an ACR70 response for 24 consecutive weeks were still in clinical remission (DAS28 <2.6).

At week 108, 13.6% of patients in the monotherapy group, 5.8% of patients in the anti-TNF-IR group and 10.6% of patients in the DMARD-IR group also maintained ACR70 for 48 consecutive weeks. The proportion of patients with low DAS (<u><</u>3.2) was also maintained over time in all three groups, while roughly 50% of the entire cohort achieved low DAS from week 60 onward. Prof. Smolen explained, “Extension trials only capture patients who have made it through to the end of the first part so this is important to bear in mind. But once patients respond well to TCZ, they continue to do well on the drug, suggesting that the effect of the drug does not wear off over a period of 2.5 years.”

In a separate analysis involving 3857 patients treated with TCZ for a mean of 1.5 years, the withdrawal rate due to adverse events (AEs) was 6.5 per 100 patient-years overall, decreasing from 11.2 per 100 patient-years during the first six months to 6.0 per 100 patient-years between seven and 12 months to 3.7 per 100 patient-years from months 13 to 18 and remaining low thereafter. Only 3.1% of withdrawals were due to insufficient therapeutic response. The overall serious infection rate was 4.3 per 100 patient-years. Continued exposure to TCZ was not associated with an increased risk; only 1.7% of patients (n=67) had to discontinue treatment because of elevations in liver enzymes. Rates of malignancy or other serious AEs similarly did not increase with continued treatment and were similar to background rates observed with anti-TNF therapy. “In the extension-phase studies, there were no surprises, nothing new that we did not know already from the initial phase III trials,” Prof. Smolen concluded, “and overall, TCZ was well tolerated.”

Evidence of Radiological Progression

Noting that up to 70% of RA patients have radiographic joint damage within two years of diagnosis, Prof. Paul Emery, Professor of Rheumatology, University of Leeds, UK, stated, “A remission that does not include radiographic remission is probably not a remission we would want.” Therefore, a study demonstrating minimal radiographic progression after 52 weeks of TCZ therapy appeared highly encouraging.

As presented by Dr. Joel Kremer, Albany Medical College, New York, the double-blind, randomized LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage) study assigned 1190 patients with moderate to severe RA who did not achieve an adequate response to methotrexate (MTX) to i.v. TCZ 4 mg/kg, 8 mg/kg or placebo every four weeks, plus weekly MTX 10 to 25 mg orally or parenterally. “Patients could have received prior anti-TNF agents but not have failed due to lack or loss of efficacy,” Dr. Kremer explained. Between 60% and 70% of patients were also on concomitant steroids.

At 52 weeks, 55.8% of the 8 mg/kg group, 46.6% of the 4 mg/kg group and 24.7% of placebo controls achieved an ACR20 (intent-to-treat [ITT] population). “There was also rapid and sustained improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores with TCZ which was significantly superior to controls,” Dr. Kremer added (Table 1).

Table 1. Disease Activity at 52 Weeks (ITT population)

The IL-6 inhibitor significantly inhibited radiographic progression as reflected by the total Sharp-Genant score, erosion score and joint space narrowing score (Table 2). A joint space narrowing score of 0 represents “no narrowing” and 4 represents “total loss of joint space.” Erosions are scored 0 to 5 (0=no erosion, 5=more than four erosions in a single joint).

Table 2. Radiographi
eks (ITT population)

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At week 52, there was no evidence of progression according to the total Sharp-Genant score (i.e. a change <u><</u>0 in erosion or joint space narrowing) in a significantly greater proportion of TCZ-treated patients (84.5% and 80.5%, in the 8 mg/kg and 4 mg/kg groups, respectively) than in placebo controls (67.2%). “No unexpected safety signals were observed across the 52-week trial compared with earlier studies,” Dr. Kremer told delegates. He concluded, “TCZ 8 mg/kg showed a substantial 74% inhibition of radiographic progression at week 52 and there was a continuous growth of effect over time in both DAS28 and ACR scores.”

Early Initiation of Therapy

Early initiation of therapy improves clinical outcomes for patients with RA and the question of whether to introduce a biologic prior to DMARD therapy was examined. Based on an analysis of TCZ vs. MTX in patients who were MTX-naive or with past exposure to MTX, TCZ appears to be a viable option.

As presented by Prof. Graeme Jones, Professor of Rheumatology and Epidemiology, University of Tasmania, Hobart, Australia, whether response was measured by ACR criteria, EULAR criteria or DAS28 remission scores, TCZ produced significantly greater responses
RD therapy (Table 3).

Table 3. Week 24: Overall ITT Population

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“If people had asked me a few years ago, what I would do if I had RA, I would have said I’d go with MTX plus an anti-TNF,” Prof. Jones stated. “But as monotherapy, TCZ is equivalent to MTX plus an anti-TNF and it’s the only agent that actually does this so TCZ seems to be a very promising treatment.”

Clinical Trials on Rheumatoid Arthritis

In clinical trials of RA, more patients tend to achieve a DAS28 remission but improvement in ACR70 is generally within the same range. In a pooled analysis of TCZ-treated patients, Dr. Edward Keystone, Professor of Medicine, University of Toronto, Ontario, and colleagues looked for factors that might have influenced patients achieving a DAS28 remission on TCZ but not an ACR70 response. In their analysis, of patients receiving TCZ 8 mg/kg, 31% achieved DAS28 remission and of these, 19% achieved an ACR70 response compared to 3% and 2% of placebo patients, respectively. Most TCZ patients in DAS28 remission had at least a 70% improvement in swollen joint count while fewer than half achieved a 70% improvement in tender joint count. In order to achieve an ACR70 response, the 70% improvement is required for both joint counts. Fifty-four per cent of TCZ-treated patients did not achieve this magnitude of improvement for both joint counts, as Dr. Keystone explained. However, patients who did achieve a DAS28 remission at week 24 (but not an ACR70 response) still achieved a mean improvement of 64.7 in ACR, a substantial clinical benefit from TCZ, as he noted.

Summary

Clinical remission, the primary goal of RA management, is increasingly achievable with early use of DMARD and biologic therapies. As monotherapy or in combination with a DMARD, TCZ led to clinically and radiographically superior outcomes compared with DMARD therapy alone, achieving sustained clinical responses out to 2.5 years. Its safety has also been established over a treatment interval of 1.5 years.