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Interleukin-1 Inhibitors in Specific Rheumatoid Diseases

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 - 75th Annual Meeting of the American College of Rheumatology

Chicago, Illinois / November 5-9, 2011

Chicago - Small-molecule inhibitors of enzymatic pathways that control inflammation in rheumatoid arthritis (RA) are advancing rapidly in clinical trials and are expected to generate the next major evolution in targeted therapy. The most advanced of these inhibitors, all of which are being developed as oral agents, are in late-stage phase III studies. Not the least important aspect of these agents is that they promise to provide a wider array of therapeutic targets, increasing options for those individuals who do not respond or who are intolerant to the current biologics. The development of a growing array of oral therapies is also expected to be well accepted by many of those patients who are now dependent on intravenous drug infusions for disease control. Although the introduction of TNF inhibitors was a critical advance for the levels of sustained disease control they made possible in patients with moderate-to-severe disease, small-molecule inhibitors are poised to greatly simplify highly effective targeted therapy.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Cryopyrin-associated Periodic Syndromes

The role of interleukin-1 (IL-1) as a pro-inflammatory signalling cytokine is well documented, but the development of inhibitors of this signal is not only proving to be clinically useful but also helping to elucidate and draw attention to specific pathological processes. One exceptional example has been the role of inhibitors of IL-1ß in the treatment of cryopyrin-associated periodic syndromes (CAPS). Caused by a group of genetic mutations in the CIAS1/NLPR3 gene that encodes cryopyrin and upregulates IL-1ß, CAPS is characterized by a collection of non-specific features that include joint pain, rash, fever and fatigue.

“IL-1ß is a powerful immune regulator and an important mediator of inflammation, which explains why CAPS is associated with a diverse array of symptoms,” reported Dr. Hal M. Hoffman, University of California, San Diego. Leader of an effort to create an international registry of CAPS patients, Dr. Hoffman reported that this disease often goes unrecognized for years, even though drugs that inhibit IL-1ß are capable of providing a complete response within days of initiating therapy.

There are several types of IL-1 inhibitors that have shown efficacy against CAPS, including rilonacept, a dimeric fusion protein; canakinumab, a monoclonal anti-IL1ß antibody; and anakinra, a competitive IL-1 receptor inhibitor. Only rilonacept and canakinumab are approved for this indication, but canakinumab, which is specific for IL-1ß, is the most recently approved and may be the most potent. At the ACR 2011 meeting, CAPS was the focus of a symposium designed to draw attention to this disease while several new studies, including a trial in systemic juvenile idiopathic arthritis (SJIA) and Schnitzler syndrome, suggested that potent IL-1ß inhibition can have major clinical benefits in specific applications.

“The challenge of CAPS is simply being unaware of the features. If you know about CAPS, it is quite easy to diagnose. If you are not familiar with these disorders, you are likely to pursue a lot of diagnostic tests with inconclusive results,” stated Dr. Robert Cartwright, Allergy Center at Brookstone, Columbus, Georgia. Asked to provide some case studies during the symposium on CAPS, Dr. Cartwright noted that there are several syndromes that are included under the name CAPS, notably Muckle-Wells syndrome and familial cold autoinflammatory syndrome, which differ by specific underlying gene mutation and most prominent features.

Importance of IL-1ß Blockade

Cryopyrin, the protein upregulated by the genetic mutations associated with CAPS, initiates a chain of molecular events that result in excess levels of IL-1ß. In CAPS, the trials with canakinumab provided a clear demonstration of the importance of IL-1ß blockade. In the pivotal 3-part trial (Lachmann et al. N Engl J Med 2009;360:2416-25), 97% of patients had a complete response in the first part. These were entered into a second part when patients were randomized to canakinumab or placebo and followed for 24 weeks. While all canakinumab patients remained in remission, 81% of those on placebo flared. In part 3, when all patients were placed on canakinumab, 90% remained in remission.

In new data presented at the ACR 2011 meeting, safety and efficacy after 1 year of canakinumab treatment was assessed in 12 CAPS patients of whom 9 were children. While 6 patients required a higher or more frequent dose over the course of follow-up, the disease remained controlled without dosage adjustment in another 5. One non-compliant patient discontinued therapy, but overall disease control remained relatively consistent after the dose adjustments and there were no serious side effects, reported Dr. Roberta Caorsi, G. Gaslini Institute, Genoa, Italy.

The efficacy of canakinumab has prompted the development of an international CAPS registry with a planned enrolment of more than 400 patients. The primary objective of this registry will be to monitor the agent’s efficacy and safety, which has become the dominant therapy for this disease, but secondary objectives include collecting data on the patterns of growth and development in children with CAPS. Not least important, the registry may help to raise awareness about the disease.

Effectiveness in Schnitzler Syndrome

The similarities of Schnitzler syndrome to CAPS, including chronic urticaria and systemic inflammation, prompted a separate study of canakinumab in this population. Although Schnitzler syndrome has not been previously characterized as IL-1ß-mediated, elevated levels of this cytokine have been observed. After a single subcutaneous injection of canakinumab 150 mg, all 12 patients experienced a reduction of symptoms within hours and all were completely asymptomatic within 7 days, according to Dr. Heleen D. de Koning, Radboud University Medical Centre, Nijmegen, The Netherlands. “We have now maintained this group of patients on canakinumab with good long-term control. It demonstrates this agent is effective in Schnitzler syndrome but also confirms that IL-1ß is the key cytokine responsible for this disease,” Dr. de Koning reported.

Expanding Applications

The applications for IL-1ß inhibition appear likely to expand based on phase III randomized trials undertaken with rilonacept for gout flare prevention in patients on uric acid-lowering (UAL) therapy and with canakinumab in patients with SJIA.

In a multinational study, 1315 patients with a history of gout and a risk of flare due to the initiation of UAL therapy were randomized to weekly subcutaneous injections of rilonacept 160 mg or placebo. At week 16, gout flares were reduced by a mean of 70.3% relative to placebo (P<0.0001). Serious infections were uncommon in either group and withdrawals due to adverse events were recorded in 4.7% of those taking rilonacept vs. 3.0% of patients taking placebo. Most withdrawals were due to injection site reactions.

The authors of this study, led by Dr. John S. Sundy, Duke University Medical Center, Durham, North Carolina, characterized the reduction in gout flares as substantial while concluding that safety and tolerability were acceptable.

Findings in SJIA

In the SJIA canakinumab study, 84 patients were randomized to 4 mg/kg of the monoclonal antibody or placebo. The primary objective was to compare efficacy with an adapted ACR PED50 on day 15. Patients ranged in age from 2 to 19 years and had an average disease duration of 3.4 years. The average number of affected joints was 14.1. The average baseline CRP was 200.6 mg/L.

The reductions in disease activity for every primary and secondary end point were highly statistically significant, including ACR PED30 (83.7% vs. 9.8%; P<0.0001), ACR PED50 (64.4 vs. 4.9%; P<0.0001) and ACR PED100 (32.6% vs. 0%; P<0.0001), reported Dr. Hermine Brunner, Cincinnati Children’s Hospital Medical Center, Ohio. While more adverse events were recorded in those receiving active therapy than placebo, there were no discontinuations due to adverse events.

In another study of SJIA, long-term follow-up was provided in a series of patients treated with the IL-1 receptor antagonist anakinra. The mean age of the 34 children in this series at the start of the study was 8.4 years with a mean disease duration of 3.05 years. Over a mean follow-up of 4.02 years, 13 (38%) were complete responders, 5 (14%) were partial responders, and 16 (48%) were non-responders. The most common side effect was skin rash. The authors of the study, led by Dr. Aldo Naselli, G. Gaslini Institute, noted that the severity of joint symptoms at baseline was an important predictor of response.

“Anakinra is able to dissect 2 distinct populations of SIJA patients on the basis of the presence or not of a severe joint involvement with a chronic polyarticular course,” reported Dr. Naselli, noting that those with the severe joint involvement were far more likely to respond.

Summary

While it is clear that IL-1ß has an important pro-inflammatory effect, the development of inhibitors of IL-1ß are permitting clinical trials to determine exactly where this cytokine is a dominant driver of pathology and where inhibition can improve outcomes. The efforts to test IL-1ß inhibition in a growing spectrum of diseases may not only provide an opportunity for better outcomes but also a window into the relative importance of specific cytokines in individual inflammatory processes.

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