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IL-6 Inhibition: Moving Towards Higher Remission Rates in Rheumatoid Arthritis

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.

Annual European Congress of Rheumatology 2008 (EULAR)

Paris, France / June 11-14, 2008

Editorial Review:

Janet E. Pope, MD, MPH, FRCPC Professor of Medicine, Head, Division of Rheumatology University of Western Ontario, London, Ontario

The success of conventional disease-modifying antirheumatic drugs (DMARDs) along with anti-tumour necrosis factor (TNF) therapy in the treatment of rheumatoid arthritis (RA) has raised expectations as to the degree of disease control now possible for patients with RA. At EULAR this year, many presentations discussed remission of RA as an achievable outcome in many patients. Thus, the goal of modern RA management is to aim for a symptom-free, fully functional patient who experiences no (further) structural damage.

That goal is not completely met by current treatment strategies. Between 30% and 40% of patients with RA do not respond to DMARDs and clinical experience suggests that many who do take methotrexate (MTX) would rather not take it due to side effects. Approximately 10% to 30% of patients never achieve a primary response to anti-TNF agents and of those who do respond initially, a sizable proportion lose their response after a few years. We do not understand why some patients lose their response to therapy over time which is a research question that needs to be answered. Thus a significant proportion of RA patients have an unmet need for more effective therapy.

The Role of IL-6

Breakthrough research into inflammatory cytokines involved in the pathogenesis of RA identifies interleukin-6 (IL-6) as a highly pro-inflammatory cytokine and important in RA. IL-6 is produced by cells in the rheumatoid joint, causing local inflammation and damage. Studies have shown that patients with RA have excessive levels of IL-6 as well as soluble IL-6 receptor (IL-6R) in their joints. As a widespread pro-inflammatory cytokine, IL-6 is a major driver of the autoimmune response and is implicated in both local and systemic inflammation in RA. Elevated IL-6 levels can also affect musculoskeletal, cardiovascular (CV) and nervous systems. IL-6 is a major contributor to the development of osteoporosis and bone damage, and it also regulates C-reactive protein (CRP) by the liver, a key inflammatory marker in RA. Excessive systemic IL-6 leads to an increase in the production of hepcidin, an acute-phase protein that blocks iron transport, causing the anemia and fatigue commonly experienced by patients with RA. Inhibition of IL-6 thus has the potential to exert profound effects in a disease such as RA, which is driven by excessive production of IL-6.

Tocilizumab (TCZ), an IL-6 receptor inhibitor, has been used in RA trials and other autoimmune disorders. It disrupts the IL-6 signalling pathway by binding to both soluble and membrane-expressed IL-6R.

Trial Results

Investigators evaluated the use of TCZ in 673 mostly MTX-naïve patients with RA, some of whom had received prior MTX therapy, but none who had failed MTX. In AMBITION (Tocilizumab vs. Methotrexate Double-Blind Investigative Trial in Monotherapy), patients were randomized to MTX 7.5 mg to 20 mg/week (n=284), TCZ 8 mg/kg every four weeks (n=288) or placebo (n=101) for 24 weeks. The primary end point was the proportion of patients who achieved a 20% reduction of RA symptoms (ACR20) at 24 weeks.

As presented by Dr. Graeme Jones, Professor of Rheumatology and Epidemiology, University of Tasmania, Australia, 69.9% of patients on the TCZ arm achieved an ACR20 at study end point compared with 52.5% of MTX counterparts (P<0.0001); 44.1% of TCZ patients vs. 33.5% with MTX achieved an ACR50 at week 24 (P=0.0023), while 28% with TCZ and 15.1% with MTX achieved an ACR70 (P=0.0002).

Based on EULAR response criteria, 82.2% of TCZ patients achieved a EULAR good/moderate response compared with 64.8% of those in the MTX group and more TCZ patients achieved a good as opposed to a moderate response than those on MTX. Clinical disease remission as defined by a Disease Activity Score 28 (DAS28) of <2.6 was also seen in 33.6% of the TCZ group vs. 12.1% with MTX. Therefore, almost three times more patients with TCZ in the AMBITION study went into remission than with MTX alone.

CRP levels decreased to within the normal range within two weeks of treatment and remained normal throughout the study period. Increases in hemoglobin (Hb) similarly occurred within two weeks and both reductions in CRP and increases in Hb were greater than those seen with MTX.

In terms of safety, there were few differences between the two treatment groups, with serious adverse events (SAEs) occurring in 3.8% in TCZ and 2.8% in MTX. Discontinuation due to AEs were similar at 3.8% in the TCZ arm vs. 5.3% in the MTX arm, while liver transaminase abnormalities were twice as common with MTX as they were with TCZ. Rates of serious infections were slightly higher at 1.4% for TCZ vs. 0.7% for MTX, but observed transient decreases in neutrophil counts were not associated with infection risk.

The results of AMBITION are impressive with very high ACR scores and between-group differences among TCZ and MTX were quite large, which is different than other biologic data such as anti-TNFs when compared first-line to MTX.

A setting where there is clearly an unmet clinical need in RA management is patients who have failed both MTX and other DMARDs as well as anti-TNF therapy. Dr. Paul Emery, Professor of Rheumatology, University of Leeds, UK, presented the safety and efficacy of TCZ/MTX in patients with an inadequate response to TNF antagonists. In RADIATE (Research on Tocilizumab Determining Efficacy after Anti-TNF Failures), 499 patients were randomized to placebo/MTX (n=160), TCZ 4 mg/kg/MTX (n=163) or TCZ 8 mg/kg/MTX (n=175). The primary end point was the proportion of patients achieving an ACR20 at 24 weeks. The mean dose of MTX at baseline was16.5 mg/week and the mean number of previous DMARDs other than MTX was two. Approximately half of patients had also been exposed to one prior anti-TNF agent, the remainder being exposed to two or three.

At 24 weeks, 50% of patients receiving TCZ 8 mg/kg had achieved an ACR20, as had 30.4% of those on the lower TCZ dose and 10.1% of placebo controls (P<0.0001 vs. placebo); 28.8% of TCZ 8 mg/kg patients, 16.8% of TCZ 4 mg/kg patients and 3.8% of placebo patients achieved an ACR50, while 12.4% of TCA 8 mg/kg patients, 5% of TCZ 4 mg/kg patients and 1.3% of placebo patients achieved an ACR70.

Remarkably, in a post-TNF setting, approximately 30% of TCZ 8 mg/kg patients achieved a clinical remission (DAS28 <2.6) while low disease activity was reported in almost 60% of the group. The efficacy of the higher-dose TCZ regimen was not compromised by the number of prior anti-TNF therapies, as there was no loss of ACR20 response to TCZ 8 mg/kg in these patients. Dr. Emery emphasized that the safety profile was consistent with IL-6 inhibition (transaminase increases, neutrophil decreases, infection and elevated cholesterol levels) and its toxicity readily manageable.

Earlier evidence from a phase III randomized trial in which TCZ was tested in patients with an inadequate response to DMARDs had suggested the IL-6 inhibitor would be effective in refractory patients, especially those refractory to DMARDs. In the TOWARD study (Tocilizumab in Combination with Traditional DMARD Therapy), 803 patients were randomized to TCZ 8 mg/kg every four weeks for 24 weeks in addition to their existing DMARD therapy. Another 413 were randomized to placebo plus their existing DMARD. Mean DAS28 at baseline was 6.7 for the TCZ/DMARD group and 6.6 for the placebo/DMARD arm, implying very high baseline disease activity in both groups. The primary end point was ACR20 at 24 weeks. The mean MTX dose at baseline was 14.7 mg/wk for the TCZ/DMARD arm and 15 mg/wk for their placebo counterparts. Dr. Juan J. Gómez-Reino, University of Santiago de Compostela, Spain, reported that 60.8% of the TCZ/DMARD group achieved the primary end point vs. 24.5% for placebo/DMARD patients. ACR50 responses were observed in 37.6% of the TCZ/DMARD group vs. 9% for the control group, while ACR70s were seen in 20.5% for the TCZ/DMARD group vs. 2.9% for controls.

Investigators also documented significantly greater improvements in swollen joint counts at -10.3 for patients on TCZ/DMARD vs. -4.9 for placebo/DMARD in controls as well as for tender joint counts at -15.7 for TCZ/DMARD patients vs. -8.5 for controls (P<0.0001). Analyzing efficacy by EULAR response criteria, 40% of TCZ/DMARD patients achieved a good response, 39.7% a moderate response and 20.3% no response. Comparable rates for placebo/DMARD patients were 4.4%, 33.2% and 62.5%, respectively (P<0.0001).

Of note, virtually identical rates of DAS28 <2.6 were achieved in TOWARD as were reported in the more recent RADIATE trial, at 30.2% for those who received the IL-6 inhibitor and 3.4% for those who did not (P<0.0001). Consistent across all TCZ trials, rapid reductions in CRP levels were observed as early as week 2, with significantly greater reductions in CRP in the TCZ-containing arm (P<0.0001) vs. virtually no change in the control arm. Corresponding increases in Hb were also seen as early as week 2, with essentially no change in mean Hb in the non-TCZ-containing group (P<0.0001). Rates of SAEs were recorded in 6.7% of the TCZ arm vs. 4.3% of the control arm. Overall, tolerability of the combination strategy with TCZ/DMARD was very good.

OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) was done in patients with moderate-to-severe RA who had received at least 12 weeks of MTX.

In a pooled analysis of TOWARD and OPTION, the efficacy of the TCZ/DMARD combination was assessed in 1625 patients. Reporting mean treatment differences between the TCZ/ DMARD arm and those on placebo/DMARD, Dr. André Beaulieu, Professor of Medicine, Université Laval, Quebec City, Quebec, and colleagues established that there was a 34% between-treatment difference in ACR20 responses in favour of the TCZ-containing arm, a 29% difference in ACR50 responses and an 18% difference in ACR70 responses by week 24. Importantly, however, a 14% mean difference in ACR20 treatment effects was seen as early as week 2.

Mean changes in DAS28 scores from baseline were also significantly greater for TCZ/DMARD-treated patients than for the placebo group and by week 24, 25% were in DAS28 remission in the TCZ/DMARD arm vs. 6% of those in the placebo/DMARD arm. Again, changes in DAS28 scores were seen as early as week 2, with a -1.16 mean between-arm treatment difference. At week 2, reductions in CRP were already pronounced in the TCZ/DMARD group, at a mean between-arm treatment difference of -2.25 mg/dL, while increases in Hb were equally rapid, with a mean between-arm treatment difference of 0.80 g/dL at week 2.

This pooled analysis is clinically meaningful, as Dr. Beaulieu explained, because after only two weeks of starting treatment with TCZ, physicians will have a very good idea whether patients will respond to TCZ, a feature that distinguishes this biologic from most other treatments used for RA. However, we do not know if some early non-responders will respond later and the maximum ACR response will take more than two weeks to occur. The rapidity of onset of TCZ seems impressive.

Concentrations and Efficacy

Another pooled analysis of OPTION and TOWARD described the relationship between TCZ concentrations and efficacy, as assessed by DAS28 over 24 weeks, using a population pharmacokinetic/pharmacodynamic (PK/PD) analysis of the data. As discussed by a Roche researcher Thasia Woodworth, Welwyn, UK, the PK/PD modelling showed that reduction in DAS directly was related to TCZ exposure. For example, 38.4% of patients achieved DAS28 remission on the TCZ 8-mg/kg dose vs. 23.9% of those on the 4-mg/kg dose. Good EULAR responses were also higher for the 8-mg/kg dose at 48.3% vs. 32.3% for the 4-mg/kg dose. Thus, if patients receive higher exposure to TCZ, they have a very reasonable likelihood of achieving DAS remission, Woodworth suggested.

Controlling Anemia

Approximately 30% of patients with RA have anemia arising from chronic inflammation, which may be accompanied by fatigue. IL-6 is a key mediator of this anemia, stimulating production of acute-phase proteins including hepcidin, a hormone that blocks iron transport. At high levels, hepcidin also causes retention of iron in macrophages as well. By blocking the IL-6 signalling pathway, hepcidin production decreases, iron is absorbed by the gut and is also immediately released from macrophages, making iron available for Hb production. This is not an epoietin-like effect but rather a Hb-production effect, so that there is an increase in Hb in red blood cells, not an increase in red blood cells themselves.

In another pooled analysis of OPTION and TOWARD, changes in Hb levels were assessed out to week 24, and the proportion of patients achieving either <1.0 g/dL or <u>></u>1.0 g/dL increase in Hb were compared between treatment groups. Changes in fatigue were also assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue score. Dr. Josef Smolen, Professor of Medicine, Medical University of Vienna, Austria, reported that the mean change in Hb from baseline was significantly greater in the TCZ/DMARD group at 1.04 g/dL compared with a loss of 0.11 g/dL in the control group. Improvements in Hb were also rapid in response to TCZ/DMARD therapy, with greater mean changes from baseline vs. control as early as week 2.

A higher proportion of TCZ/DMARD patients at 51.7% also achieved an increase in Hb of <u>></u>1.0 g/dL compared with controls at 17.1% (P<0.0001). Mean changes in FACIT-fatigue scores at study end point were significantly greater in TCZ/DMARD patients than controls, especially in patients who achieved a <u>></u>1.0 g/dL increase in Hb. We do not know if the improvement in fatigue is from suppressing inflammation or from other effects of down-regulating IL-6.

Dr. Smolen also reported pooled safety data from OPTION and TOWARD. In this analysis, SAEs were reported in 6.6% of the TCZ-containing arm vs. 4.9% in the control arm, while discontinuations due to AEs at 4.4% were higher in the TCZ arm than the placebo group (2.1%). Rates of infections were also higher at 36.7% in the TCZ/DMARD arm vs. 30.7% in the placebo/DMARD arm, but rates of serious infections were low at 2.8% and 1.6% for the TCZ-containing and non-TCZ-containing arms, respectively.

Approximately 40% of patients in the TCZ/DMARD group had an increase in mean plasma lipids but as investigators pointed out, increases were generally within the normal range and in some cases, appeared to coincide with moderate to large decreases in CRP. As CRP is a major risk factor for CV disease, the CV risk that could be associated with elevations in lipids may well be offset by reductions in CRP. In addition, increases in HDL levels were also observed.

An increase in mean hepatic transaminases—generally within the normal range—was seen in TCZ patients, but the majority of those who experienced an increase in ALT to over the upper limit of normal (ULN) were <3 x ULN. All but two cases of liver enzyme values either declined or had normalized by the last observation visit following discontinuation of therapy. Thus far, it can be said that there are no unusual safety signals associated with IL-6 inhibition, though longer-term follow-up is needed. It appears that the main side effects of TCZ are transient elevations of liver enzymes, transient drops in neutrophil count and elevated cholesterol. However the benefits with respect to especially high bar outcomes are virtually the highest we have seen compared to other biologics.

Summary

With the introduction of biologic therapies for the management of RA, the goal of disease remission may be a reality in some patients. However, even with the best available treatments, a significant proportion of patients either do not achieve an initial excellent response or lose response over time. There is therefore a significant need for innovative new therapies that target different pro-inflammatory cytokines responsible for the pathogenesis of RA. IL-6 is a major mediator of local and systemic inflammatory responses and a driver of the autoimmune response. TCZ can bind to both membrane-bound and soluble IL-6 receptors. Evidence from four phase III clinical trials indicates that IL-6R inhibition provides significant clinical benefits to RA patients with a significant proportion of patients achieving low disease states and even disease remission.

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