Reports

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PRIORITY PRESS - 73rd Annual Meeting of the American College of Rheumatology

Philadelphia, Pennsylvania / October 17-21, 2009

In an analysis of five randomized controlled trials plus three long-term extension studies, Prof. Josef Smolen, Professor of Medicine, Medical University of Vienna, Austria, and multicentre colleagues assessed treatment response to the novel interleukin-6 (IL-6) receptor antagonist tocilizumab (TCZ) in a total of 3986 patients followed for approximately 3.5 years. At the cut-off date of February 2009, only 4% of the cohort had discontinued treatment due to insufficient therapeutic response, while approximately 14% had discontinued due to safety concerns, including intercurrent illness. For this analysis, patients were divided into those with inadequate response (IR) to either methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs), those with an inadequate response to an anti-tumour necrosis factor (TNF) agent (anti-TNF), and those who had never been exposed to—or who had never failed—MTX. Efficacy data were reported to a maximum of 180 weeks in the DMARD-IR group and up to 156 weeks for the other two groups.

As investigators demonstrated, the proportion of patients achieving an ACR20, 50 or 70 response with TCZ generally stabilized or increased over time. Clinically significant improvements in all ACR core components were achieved with TCZ treatment in all groups at week 96; decreases in mean tender joint counts (TJC) and swollen joint counts (SJC) were well maintained in all groups over time. Proportions of patients who achieved 0 SJC and 0 TJC were 40.4% and 25.1% in the never-exposed or never-failed MTX group, 22.9% and 14.8% in the anti-TNF-IR group, and 35.7% and 26.7% in the DMARD-IR group. As well, proportions of patients who achieved a Health Assessment Questionnaire (HAQ) score of 0 were 22.5%, 7.9% and 14.6% in the never-exposed or never-failed MTX, anti-TNF-IR and DMARD-IR groups.

Equally important, the number of patients who achieved a disease activity score (DAS)28 remission (<u><</u>2.6) in the DMARD-IR group increased up to week 72. Follow-up is not yet long enough to allow interpretation of later time points. Similar patterns emerged in the never-exposed or never-failed MTX group as well as in the anti-TNF-IR patients.

“These data show that the most profound responses to TCZ such as low disease activity or remission appear to increase [over time] because the number of patients who achieved these states increased over time,” Prof. Smolen told delegates, “and this is reassuring in that the activity of the drug is clearly not only a short-term effect.”

Long-term Safety Data

Safety data out to 2.4 years were presented by Dr. Ronald van Vollenhoven, Associate Professor of Rheumatology, Karolinska Institute, Stockholm, Sweden. Some 4009 patients were initially exposed to TCZ during the phase III clinical trials program and the long-term extension studies and over 700 patients remained for the safety analysis at 2.4 years. Expressed in terms of rates per 100 patient-years over 2.4 years, the rates of adverse events (AEs) and infection were 278.2 and 108.0 in all TCZ exposed patients and 339.0 and 95.9 among controls, respectively. Serious AEs and infection rates were 14.4 and 4.7 and 14.4 and 3.4, respectively. Equally, there was no sign that either the AE or serious infection rate increased over time, as both remained stable across the 2.4-year follow-up.

The gastrointestinal (GI) perforation rate was 2.8 per 1000 patient-years, all occurring in patients who had at least one risk factor for this complication, as Dr. van Vollenhoven emphasized. Results from the United Health Care database presented here showed GI perforation rates among RA patients exposed to anti-TNF agents at 1.3 per 1000 patient-years and at 3.9 per 1000 patient-years for those exposed to corticosteroids. In this same database, GI perforation rates among TCZ-exposed patients were 1.9 per 1000 patient-years.

While follow-up is still short, malignancy rates were low at 1.1 per 100 patient-years and there was no sign of any excess malignancy of a particular type or an increase in malignancy rate over time. Rates of myocardial infarction per 100 patient-years were low at 0.25 for TCZ-exposed subjects vs. 0.49 for controls, while stroke rates for TCZ patients were 0.19 vs 0.24 per 100 patient-years for controls. LDL-C levels do tend to rise modestly in some patients on treatment initiation, as Dr. van Vollenhoven noted, but HDL-C also tends to rise and may offset any increase in LDL-C. As well, increases occur by six weeks and then remain relatively stable over time.

“Liver enzymes also go up in some patients but it doesn’t happen very often and the number of patients in whom big increases in liver enzymes are seen is quite small,” Dr. van Vollenhoven noted. Moreover, rates of transaminase elevations did not increase over time, nor were they associated with any clinically apparent hepatitis or hepatic dysfunction. Overall, investigators concluded that no new safety signals have emerged with prolonged exposure to TCZ.

LITHE Study at Two Years

Here at the ACR, Dr. Roy Fleischman, Clinical Professor of Internal Medicine, University of Texas Southwestern Medical Centre, Dallas, presented findings from the LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage) study. Prof. Smolen discussed these findings in an interview.

At two years, patients who received either a 4 or 8 mg/kg dose of the IL-6 receptor antagonist in combination with MTX were significantly less likely to have signs of radiographic progression compared with patients who received MTX alone. At one year, patients originally enrolled in LITHE were started on open-label TCZ 8 mg/kg plus MTX and were followed out to year 2, unless they had achieved at least a 70% or greater improvement in SJC and TJC during the first year of therapy, at which point they continued on the blinded therapy. The intent-to-treat analysis included 393 patients in the MTX monotherapy arm, 399 patients in the TCZ 4 mg/kg plus MTX arm and 398 patients on the TCZ 8 mg/kg plus MTX arm.

At the end of two years, patients on TCZ 8 mg/kg plus MTX had 81% less radiographic progression according to the total Sharp-Genant score compared to the MTX monotherapy group (0.37 vs.1.96; P<0.001), while 82% of patients on the 8 mg/kg dose had no evidence of radiographic progression compared with 60% of those on MTX alone. In those patients who were initially randomized to the 8 mg/kg arm, low disease activity was seen in greater than 60% of the group overall, while the percentage of patients who had achieved remission at week 52 (48%) continued to increase out to week 104 (65%). Mean SJC and TJC also continued to decline from week 52 to study end point at two years.

“The LITHE study clearly shows that TCZ not only affects clinical aspects of the disease but also radiographic effects, which is the goal for every disease-modifying compound,” Prof. Smolen commented, “and this is very important as radiographic progression over time leads to irreversible loss of function.”

TAMARA Findings

Clinical trial data are important to establish the safety and efficacy of any new agent, but it is real-life experience that most interests practicing rheumatologists. The TAMARA (Tocilizumab and DMARD Achievement in RA) study is one such example.

A total of 293 patients with RA from 70 sites who had not achieved an adequate response to either conventional or biological DMARDs were enrolled in TAMARA. The mean DAS28 score at baseline was 7.7 and a low DAS (<u><</u>3.2) was the primary end point of the trial.

Dr. Gerd Burmester, Professor of Medicine, Charité University Hospital, Berlin, Germany, presented the interim analysis. At week 4, moderate and good EULAR response rates were achieved by approximately 52% and 10% of patients, respectively. By week 24, these rates were achieved by 37% and 31% of patients, respectively. HAQ response at week 4 was achieved by some 60% of patients and by 65% by week 24. At week 24, a low DAS was reported in more than 30% of the cohort. Dr. Burmester commented, “This was very surprising to me because the disease activity was so extremely high to begin with.” The mean C-reactive protein value dropped from 26.6 mg/L at baseline to almost normal levels at a mean of 5.4 mg/L after one week of treatment, and early improvement was seen in both the Functional Assessment of Chronic Illness Therapy-Fatigue scores and HAQ responses.

Patients tolerated treatment well and no additional safety signals beyond those that have been identified in clinical trials were reported. Investigators concluded that treatment with TCZ achieves rapid improvement of signs and symptoms of RA in a setting that mimics real-life medical care, and that this improvement was observed in patients with very high baseline disease activity despite prior treatment with standard and biologic DMARDs.