Reports

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.

72nd Annual Meeting of the American College of Rheumatology

San Francisco, California / October 24-29, 2008

The ligand interleukin-6 (IL-6) plays a key role in rheumatoid arthritis (RA) and other inflammatory processes, according to Dr. Ernest Choy, Head of Therapeutic Rheumatology, Guy’s, King’s College and St. Thomas’ Hospitals, London, UK. As well as its effects on B and T cells, overproduction of IL-6 has local effects leading to inflammation and joint damage (osteoclast activation, neutrophil recruitment and survival, pannus formation), accounting for many of the systemic effects seen in RA patients (increased cardiovascular [CV] risk, anemia, osteoporosis, effects on mood and fatigue). Furthermore, IL-6 levels have a much higher correlation with clinical and radiological indicators of joint damage than do C-reactive protein (CRP) and tumour necrosis factor (TNF). Accordingly, noted Dr. Choy, IL-6 is a logical target for RA therapy.

IL-6 Receptor Inhibition Trial Review

Three phase III studies (OPTION, LITHE, TOWARD) have evaluated tocilizumab following inadequate response to disease-modifying anti-rheumatic drugs (DMARDs). The results of these studies were very consistent, noted Prof. Josef Smolen, Department of Internal Medicine (Rheumatology), University of Vienna, Austria. In the TOWARD and OPTION trials, the results for the 8 mg/kg dose approximated 60%, 40% and 20% of patients achieving ACR20, ACR50 and ACR70, respectively, at 24 weeks. Similarly, approximately 25%, 10% and 3% of patients in the placebo arms achieved these ACR levels. These results were also duplicated at 52 weeks in the ongoing two-year LITHE study. DAS28 scores <2.6 (remission) were achieved by approximately 30% of patients in each of these studies, compared to placebo results in the 1 to 3% range.

Quality of life measures (HAQ-DI, SF-36 physical and mental, FACIT) were all significantly improved by the 8 mg/kg dose. “This improvement in the 8 mg/kg group is in the order of two times better than control to even sometimes three times better than control,” Dr. Smolen remarked.

The RADIATE trial examined the response to tocilizumab of patients who had inadequate response to one or more previous anti-TNF medications. ACR responses were somewhat lower, noted Dr. Smolen, but the DAS remission rate was the same as in the DMARD-IR studies, at 30%. The ACR20 responses for 8 mg/kg remained close to 50% regardless of the number of prior anti-TNF therapies.

The phase III AMBITION trial, designed to show non-inferiority of tocilizumab monotherapy compared to MTX monotherapy in MTX-naive patients, demonstrated the superiority of tocilizumab at 24 weeks. “And this we have not seen for the TNF inhibitors, because neither adalimumab as monotherapy or etanercept as monotherapy were superior to MTX in the PREMIER and TEMPO studies,” Dr. Smolen told delegates.

A radiographic study of 306 patients (Ann Rheum Dis 2007;66:1162-7) indicated that tocilizumab monotherapy improved the Sharp score by about 60% compared to DMARDs. This was confirmed by the results of the LITHE study, noted Dr. Smolen. The Genant-modified Sharp score was about 75% better than for MTX alone, with improvements in both bone and cartilage damage. Moreover, 85% of patients showed no evidence of progression at one year as measured by the total Sharp score (no progression defined as <u><</u>0 change in total Sharp score).

IL-6 Inhibitor Safety Overview

Thanks to an extensive development program, approximately 6000 patient-years of safety data from about 4000 patients is available, including some longer term data, remarked Dr. Arthur Kavanaugh, Professor of Medicine, University of California San Diego, La Jolla. ALT/AST elevations are quite common, but subside to normal levels following each dose. Even patients who were withdrawn due to excessive elevations returned to normal after discontinuation. Similarly, neutrophil counts tended to decrease after dosing, but increased again thereafter. Lipid elevations were also frequent, but this was mitigated by the fact that all lipids increased, with the result that LDL-C:HDL-C ratios were not affected. Serious adverse events were generally in the 13 per 100 patient years range and did not change over time (up to 1.5 years’ duration) (n=2562). Serious infection events (SIE) in long-term therapy occurred at a comparable rate to that seen in the shorter studies. For example, SIEs per 100 patient years were 3.2 for tocilizumab 8 mg/kg and 3.9 for placebo + DMARD in the pooled six-month safety data, compared to 3.8 for long-term tocilizumab therapy.

The Role of Inflammation in Cardiovascular Disease Complications

One of the most serious implications of RA is the associated increased risk of CV disease. IL-6 is known to stimulate the production of CRP. Dr. Paul Ridker, Director, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Boston, Massachusetts, explained that CRP is more predictive of cardiac risk than LDL-C. Furthermore, high levels of both LDL-C and CRP result in a much higher risk of cardiac events than either alone. Dr. Ridker’s own work demonstrated that high levels of IL-6 also predict CV disease (Circulation 2000;101(15):1767-72) and Fisman et al. (Am J Cardiol 2006; 98(1):14-8) showed a correlation between high plasma IL-6 and cardiac morbidity and mortality, with an increase in myocardial infarction (MI) or death from approximately 80 to 180 per 1000 person-years. RA has been found to be associated with roughly a doubling of cardiac risk (Arthritis Rheum 2006;54(12):3790-8, Circulation 2003:107(9):1303-7). There is a similar risk of increased congestive heart failure (CHF), he added.

More data are needed to explore the effectiveness of anti-inflammatory medications used for RA in simultaneously reducing CV risk. “There are data out there,” remarked Dr. Ridker, “but it’s mostly from non-randomized observational cohorts, which come with many caveats.” However, encouraging data are available on risk reduction with ASA and MTX, although anti-TNF data have been ambivalent. IL-6 inhibition with tocilizumab has demonstrated a “very nice dose response effect on CRP itself” in the OPTION study (Ann Rheum Dis 2007;66(suppl 2):OP0117), Dr. Ridker commented. At a dose of 8 mg/kg, it maintained CRP levels at or below 0.5 mg for 24 weeks. Maintaining CRP levels below 2 mg/L reduces the risk of recurrent MI and death (N Engl J Med 2005;352(1): 20-8, Am Heart J 2008;155(1):49-55).

A concern with the use of biologics is the fact that they also increase lipid levels, Dr. Ridker noted. This raises the question of whether statins, which lower both lipids and CRP, should be used concomitantly. The JUPITER trial, which investigated the effects of rosuvastatin on patients with normal cholesterol levels but with CRP levels of more than 2 mg/L, was stopped three years early because of efficacy. Detailed results were presented at the American Heart Association 2008 scientific sessions. Dr. Ridker predicted that new CV guidelines currently being prepared might recommend preventive statin therapy for all patients aged 45 years and older with CRP levels >2 mg/L. “You’ll have to ask yourselves, is the magnitude of benefit sufficient that you might want to think about this in a very different population: your patients with RA, with other inflammatory conditions, who we know are at high vascular risk,” he concluded.

Driving Therapeutic Choice

To date, there are no direct comparison studies of biologics with optimum dosing. The published randomized controlled trials are not directly comparable because of differences in study design and demographics. Efficacy and serious infection incidence are similar for all biologics. As a result, noted Dr. Edward Keystone, Professor of Medicine, University of Toronto, Ontario, choosing a biologic is problematic. In order to differentiate, he suggested that factors such as onset of action, the need for MTX, radiographic outcome and sustainability of therapy be considered. Granulomatous and opportunistic infection and malignancy may be factors, and ease of administration is also significant. “At the end of the day,” remarked Dr. Keystone, “it’s really cost and access that seems to be the driver.”

In the case of TNF-a inhibitors, concerns include the apparent reduced response with successive drugs, with responses particularly reduced for ACR50 and ACR70. The risk of serious infections also increases with successive TNF-a inhibitor regimens. Some specific issues in choosing a TNF-a inhibitor include the low risk regarding reactivation of tuberculosis and opportunistic infections with etanercept, as well as the fact that MTX may not be required. For the monoclonal antibodies, there is a more rapid onset of action and lower frequency of administration. For example, certolizumab plateaus in about 14 weeks, and also has a low incidence of injection site pain.

Among other biologics, reasons for considering abatacept include good sustainability and infrequent infusion reactions, according to Dr. Keystone, while rituximab has the advantages of infrequent administration and safety in patients at high risk of tuberculosis, connective tissue disease and lymphoma. Dr. Keystone stated that tocilizumab is the only monotherapy shown to be superior to MTX, and also has a high DAS28 remission rate across multiple studies.

Note: At the time of printing, tocilizumab is not available in Canada.