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Success of Biologics in Rheumatoid Arthritis: From Efficacy of IL-6 Inhibition to Validation of Targeting New Inflammatory Pathways

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 12th Annual European Congress of Rheumatology (EULAR)

London, UK / May 25-28, 2011

The introduction of biologic therapies for RA has been a landmark by introducing an unprecedented level of disease control in many patients refractory to previous options. With more than a decade of use, tumour necrosis factor inhibitors (TNFi) such as infliximab, etanercept, adalimumab, certolizumab, and more recently golimumab have proven their efficacy. These agents have provided proof that specific molecular steps in the inflammatory cascade are targetable such as inhibition of the IL-6 receptor. The IL-6 receptor inhibitor, tocilizumab (TCZ) has demonstrated long-term rates of efficacy and safety consistent with TNFi agents.

“The efficacy and safety of TCZ has been established, but we have not fully explored the ways in which we might maximize its benefit,” reported Dr. Maxime Dougados, Professor of Rheumatology, Université Paris Descartes, France, here at EULAR. He indicated that the large body of new data being generated with this agent as well as with TNFi agents has expanded the context for its use within the framework of a disease for which no therapy is uniformly effective.

ACT-RAY Findings

The double-blind ACT-RAY study was conducted specifically to evaluate whether there is any additional benefit from adding methotrexate (MTX) to TCZ monotherapy. The study enrolled RA patients with inadequate response (IR) to a stable dose of MTX. All 556 RA patients began treatment with TCZ in an intravenous dose of 8 mg/kg q4 weeks with continued MTX or with placebo. The primary end point was the proportion of patients achieving remission on a 28-joint disease activity score (DAS28) defined as <2.6.

At the end of 24 weeks of follow-up, DAS28 remission was achieved in 40.4% in the TCZ/MTX group vs. 34.8% in those on TCZ/placebo, a difference that was not statistically significant (P=0.189). The respective rates of a good EULAR response were 89.5% vs. 85.8% (P=0.19). The American College of Rheumatology (ACR) scales of disease control were even closer: ACR70 rates on TCZ alone vs. TCZ/MTX were 25.7% vs. 24.9% (P=0.679), respectively, and ACR 90 rates were 5.8% and 5.1% (P=0.837), respectively.

“Overall, the results suggest that the combination of TCZ plus MTX does not provide an additional clinical benefit relative to TCZ alone,” Dr. Dougados told delegates, also noting that the combination “was not associated with any particular safety concerns.” He reported that the rate of serious events/100 patient-years of follow-up was 21 and 18 for TCZ/MTX and TCZ/placebo, respectively. Discontinuations for side effects were reported in 3.9% and 2.9%, respectively, which did not differ significantly. Liver enzyme elevations were higher on TCZ/MTX (18% vs. 6%) but discontinuations for this reason were not.

The key issue with biologics has been long-term safety because of concern that suppression of inflammatory mediators can adversely affect immune function, thus increasing the risk of immune-related events, including serious infections. However, there is now very-long term follow-up with the TNFi agents demonstrating no increased risk over time. This is important because it helps patients recognize the benefit:risk ratio of an agent that can provide durable disease remission.

“With the biologics, clinical remission in RA now represents a realistic treatment goal for a much larger proportion of the RA population,” reported Dr. Iain McInnes, Centre for Rheumatic Diseases, University of Glasgow, UK. “These agents are not without risks, but we can say that we have a very good understanding of these risks now that we have so many patients followed long-term.”

While the most extensive data has been generated by the TNFi agents infliximab and etanercept, data with TCZ are growing. In a summary of safety data from 7 studies that enrolled 4000 patients followed with a median duration of 3.6 years (mean 3.1) and a total observation time of 12,293 patient-years, its safety and tolerability is similar to that of TNFi agents.

“Our data indicate that the safety profile of TCZ is not changing with long-term exposure. The rates of serious adverse events, serious infections, malignancies and cardiovascular events have remained stable with continued exposure in long-term trials,” Dr. Mark C. Genovese, Chief, Immunology Clinic, Stanford University Medical Center, California, told EULAR delegates.

Expressed as events/100 patient-years of follow-up, the rate of adverse events dropped from 418.4 the first year to 251.4 events the fourth year. The rate of serious adverse events remained relatively constant over the 4 years, ranging from 13.9 to 15.7. Serious infections were also relatively constant over time, ranging from 3.9 to 5.2 events/100 patients- years of follow-up.

ACT-SURE: Safety in Intensively Treated Patients

There is no clear order in which biologics should be used on the basis of safety, according to a third study designed to evaluate TCZ in a real-world setting. In the ACT-SURE study, there were no restrictions in regard to previous exposure to DMARDs, TNFi or TNFi washout period. With 1681 patients treated in a variety of clinical practice settings, including private offices, the results were reassuring in their ability to reproduce the phase III safety and efficacy data.

“Most patients [86%] in the ACT-SURE trial received DMARD therapy at close to the maximum effective dose and remained inadequate responders, making ACT-SURE the first trial to document TCZ efficacy in this intensively treated population,” reported Dr. Vivian P. Bykerk, Division of Rheumatology, Allergy, and Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachsetts. She also informed EULAR delegates that due to lack of restrictions, patients could be offered TCZ as monotherapy or in addition to DMARDs.

When stratified by exposure (DMARD-IR; TNFi-IR previous use: TNFi >2 months before baseline; and TNFi-IR recent use: TNFi =2 months before baseline), the rate of serious adverse events on TCZ was 18.6/100 patient-years of follow-up in those who were TNFi naive, 28 in those with previous exposure and 18 in those with recent exposure. Serious infections rates were 4.2, 6.8 and 6.0, respectively. Rates of adverse events leading to withdrawal were 4.5, 7.0 and 5.2, respectively.

Efficacy was somewhat greater in those without previous TNFi exposure. For example, the ACR90 rates were 10.3%, 6.4% and 6.6% in the naive, previous and recent exposure groups, respectively. The ACR70 rates were 31.8%, 17.8% and 19.7% respectively. The DAS28 <2.6 were 61.6%, 48.5% and 50.4%, respectively. A sub-analysis of the study demonstrated that 49.6% of those on TCZ monotherapy achieved a DAS28 <2.6. Improvements from baseline in tender and swollen joint counts, and pain were similar in all patient groups and were observed as early as week 4. They increased through week 12 and were maintained through week 24.

“TCZ is effective when used as a first-line biological agent in patients intolerant to, or with IRs to, conventional DMARDs and [as second line] in patients with IRs to TNFis,” Dr. Bykerk stated. As with TNFis Dr. Bykerk reported that TCZ “was characterized by rapid onset and increasing efficacy over time” and is suitable for use “immediately after stopping TNFi therapy.”

All of the approved biologics are capable of providing remissions in patients who had an inadequate response to DMARDs. All appear to be reasonable choices when intensifying therapy. In patients with refractory disease, the benefit:risk ratio of these agents appears acceptable. The increasing array of biologics is expected to increase the opportunity for disease control in a growing percentage of patients.

Emerging Options and Pathways

The viable pathway of inhibiting IL-6 is being explored with the new agent CNTO136, another IL-6 inhibitor. Results from a phase II multicentre, randomized, double-blind, dose-finding study showed that patients treated with this IL-6 inhibitor achieved a similar rate of ACR20 response to TCZ vs. placebo.

While biologics target cytokines and extracellular signaling, small molecule inhibitors such the janus kinase (JAK) and spleen kinase (SYK) block intracellular signaling. They build on the same concept of targeting very specific steps in the inflammatory process, can be taken orally and have the potential of circumventing unwanted inhibition of the immune response. In late-stage development is the JAK inhibitor tofacitinib. A phase III placebo controlled study demonstrated that at month 6, 58.3%, 52.7% and 31.2% achieved ACR20 rates in the 10 mg and 5 mg b.i.d., and placebo groups, respectively.Also, a significant proportion of patients on tofacitinib achieved a DAS28 <2.6 at month 6, 14.8%, 11%, respectively vs. 2.7%, of placebo patients. However, the JAK inhibitor increased lipid, ALT and creatinine levels; the implications of which need further study.

Summary

Biologic agents have been life-altering for patients with RA refractory to DMARDs. The extensive safety and efficacy data with TCZ, IL-6 receptor inhibition has joined the large body of evidence with TNFis that efficacy persists long-term without a rising risk of adverse events. Promising results with the newer IL-6 inhibitor CNTO 136 may provide a needed increase in options for RA.The specific action of small molecule inhibitors of inflammatory pathways such as JAK are potentially important for better understanding the pathophysiology of autoimmune inflammatory processes and may provide insight into the optimal targets for control.

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