Reports

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PRIORITY PRESS - 2010 Annual European Congress of Rheumatology (EULAR)

Rome, Italy / June 16-19, 2010

Important new research was presented here on the use of targeted biologic agents for the treatment of rheumatoid arthritis (RA). Recently completed or updated studies included trials conducted with tocilizumab, abatacept, rituximab and atacicept. Tocilizumab, which is approved in Canada and is entering routine clinical practice, is a monoclonal antibody (MAb) that targets the interleukin 6 (IL-6) receptor; abatacept binds to CD28 and CD80 on T cells to prevent activation; rituximab targets the CD20 antigen on B cells to trigger immune system activity; and atacicept binds to cytokines that promote B cell survival. The research data for tocilizumab was particularly robust.

ACT-SURE Trial

“In a setting resembling day-to-day clinical practice, [our] results confirm the safety and efficacy of tocilizumab as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs) when used as a first line biologic in patients intolerant of, or with inadequate response to, conventional DMARDs and in patients with inadequate response to TNF inhibitors,” reported Dr. Vivian Bykerk, Mount Sinai Hospital, Toronto, Ontario. Presenting preliminary results from the ACT-SURE study, Dr. Bykerk reported that the data confirm the results of phase III studies by demonstrating a rapid onset of action with more than 25% of patients achieving remission by week 8. Efficacy of treatment increased steadily over time.

The previous phase III research that led to the approval of tocilizumab in Canada and elsewhere included studies that consistently associated it with substantial relative advantage when compared to standard therapies, particularly methotrexate (MTX). For example, the double-blind AMBITION trial randomized RA patients to tocilizumab 8 mg/kg monotherapy every four weeks, 7.5 mg/week MTX (which could be titrated up to 20 mg/week) or placebo (Jones et al. Ann Rheum Dis 2010;69:88-96). At the end of 24 week, the proportion of patients who achieved ACR 20 responses was 33% greater on tocilizumab relative to MTX on an intention-to-treat (ITT) basis (69.9% vs. 52.5%; P<0.001). Tocilizumab was significantly better than MTX by week two. In the subgroup of patients who were MTX naive, the advantage of tocilizumab was of a similar magnitude and statistical significance (P<0.004). Serious adverse events in this study were uncommon and not statistically different between the two groups.

In the ACT-SURE study, the goal was to assess the efficacy and safety of tocilizumab in general clinical practice in patients with inadequately controlled RA. “Up to 40% of patients with RA have inadequate response to treatment with conventional DMARDs or TNF inhibitors,” observed Dr. Bykerk. ACT-SURE was conducted in 25 countries including Canada; 1681 patients with moderate to severe active RA were enrolled. Their mean age was 54 years, 81% were women and the mean duration of RA was 9.6 years. Patients were required to have previously received at least one conventional DMARD, TNF inhibitor (TNFi) or both for at least eight weeks with an inadequate response. The results of ACT-SURE were at least as positive as those reported in previously published phase III studies, whether patients were sub-grouped by those previously treated with DMARDs and had an inadequate response (DMARDS-IR), a TNFi, or both. At week 24, 56.8% had achieved a clinical remission, defined as a disease activity score 28 (DAS28) of <2.6. Moreover, by this time 26.4% of tocilizumab patients had achieved an ACR 70 response. On tocilizumab, more DMARD-IR patients (31.8%) achieved an ACR 70 response than did TNFi-IR/previous use (17.8%) or TNFi-IR/recent use (19.7%) patients. Only 4.8% withdrew due to adverse events. These results are particularly noteworthy because of the urgent need for more well tolerated treatment options.

There was no evidence that those who did not complete a TNFi washout had an increased risk of adverse events, such as infections (6.0 vs. 7.6/100 patient years), compared to those with a TNF inhibitor washout. The absence of apparent need for washout “facilitates the implementation of a tight control strategy for RA patients,” Dr. Bykerk told delegates. She further emphasized that 86% of the patients in this study had received a DMARD at or close to the maximum dosage before switching to the MAb. This study feature makes ACT-SURE “the first trial to document tocilizumab efficacy in this intensively treated population.”

Long-term Safety and Efficacy

While this real-world treatment data reinforces the results of phase III trials, compelling long-term safety data has also been generated by follow-up of the phase III studies that first led to the approval of tocilizumab. In a new analysis, safety data was pooled from the four major 24-week phase III trials, known as OPTION, AMBITION, RADIATE and TOWARD, as well as from several earlier and ongoing studies. This produced a pool of 4,009 patients who had been treated for a mean duration of 2.4 years. The analysis showed no further increase in abnormal liver function tests over time and no progressive changes in lipid abnormalities. Overall, the long-term safety profile was very similar to the short-term safety profile.

“No new safety signals emerged with prolonged exposure to tocilizumab. Rather, the rates of both adverse events and serious adverse events were stable over time,” noted Dr. Ronald F. van Vollenhaven, Department of Rheumatoid Arthritis, Karolinska Institute, Stockholm, Sweden. “Overall, these long-term data support a favourable benefit:risk ratio for tocilizumab in patients with moderate to severe RA.”

In a three-year extension of the AMBITION study, which initially randomized patients who had never been exposed or never failed MTX, low disease activity was maintained in approximately 68% of patients who remained on tocilizumab at each time point from 60 to 156 weeks. In the patients who were on tocilizumab monotherapy (almost one-third of the study population) 61% of those still on therapy at 156 weeks remained in DAS28 remission.

The MAb also appears versatile. For example, an ACR30 response without fever was achieved at the end of 12 weeks of treatment in 85% of 75 systemic juvenile idiopathic arthritis (SJIA) patients vs. 24% (P<0.001) of 37 SIJA patients receiving placebo, according to senior author Dr. Fabrizio De Benedetti, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy. Although there were serious adverse events in 4% of patients on tocilizumab, including one case each of angioedema and bacterial arthritis, these resolved in all cases and the drug was otherwise well tolerated.

Role in the Inflammatory Cascade

One of the most intriguing aspects of biologics is their potential for turning off the inflammatory cascade. Drugs that downregulate IL-6 activity, of which there are several other than tocilizumab in clinical development, are of particular interest because of evidence that this cytokine may be a pivotal trigger of ongoing inflammation. In a new analysis of a tocilizumab study that enrolled 187 patients, long-term remission was found to correlate with low IL-6 and low matrix metalloproteinase 3 (MMP-3) levels, according to Dr. Norihiro Nishimoto, Wakayama Medical University, Ibaraki-City, Japan. “In this study, an IL-6 level <35 pg/mL and normalization of MMP-3 levels were independent predictive markers for longer duration of efficacy. In almost 10% of the patients, we were able to induce a drug-free remission for 52 weeks after tocilizumab therapy, and these individuals had the lowest levels of IL-6,” Dr. Nishimoto told delegates. He indicated that these studies help validate the potential for highly targeted therapies to alter the natural history of RA.

Summary

Opportunities to improve RA control in patients who are poorly responsive to DMARDs and TNF inhibitors are expanding rapidly because of success in identifying new pro-inflammatory molecular targets that appear to diminish disease activity. The recent approval of a MAb targeted at IL-6 receptor activity is representative of progress in this area and may eventually alter the sequence of therapies employed first and second-line in moderate to severe disease if safety data continued to be encouraging. The potential for these agents to change the natural history of RA by modifying or disabling the inflammatory cascade is at an early stage of investigation.