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Perspectives on IL-6 Inhibition in Rheumatoid Arthritis: An Analysis of Recent Data

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.

ABSTRACTS in PERSPECTIVE based on presentation from the 72nd Annual Meeting of the American College of Rheumatology

San Francisco, California / October 24-29, 2008

EDITORIAL OVERVIEW:

Louis Bessette, MD, MSc, FRCPC

Clinical Professor, Department of Medicine, Université Laval, Rheumatologist, CHUQ-Centre hospitalier de l’Université Laval, Quebec City, Quebec

Biologic therapy for rheumatoid arthritis (RA) has become part of established practice in the past decade. Results from studies such as PREMIER, COMET and BeSt have demonstrated the benefit of starting early combination methotrexate (MTX) with a tumour necrosis factor alpha (TNF-a) inhibitor in order to significantly slow disease progression compared to conventional therapy. However, there are still patients with inadequate response to MTX or TNF-a inhibitors or who lose response over time. As well, the possibility of finding an agent that can provide the same disease control in monotherapy as the combination treatments is an attractive option. For treating RA, another emerging option in biologic therapy is interleukin (IL)-6 inhibition. The phase III clinical trials programme carried out on the novel IL-6 inhibitor tocilizumab generated a wealth of data that is reviewed in this issue.

Onset of Action, Biomarkers and Joint Status

A rapid onset of action is desirable in RA therapy, to quickly provide relief of symptoms and hopefully arrest the course of the disease. Dr. Josef Smolen, Professor of Medicine, Medical University of Vienna, Austria, led a team of researchers who examined pooled data from four phase III trials of tocilizumab in a variety of regimens and settings.

Rapid onset seen as early as two weeks was similar in each of the studies, and 17% to 25% of patients treated with tocilizumab achieved ACR20 within two weeks compared to 7% to 10% in the controls. Disease activity score (DAS) 28 improved at this point in treated patients, with some remissions reported (DAS<2.6), and C-reactive protein (CRP) levels had dropped to below the upper limit of normal (ULN) (0.3 mg/dL) with low levels persisting for the remainder of the study periods. ACR50 and ACR70 responses improved at one to two months. DAS28 remission rates at 24 weeks ranged between 27.5% and 33.6% among studies, depending on the treatment regimen.

A substudy of the phase III OPTION trial conducted by Dr. Thasia Woodworth, Welwyn, UK, and colleagues found that there were significant improvements in biomarkers for joint degradation, including type IIA collagen N-propeptide (PIIANP), type II collagen helical peptide (Helix–II) and matrix-metalloprotease-3 (MMP-3) among patients using tocilizumab. These improvements were associated with achievement of an ACR50 response.

Dr. Joel Kremer, Professor of Medicine, Albany Medical College, New York, presented radiographic findings at 12 months from the two-year LITHE study of tocilizumab therapy. Patient criteria included inadequate response to MTX (but not to anti-TNF therapy). Treatment with tocilizumab over 52 weeks showed continuing improvement in the signs and symptoms of RA, especially for the major clinical response end points of DAS28 remission, ACR50 and ACR70. DAS28 remission was seen in 47.2% of patients at 52 weeks with the 8-mg/kg dose compard to 8% in the control group (placebo/MTX). Significant Health Assessment Questionnaire-disability index (HAQ-DI) scale reductions were seen and maintained to 52 weeks. In patients treated with the 8-mg/kg dose, significantly greater inhibition of the progression of structural joint damage was observed with a 74% reduction of the progression of the total Sharp score compared to placebo/MTX. In 86.8%, there was no progression of erosion as defined as a change from baseline in the erosion score of =0 and no evidence of joint space narrowing in 90.5% of patients, compared to 70% and 84.5% in the placebo arm, respectively.

Inadequate Responders to TNF-a Inhibitors

The RADIATE study demonstrated that tocilizumab can provide significant therapeutic benefit to patients who experience inadequate response to a TNF inhibitor, according to Dr. Paul Emery, Professor of Rheumatology, University of Leeds, UK. This paper is important in that it indicates that there are useful potential therapies beyond anti-TNF failure. DAS28 remission was seen in 30% of patients in the 8-mg/kg cohort compared to 1.6% in the control arm, which is good, considering the severity of disease in these patients. From another presentation by Dr. Emery, it is notable that ACR20 responses were seen in half of patients after one (49%), two (50%) or even three (54%) prior anti-TNF failures.

The AMBITION trial, which was conducted by Dr. Graeme Jones, Professor of Rheumatology and Epidemiology, University of Tasmania, Australia, and colleagues, was designed to show non-inferiority of tocilizumab monotherapy to MTX. However, the data were strong enough to demonstrate superiority to MTX for all measures of efficacy. As might be expected, given the relatively low average duration of disease, ACR results were better than those seen in trials such as TOWARD, OPTION and LITHE, with 70.6%, 43.4% and 28% of patients achieving ACR20, ACR50 and ACR70, respectively (all significantly higher than MTX alone). At 33.6%, DAS28 remission was almost three times higher than for MTX.

Analysis of Adverse Events

In pooled data from five phase III trials, safety analyses were carried out from two perspectives, one approach led by Dr. Mark Genovese, Associate Professor of Medicine, Stanford University School of Medicine, Palo Alto, California, observed the lipid parameters and biomarkers and the other, led by Dr. Smolen, the incidence of adverse events.

From the perspective of lipid parameters and biomarkers, findings showed that increases in LDL-C observed in patients using tocilizumab plateaued after six weeks. Furthermore, HDL-C levels also increased, so cholesterol ratios were relatively maintained. Investigators noted that statin use at baseline reduced LDL-C elevations by about 7 mg/dL, while initiation of statins during the study period resulted in mean LDL-C decreases of 28.9 mg/dL by week 24.

Increased risk of cardiovascular (CV) disease in RA is believed to be mediated at least to some degree by IL-6 and CRP. However, in the analysis, as the lipid levels increased, CRP and other inflammatory biomarker levels declined. In the case of CRP, levels returned close to normal and remained low for the duration of the studies. The net effect of these changes remains to be elucidated.

Biologic drugs are immunomodulatory and consequently may increase the risk of occurrence of serious infections. From the perspective of the incidence of adverse events, Dr. Elena Fisheleva, Welwyn, UK, presented the overall safety analysis at 24 weeks.

Serious adverse events were similar in the IL-6 inhibitor and control cohorts. Serious infection rates were low in all cases, although higher in tocilizumab-containing regimens. No increase in CV events was seen, and the incidence of malignancies was very low. This trend continued in the extension studies at 1.5 years with no new safety signals and no increase in adverse event rates over the original six-month study period. At that time, 15.3% of patients experienced serious adverse events, the most common being infections (5.2%).

The analysis of the pooled data identified several risk factors in patients treated with tocilizumab with a median exposure of 1.5 years: age =65 years (odds ratio [OR] 1.9), diabetes (OR 2.0), history of infection (OR 2.2), and baseline corticosteroids (OR 1.8).

Liver enzyme disturbances are not uncommon with biologic therapy. There were 25 perprotocol treatment discontinuations among 4098 patients in the tocilizumab clinical program due to ALT/AST increases of >5x ULN. About 6% of patients experienced elevations >3x ULN; however, these were transient and normalized with treatment interruption or dose reduction. No liver pathologies have been observed to date, according to investigators led by Dr. Kremer.

Another study presented by Dr. Genovese examined the immunogenicity of the IL-6 inhibitor. The analysis was generated from four phase III trials (n=1747). A small number of patients developed human anti-human antibodies (HAHAs) (n=24) to tocilizumab. The adverse event profile of these patients was no different than that of the total treated patient population. Occurrence of HAHAs was highest in patients treated with the 8-mg/kg dose combined with a DMARD. However, as assessed by CRP levels and DAS28, there was no evidence of reduced efficacy with the IL-6 inhibitor.

Summary

The comprehensive phase III clinical trials programme with the IL-6 inhibitor tocilizumab has demonstrated that it is a viable and welcome option for inadequate responders to MTX or TNF-a inhibitors. Analyses have shown this agent to be effective with a rapid onset of action and an acceptable safety profile. However, there is a need to elucidate the effect of lipids on the overall long-term CV risk as well as determine when and which patients would benefit from the addition of statin therapy. Moreover, as the first biologic agent to have demonstrated superiority to MTX, further exploration of a monotherapy regimen with tocilizumab is warranted.

Note: At press time, tocilizumab is not available in Canada.

ABSTRACT 989 - Tocilizumab Treatment Results in Rapid Improvements in the Signs and Symptoms of Moderate-to-Severe Rheumatoid Arthritis in Four Patient Populations with Different Prior Therapy Exposure

J. S. Smolen, M. Churchill, W. Rizzo, D. Ridley, A. Law, K. Bahrt, M. C. Genovese

Background: In patients with active rheumatoid arthritis (RA), therapies that induce a rapid, sustained response are highly desirable. In four recently completed phase 3 clinical trials, tocilizumab (TCZ), a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody, improved the signs and symptoms of RA as a monotherapy and in combination with traditional DMARDs.

Objective: To determine the onset of response of TCZ 8 mg/kg in the four different populations of patients with active RA evaluated in phase 3 trials.

Methods: Data from four international, randomized, double-blind, 24-week, phase 3 clinical trials investigating the safety and efficacy of TCZ therapy in patients with moderate-to-severe, active RA were evaluated. Four populations were assessed: in TOWARD, patients with inadequate response (IR) to prior DMARDs (DMARD-IR) received TCZ 8 mg/kg intravenously (IV) or placebo IV (control) every 4 weeks plus DMARDs; in OPTION, methotrexate (MTX)-IR patients received TCZ 8 mg/kg IV or placebo IV plus MTX 10-25 mg/week; in RADIATE, anti-TNF-IR patients received TCZ 8 mg/kg IV or placebo IV (control) plus MTX 10-25 mg/week; in AMBITION, patients who had not failed previous MTX or biologic treatment (43% DMARD-naïve) received TCZ monotherapy (8 mg/kg IV every 4 weeks) or MTX monotherapy (escalating dose 7.5-20 mg/week). Outcome measures included ACR20/50/70 responses, remission rates (DAS28 <2.6), EULAR response criteria (good or moderate), and change from baseline C-reactive protein (CRP) levels.

Results: Separation of the TCZ and control groups was observed at the first time point measured (Week 2), with 56%-65% of TCZ-treated patients achieving a good or moderate EULAR response, regardless of prior RA therapy (Table). In TCZ-treated patients, CRP levels had also normalized by Week 2, and 17%-25% had achieved ACR20 responses. In all populations, the improvements observed with TCZ were sustained throughout the 6-month study period (data not shown).

Conclusions: TCZ as monotherapy, or in combination with DMARDs/MTX, produced rapid and sustained improvements in the signs and symptoms of RA (assessed by ACR, EULAR and DAS28 criteria) and normalization of CRP levels within 2 weeks. This rapid onset of response was consistent regardless of prior therapy.


Commentary on abstract 989

In this analysis of the phase III trials, tocilizumab 8 mg/kg proved to have a rapid onset of response in all major outcome measures. Observed results were similar regardless of concomitant therapy with MTX, and of prior therapy with DMARDs, MTX or anti-TNFs. Some responses were seen at the first visit at two weeks: 17% to 25% of treated patients achieved ACR20, compared to rates of 7% to 10% in the control groups. DAS28 scores had also increased by week 2 in treated patients, and there were some DAS28 remissions by this stage. CRP levels normalized in all studies by week 2 (ULN=0.3 mg/L), and levels remained low for the duration of the trials. ACR50 response separated from placebo at week 4, and ACR70 at week 8. Tender and swollen joint counts also took a little longer, but were separated from placebo by week 4. It should be noted that statistical significance was not provided for the data in this study.

Questions and Answers with Dr. Josef Smolen, Medical University of Vienna, Austria

Q: Were there any predictors of response rate in terms of concomitant therapy, baseline status, etc.?

A: Sorry to say, we have no predictors for any of these therapies for response. The one thing we have is that the higher your disease activity, the less likely you will attain remission. But this is only a marginal effect; it is a significant but a marginal effect on the group. We would not be able to predict this for the individual.

Q: What research needs to be done in order to be able to predict response?

A: We have never done strategic trials. We have never taken a population of patients and randomized them to an IL-6 inhibitor, a TNF inhibitor, or a B-cell inhibitor and then swapped them once they did not respond. This way we would probably reach the answer to your question.

ABSTRACT 992 - The Anti-IL-6 Receptor Inhibitor Tocilizumab (TCZ) Combined with Methotrexate (MTX) Induces a Rapid and Sustained Decrease of Bone and Cartilage Degradation in Patients with Rheumatoid Arthritis (RA)

P. Garnero, E. Mareau, L. Thompson, T. Woodworth

Purpose: Tocilizumab (TCZ) combined with MTX has been shown to improve clinical symptoms in patients with RA, but the structural effects of this combination remains to be evaluated. Early changes in biochemical markers of bone and cartilage turnover and of matrix-metalloprotease- 3 (MMP-3) have shown to predict later radiographic progression in patients with RA receiving conventional disease modifying therapies or anti-TNF therapies. The objective of this study was to investigate the time and dose-dependent effects of combined TCZ and MTX on markers of bone and cartilage turnover in patients with moderate to severe RA from the OPTION randomized placebo controlled phase III study.

Methods: 416 of the initial 623 patients randomized in OPTION (80% female, mean age: 52 yr, mean disease duration 7.5 yr, mean DAS 28, 6.82 units) with an inadequate response to MTX were included, based on providing consent for biochemical specimen analysis. They were randomized to receive an infusion of TCZ at 8 mg/kg +MTX, 4 mg/kg +MTX, or placebo +MTX (10 to 25 mg weekly) every 4 weeks for 20 weeks with final follow-up at week 24. Serum markers of bone formation (type I collagen N-propeptide, PINP), bone resorption (ICTP), cartilage turnover (type IIA collagen N-propeptide, PIIANP), cartilage degradation (type II collagen helical peptide, Helix-II) and matrix-metalloprotease-3 (MMP-3) were measured at baseline and after 4, 16 and 24 weeks.

Results: Compared to placebo + MTX, TCZ+ MTX induced a decrease of ICTP which was significant at week 16 in the 8 mg/kg dose with further reduction at week 24 (table). TCZ 8 mg/kg + MTX induced a decrease of the cartilage turnover markers PIIANP and Helix-II and of MMP-3 which was significant as early as 4 weeks, with further reduction at week 16 and week 24 (table). TCZ+MTX induced a modest increase of the bone formation marker PINP, which was significant for both doses at week 4. Patients receiving TCZ + MTX with clinical remission at week 24 (DAS 28 <2.6) had a significantly larger decrease in ICTP (median: -25.6% vs -8.4%, p<0.01), Helix-II (-68.8% vs -36.7%, p<0.0001) and MMP-3 (-60.6% vs -50.0 p<0.05) than non-responders.

Conclusion: TCZ at 8 mg/kg combined with MTX rapidly and markedly reduces biochemical markers of bone resorption, cartilage turnover and MMP-3. These biochemical markers data suggest that TCZ at 8 mg/kg + MTX may have structural effects which
y radiological data.

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Commentary on abstract 992

This was a substudy of the OPTION phase III trial in which 416 of the 623 patients consented to provide samples for biochemical analysis. The phase III SAMURAI (Study of Active Controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor) study had already radiographically demonstrated activity of tocilizumab 8 mg/kg in Japanese patients. The present study included two doses of tocilizumab together with MTX. The results confirm the greater activity of the higher dose. Rapid and sustained decreases in PIIANP, Helix-II and MMP-3 are indicators that tocilizumab reduces cartilage destruction, while reduced (carboxy-terminal telopeptide of type-I collagen) ICTP levels suggest improvements in systemic bone metabolism. A clinical relationship was seen in this study; percentage reductions in ICTP (18.5% vs. 5%), Helix-II (54.3% vs. 38.9%) and MMP-3 (63% vs. 28.5%) were significantly greater in patients who achieved an ACR50 response at week 24 than in those who did not (combined results for 4 and 8 mg/ mL). The magnitude of the reductions in PIIANP and MMP-3 were consistent with those seen in SAMURAI. These results were confirmed radiographically by the LITHE study, which tends to validate these indicators as markers of improved joint status.

Questions and Answers with Dr. Thasia Woodworth, Welwyn, UK

Q: Are the markers that were investigated in this study validated as predictors of joint status?

A: Particularly the HELIX-II and the MMP-3 have been tightly linked to predicting a decrease in joint destruction. There are at least five studies that have shown that linkage, and it also links to the lowering of CRP, which is not something we have captured in this poster.

Q: Do baseline marker levels predict the amount of improvement seen?

A: We have not looked explicitly at that. It is something that we will do when we have a larger data set.

Q: What can be learned from comparing this study with the radiological LITHE study?

A: The LITHE study validates the decrease in HELIX-II with the improvement in ICTP and the lowering of MMP-3 as a leading indicator that a patient is responding and is going to experience joint structure preservation.

ABSTRACT L14 - Tocilizumab Inhibits Structural Joint Damage in Rheumatoid Arthritis Patients with an Inadequate Response to Methotrexate: The LITHE Study

J. M. Kremer, R. M. Fleischmann, A-M. Halland, J. Brzezicki, T. Woodworth, E. Fisheleva, E. Alecock, R. Burgos-Vargas

Purpose: Tocilizumab (TCZ), an anti-interleukin-6 (IL-6) monoclonal antibody, improves the signs and symptoms of RA in patients with inadequate response (IR) to DMARDs, including methotrexate (MTX). The efficacy of TCZ plus MTX in preventing structural joint damage in MTX-IR patients and improving patient function was investigated in a planned 12-month analysis of a 2-year study.

Methods: Phase 3, randomized, double-blind, placebo-controlled trial. MTX-IR patients with moderate-to-severe active RA received MTX once weekly (10-25 mg oral or parenterally) plus TCZ 4 or 8 mg/kg, or placebo (control) IV every 4 weeks for 1 year. A switch to blinded rescue treatment was available at Weeks 16 and 28, if required. Primary endpoints included changes from baseline in Genant-modified Sharp score (linear extrapolation) and the area under the curve (AUC) in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 52.

Results: The analysis population (ITT) included 1190 randomized patients (TCZ 8 mg/kg n=398, TCZ 4 mg/kg n=399, control n=393). Mean joint erosion, joint space narrowing, and total Genant-modified Sharp scores showed significant inhibition of radiographic progression from baseline in both TCZ groups compared with control (Table). The mean change from baseline in HAQ-DI significantly decreased in TCZ-treated patients compared with control. DAS28 remission rates were significantly higher in the TCZ 8 mg/kg group compared with control, and low disease activity rates were significantly higher with both TCZ groups compared with control (Table). The safety profile was consistent with previous studies and did not change from 6 to 12 months. The most common serious adverse events were serious infections (TCZ 8 mg/kg 3.0%, TCZ 4 mg/kg 2.5%, control 1.5%). Medically significant infusion events were reported in the TCZ 4 mg/kg group only (4 anaphylactic reaction, 2 hypersensitivity).

Conclusion: Significantly improved DAS remission rates were achieved with TCZ treatment, suggesting an important role for IL-6 blockade in MTX-IR patients with RA. TCZ therapy significantly inhibited the progression of structural joint damage, improved function (HAQ-DI), and the sign
ignificantly more than control, with an acceptable safety profile.

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Commentary on abstract L14

LITHE (Tocitizumab Safety and the Prevention of Structural Joint Damage) is a significant study. Its purpose was to provide radiographic evidence of actual change in the course of disease in order to augment the growing body of data supporting the efficacy of tocilizumab in inducing reduction of RA symptoms. The clinical results and safety profile of the IL-6 inhibitor seen in this trial confirm the benefits demonstrated in the six-month OPTION trial and extend them to 12 months (LITHE will continue to two years, with a further open-label extension to five years). DAS28 remission rates were good at 47.2% at 52 weeks with the 8-mg/kg dose. Both study dosage regimens rapidly exceeded the minimum clinically important difference on the HAQ-DI scale, and maintained clinically significant scores for the duration of the study. The placebo group did not cross this threshold. The 8-mg/kg dose also yielded significant reductions in radiographic progression, with 86.8% of patients experiencing no progression of joint erosion compared to 70% with placebo, and no increase in joint space narrowing in 90.5% of patients, compared to 84.5% in the placebo arm.

Questions and Answers with Dr. Joel Kremer, Albany Medical College, New York

Q: Patients who had terminated prior TNF inhibitors were admitted, provided they had not discontinued for lack or loss of efficacy. How many such patients were in the trial?

A: There were approximately 11.5% of patients who had received prior anti-TNFs.

Q: Why do you think that the Genant-modified Sharp score of the MTX-only control group progressed by only a single point in a year?

A: This was curious. I think it was a vagary of the study. One can speculate that perhaps the 70% who were on corticosteroids may have influenced an overall response. Nevertheless, the delta from baseline was substantial.

Q: Do you see a dissociation between the clinical response and the radiographic response, in that ACR20 non-responders might still have inhibition of radiographic progression?

A: I did not see non-responders dissected out from radiographic response, but those data are accessible.

ABSTRACT 1209 - Tociluzumab (TCZ) Rapidly and Significantly Improves Outcomes in Patients with Rheumatoid Arthritis (RA) Who Have Inadequate Response (IR) to TNF Antagonists

P. Emery, E. Keystone, HP Tony, A. Cantagrel, R. van Vollenhoven, A. Sanchez, E. Alecock, J. Lee, J. Kremer

Background: RA has complex pathophysiology and a substantial number of patients fail to achieve an adequate response to TNF antagonist therapy or lose response over time. TCZ is a novel monoclonal antibody that inhibits interleukin-6 signaling, which may provide an alternative treatment for TNF-IR patients. The Research on Actemra Determining efficacy after Anti-TNF failurEs (RADIATE) study investigated the efficacy and safety of TCZ + methotrexate (MTX) in TNF-IR patients with RA.

Methods: Patients (N=499) who had moderate to severe active RA for =6 m were enrolled in this multicenter, randomized, double-blind study. All patients had an IR to =1 TNF antagonist and had received stable-dose MTX for 12 wks prior to baseline. Patients received MTX 10-25 mg/wk in combination with iv placebo (controls) or in combination with iv TCZ 4 or 8 mg/kg every 4 wk, for 24 wk.

Results: All outcomes in the TCZ 8 mg/kg group and most in the 4 mg/kg group were significantly better than with controls (table). Withdrawal or need for rescue therapy occurred in 25, 34 and 60% of patients, respectively. Logistic regression analysis showed patients were 9 times more likely to achieve an ACR20 response at Wk 24 if they received TCZ 8 mg/kg, and 4 times more likely if they received TCZ 4 mg/kg, than controls (p<0.0001). There was a clear separation between TCZ 8 mg/kg and controls in ACR20 response rates by Wk 4; separation in ACR50/70 responses was observed by Wk 8. In both TCZ treatment groups, DAS28 remission was first achieved by Wk 2 (1.3% of 4 mg/kg and 1.9% of 8 mg/kg recipients) compared with Wk 12 in the control group (0.7%). DAS28 remission rates increased continually over time through to 30% at Wk 24 with TCZ 8 mg/kg. Adverse events (AEs) occurred in 84.0, 87.1 and 80.6% of TCZ 8 mg/kg, TCZ 4 mg/kg and controls, respectively. Common AEs included diarrhea, upper abdominal pain, rash and dizziness. Serious AEs occurred in 6.3, 7.4 and 11.3% of TCZ 8 mg/kg, TCZ 4 mg/kg and controls, respectively. Serious infections occurred in 4.6, 1.8 and 3.1%, respectively.

Conclusions: TCZ+MTX therapy was associated with rapid and significant clinical improvements in th
ion. 30% of patients achieved remission with the 8 mg/kg dose. Treatment was reasonably safe and well tolerated.

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Commentary on abstract 1209

Patients who have already failed on a biologic might be expected to be a challenging group and indeed, the ACR results were lower than those seen in the other phase III studies. However, responses achieved statistical significance over MTX alone in all cohorts except ACR70 rates for patients on 4 mg/kg tocilizumab. DAS28 remission and low disease rates were impressive in the 8 mg/kg cohort given the severity of disease in the study population, but failed to achieve significance at 4 mg/kg. It is notable that DAS28 remission increased in a linear fashion throughout the study period. Another encouraging result was the fact that ACR20 was achieved by approximately half of all patients at the 8 mg/kg dosage, regardless of whether they had failed one, two or three TNF antagonists, although ACR50 and ACR70 responses were somewhat diminished by multiple prior TNF antagonist failures. Tocilizumab therapy was not associated with any increase in serious adverse events compared to the placebo group (6.3% vs. 11.3%, respectively).

Questions and Answers with Dr. Paul Emery, University of Leeds, UK

Q: There is some controversy surrounding the use of DAS28 <2.6 as an indicator of remission. Do you have data concerning tender and swollen joint counts in patients considered to be in remission for this study?

A: We have looked at the patients with no tender and no swollen joints, and they are not very different, surprisingly… Although the domains are not necessarily what we think, they are in remission—certainly oncological remission is not the same. I’m quite happy in what we are talking about: very low disease activity states, and patients who exhibit what we as clinicians would understand as very little disease.

Q: What action did you take with patients who had slight but sustained elevations of ALT?

A: Most of them were not sustained. That was the fact that allowed them to stay in the study. If they were sustained, eventually they would come out. Nearly all the elevations were self-limiting.

ABSTRACT 1210 - The AMBITION Study: Superiority of Tocilizumab (TCZ) vs. Methotrexate (MTX) Monotherapy in Patients with Rheumatoid Arthritis (RA)

G. Jones, JR Gu, M. Lowenstein, A. Calvo, JJ Gomez-Reino, D. Siri, M. Tomsic, R. Blackburn, T. Woodworth, A. Sebba, M. Genovese

Background: Despite the recognized role of biologic agents in the treatment of RA, methotrexate remains the gold-standard. The Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy (AMBITION) study compared the efficacy and safety of monotherapy with the novel anti-interleukin-6 receptor monoclonal antibody, TCZ, versus MTX monotherapy in patients with active RA.

Methods: International multicenter, randomized, double-blind trial. All patients (n=572) had moderate to severe active RA and had not failed prior MTX or biologic therapy. Over a 24-wk period, patients received either TCZ 8 mg/kg every 4 wk, or MTX 7.5 mg/wk titrated up to 20 mg/wk within 8 wk. Primary efficacy analysis examined non-inferiority of TCZ ACR20 response at Wk 24 vs MTX in the PP population (n=524). If non-inferiority was established, secondary analyses investigated the superiority of TCZ over MTX for other efficacy outcomes in the ITT population (n=570).

Results: TCZ non-inferiority vs MTX was established: 70.6% of TCZ and 52.1% of MTX patients achieved an ACR20 response by Wk 24 (PP population; weighted difference 0.21, 95% CI 0.13, 0.29). In the ITT population, TCZ was superior to MTX, with a significantly higher proportion of TCZ patients achieving Wk 24 ACR20/50/70 responses (table). The odds of achieving DAS28 remission were >5 times higher, and good/moderate EULAR response was >4 times higher, with TCZ vs MTX in this population. Mean change from baseline to Wk 24 in CRP level was -2.6 mg/dL for TCZ vs -1.9 mg/dL for MTX; CRP normalisation (hsCRP <0.3 mg/dL) occurred in 88.5% of TCZ and 31.0% of MTX patients. Hemoglobin levels improved in the TCZ arm by Wk 24 (adjusted mean change from baseline +1.2 g/dL vs +0.1 g/dL with MTX). Adverse event (AE) rates were similar: 79.9% with TCZ and 77.5% with MTX. Serious AEs occurred in 3.8% of TCZ vs 2.8% of MTX patients, while serious infections occurred in 1.4 vs 0.7% of patients.

Conclusions: After 24 wk of treatment, TCZ monothera
monotherapy for alleviating symptoms in patients with RA who had not failed prior MTX or biologic therapy. TCZ was safe and well tolerated in these patients.

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Commentary on abstract 1210

Unlike the other phase III tocilizumab trials, the AMBITION study examined its use as monotherapy in a first-line setting, in patients who were essentially naïve to MTX or biologic therapy (prior therapy was permitted as long as it had been discontinued for at least six months and for reasons other than treatment failure). The trial met its primary objective of demonstrating non-inferiority to MTX, and further demonstrated superiority to MTX using an ITT analysis. ACR results were better than those seen in trials such as TOWARD, OPTION and LITHE, with 70.6%, 43.4% and 28% of patients achieving ACR20, ACR50 and ACR70, respectively (all significantly higher than MTX alone). However, the average duration of disease was relatively low, as would be expected in a comparatively treatment-naive population of patients. DAS28 remission was good at 33.6%, almost three times higher than that for MTX alone. Safety data were unremarkable, with the exception of cholesterol. In this study, tocilizumab had almost no effect on HDL-C levels, while 23% of patients experienced an LDL-C increase to more than 160 mg/dL (4.14 mmol/L). Presumably this indicates that at least some patients may experience an unfavourable change in lipid ratios, in addition to an increase in total cholesterol.

Questions and Answers with Dr. Graeme Jones, University of Tasmania, Australia

Q: Why do you think the percentage of patients on MTX with elevated liver enzymes was so high?

A: A lot of patients were on corticosteroids, and I think the liver function changes were more failing liver than necessarily related to medications in this study. They were the same in both groups, with minor variations.

Q: What was the protocol for dealing with ALT or AST elevation?

A: If they went five times above normal, the protocol recommended cessation; if they had three times [above normal], the protocol recommended dose reduction.

Q: Can you describe the MTX escalation procedure?

A: We started at 7.5 mg and increased to 20 mg over eight weeks. Ninety per cent of the subjects achieved 20 mg and the mean dose was 17 mg.

Q: Can you explain the reasons that patients came to be off treatment for six months prior to this study?

A: Patients were not eligible if they had serious toxicity, but if they discontinued due to mild adverse events, they were eligible. If they had stopped due to pregnancy, that was allowed.

ABSTRACT 987 - Lipid and Inflammatory Biomarker Profiles in Patients Receiving Tocilizumab for Rheumatoid Arthritis: Analysis of Five Phase III Clinical Trials

M. C. Genovese, J. S. Smolen, P. Emery, G. Jones, J. S. Lee, E. Alecock, J. M. Kremer

Background: Traditional cardiovascular (CV) risk factors may contribute to CV disease in patients with rheumatoid arthritis (RA) but do not adequately explain the increased CV risk. Inflammation is thought to play a key role in driving CV disease in RA. Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, has been shown to improve RA signs and symptoms and reduce inflammation with a reasonable tolerability profile.

Objective: To characterize lipid and inflammatory biomarker changes during TCZ monotherapy, or in combination with DMARDs, using pooled clinical trial data.

Methods: Analysis of five double-blind, randomized, 24-week, phase 3 clinical trials enrolling patients with moderate-to-severe, active RA. Patients with inadequate response to DMARDs (LITHE, OPTION, TOWARD) or anti-TNF therapy (RADIATE) received DMARDs plus TCZ 8 mg/kg (TCZ+DMARD; n=1582) or placebo (PBO+DMARD; n=1170) intravenously (IV) every 4 weeks. Patients who had not failed previous methotrexate (MTX) or biologic therapy received monotherapy with TCZ 8 mg/kg IV every 4 weeks (n=288) or MTX escalating dose 7.5-20 mg/week (n=284; AMBITION). Periodic fasting lipid levels and 4-weekly inflammatory biomarker levels were evaluated during the 24-week treatment period.

Results: Unlike typical dyslipidemia (increased LDL and decreased HDL), increases from baseline in mean total cholesterol, LDL, HDL, triglycerides and apolipoproteins A1 and B were observed within 6 weeks of initiating treatment, persisting to Week 24 in TCZ-treated patients (Table). Concurrent substantial reductions from baseline in mean levels of several inflammatory biomarkers, including C-reactive protein (CRP), serum amyloid A (SAA), haptoglobin and lipoprotein (a), were observed in TCZ-treated patients (Table).

Conclusions: Elevations in lipid parameters were observed with TCZ monotherapy and TCZ+DMARD. These elevations occurred concomitantl
uctions in inflammatory biomarkers. The clinical relevance of the simultaneous changes in lipids and CRP with regard to CV disease in patients with RA is presently unclear and will require further study.

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Commentary on abstract 987

Lipid levels in patients with RA tend to be normal or even low, yet independently of this there is an elevated risk of atherosclerosis and cardiac events. It is now believed that the high levels of IL-6 and CRP seen in RA are associated with these increases in CV disease. This analysis clearly shows a dose-dependent elevation of lipids during tocilizumab use, although there is evidence that levels begin to decline again at about 14 weeks, particularly with the 4-mg/kg dose. There are also indications that patients with higher baseline levels experience less marked increases, and those with higher LDL-C levels have larger decreases with time. The reduction of inflammatory biomarkers seen with tocilizumab use was marked: at the 8-mg/kg dosage, levels of CRP decreased rapidly and remained close to zero for the remainder of the 24-week analysis period. Further study is needed to elucidate whether there is any net effect of tocilizumab therapy on CV risk.

Questions and Answers with Dr. Mark Genovese, Stanford University School of Medicine, Palo Alto, California

Q: Did you observe the incidence of CV events?

A: Yes, and we did not see any. Now these are short studies, but I think there would be strong reason to believe that the significant improvement in inflammation that we are seeing probably obviates at least some of the potential risk we think may occur, if at all, with the lipid changes. Time will tell us that.

Q: Do the HDL-C and LDL-C levels increase proportionately, so that cholesterol ratios are preserved?

A: You see a slightly higher change in LDL-C than in HDL-C; the ratios do not change that much.

Q: Are statins effective in treating patients who experience very high lipid levels due to tocilizumab?

A: Yes, there were roughly 23 patients in the TOWARD trial who were treated with statins. They all had a fairly rapid response and returned to a normal level; there was no clear evidence of any liver function test abnormalities or muscle breakdown or any other problems.

Q: Can statins be used prophylactically to prevent the lipid changes?

A: Theoretically, yes, but I think you are better off looking to see first whether the change actually happens, because it has not happened in all patients in any meaningful way, so I think you are probably better off measuring it after the patient starts.

ABSTRACT 1672 - Concomitant Use of Statins in Tocilizumab-Treated Patients with Rheumatoid Arthritis with Elevated Low Density Lipoprotein Cholesterol: Analysis of Five Phase III Clinical Trials

M. C. Genovese, J. S. Smolen, P. Emery, G. Jones, J. S. Lee, E. Alecock, J. M. Kremer

Purpose: Tocilizumab (TCZ) has demonstrated efficacy and safety in patients with rheumatoid arthritis (RA) in phase 3 clinical trials. Low-density lipoprotein cholesterol (LDL-C) levels and adverse events (AEs) were examined in TCZ-treated patients who received statins treatment in these trials.

Methods: Five international, randomized, double-blind, placebo-controlled, 24-week trials included patients with RA who received TCZ 4 mg/kg or 8 mg/kg or placebo (control) via intravenous infusion every 4 weeks, in combination with DMARDs (OPTION, TOWARD, RADIATE, and LITHE), or who received TCZ 8 mg/kg or MTX (control) monotherapy (AMBITION). An exploratory post-hoc analysis of LDL-C levels was performed in patients who initiated statin treatment prior to baseline or during the trials. AEs were compared between patients who were treated with statins at baseline and the entire patient population.

Results: In 195 TCZ-treated patients who were receiving statins at baseline, mean LDL-C levels increased between baseline and the first fasting lipid assessment at Week 6, and then stabilized, with a mean increase of 11.7 mg/dL at Week 24 (Table). A mean LDL-C increase of 18.7 mg/dL was observed for the entire population of TCZ-treated patients regardless of statin use. Statin treatment was initiated in 37 TCZ-treated patients at any time following randomization and despite an initial increase by Week 6, a decrease of 28.9 mg/dL in LDL-C values from baseline to Week 24 was observed (Table). AEs of myalgia, musculoskeletal pain, and arthralgia, commonly associated with statins, occurred at similar rates in patients treated concomitantly with lipid lowering agents (74%
ho were randomized to TCZ and in the entire TCZ-treated population (2.7% and 2.4%, respectively). Transient elevations >3xULN in liver enzymes (ALT), during the studies, were also comparable between the same groups (2.2 % vs 5.9%, respectively).

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Conclusions: TCZ-induced increases in mean LDL-C levels were less pronounced for patients treated concomitantly with statins at baseline compared with the entire TCZ-treated population. Initiation of statin treatment after receiving TCZ was effective in reducing LDL-C levels to below baseline values.

Commentary on abstract 1672

Although patient numbers were quite low in this study (195 patients on statins at baseline and 37 patients initiated on statins during the studies), the effects seemed quite similar between the various tocilizumab treatment cohorts. For patients using statins at baseline, LDL-C increased rapidly, then stabilized after the first assessment at six weeks as seen in the total tocilizumab population, but the increases averaged about 7 mg/dL less for statin users. Patients who were started on statins during the studies had higher than typical baseline LDL-C, as might be expected. These patients were initiated on statins at varying times during the studies, so the changes in LDL-C levels from one assessment to the next was very variable, but all cohorts showed considerable decreases from baseline by week 24, with a mean drop of 28.9 mg/dL. The addition of statins to the regimen did not appear to affect the adverse event profile. It remains to be seen whether intervention to reduce LDL-C will prove necessary in patients with RA who are treated with tocilizumab, given the rather complex relationship between lipid levels and CRP during IL-6 inhibitor therapy, and the need to clarify its effect on CV risk.

Questions and Answers with Dr. Mark Genovese, Stanford University School of Medicine, Palo Alto, California

Q: How long had the patients using statins at baseline been taking this medication?

A: It’s quite variable. Some patients had been on statins for a period of weeks, some had been on it for a period of years. I don’t have the mean duration of statin treatment prior to study initiation. The only thing we know is that they were on a stable dose for a period leading into the trial.

Q: Why were they on statins at that time?

A: Simply for the treatment of hypercholesterolemia.

Q: Is there a basis for recommending statins as prior therapy for patients starting on tocilizumab?

A: No, I wouldn’t. I would suggest that what we should be doing is having an understanding as to what a baseline with the profile looks like for our patients, checking again between six weeks and three months. If we see a significant alteration of lipid profile for a given patient, such that they have now reached an area where they are at increased risk based on traditional guidelines, and that a statin be considered to be added to the regimen.

ABSTRACT 1669 - Safety of Tocilizumab in Patients with Rheumatoid Arthritis: Pooled Analysis of Five Phase III Clinical Trials

J. S. Smolen, A. D. Beaulieu, A. Dikranian, I. Fenton, E. Fisheleva, E. Alecock, P. Emery

Purpose: Tocilizumab (TCZ) is a humanized interleukin-6 receptor inhibitor that has demonstrated significant improvements in the signs and symptoms of moderate-to-severe rheumatoid arthritis (RA) in five Phase 3 clinical trials. This pooled analysis evaluated the safety and tolerability of TCZ as monotherapy and in combination with DMARDs.

Methods: Five international, randomized, double-blind, placebo-controlled trials enrolled patients with moderate-to-severe RA. Patients who were inadequate responders to DMARDs (LITHE, OPTION, TOWARD studies) or anti-TNF biologic therapy (RADIATE) received combination treatment with DMARDs plus TCZ 8 mg/kg (TCZ+DMARD; n=1582) intravenously every 4 weeks, or placebo (PBO+DMARD; n=1170), while patients who had not failed previous methotrexate (MTX) or biologic treatment received monotherapy with TCZ 8 mg/kg (n=288) or MTX (n=284; AMBITION). Adverse event (AE) rates were evaluated during the 24-week treatment period.

Results: Baseline demographics were generally similar across the four treatment groups; there were differences in disease characteristics as expected including mean disease duration (TCZ+DMARD 9.7, PBO+DMARD 9.4, TCZ monotherapy 6.4, MTX 6.2 years) and mean number of prior DMARDs/anti-TNFs used (TCZ+DMARD 1.8, PBO+DMARD 2.0, TCZ monotherapy 1.2, MTX 1.1). Serious AE rates did not differ between TCZ and control groups (Table). Withdrawals due to AEs were more frequent with MTX monotherapy (5.3%) compared with TCZ monotherapy (3.8%). Infections were the most frequent type of AEs observed in all groups; there were no cases of tuberculosis. Serious infection rates were low in all groups; slightly higher rates were observed in TCZ vs control arms, with overlapping confidence intervals. The incidence of malignancy was low in all groups. Increases from <200 mg/dL fasting total cholesterol at baseline to = 240 mg/dL at last visit were observed in 6.3% TCZ+DMARD patients, 1.3% PBO+DMARD patients, 9.7% TCZ monotherapy patients and 3.2% MTX monotherapy patients. Increases in ALT from normal at baseline to highest value >3x ULN were observed in 5.
1.0% PBO+DMARD patients, 1.7% TCZ monotherapy patients and 3.5% MTX monotherapy patients.

Conclusions: TCZ combination treatment and monotherapy was well tolerated in a broad range of patients with moderate to severe RA, with low rates of serious AEs, serious infections and malignancies.

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Commentary on abstract 1669

This pooled safety analysis helped to confirm the impressions gained from the individual phase III studies that tocilizumab is generally well-tolerated, with low incidence of serious adverse events. It would be interesting to know what proportion of adverse events requiring withdrawal were per-protocol withdrawals that might be handled differently in a real-world clinical setting. The rate of serious infections with tocilizumab/DMARD therapies was higher than with DMARDs alone, but was still low, and with overlapping confidence intervals. However, serious infection rates were similar in tocilizumab and MTX monotherapies. Liver and lipid data are discussed elsewhere, but it is worth reiterating that the effects seen were self-limiting and reversible, and on-treatment lipid therapy with statins was effective. No increases in CV events were observed. Incidence of neoplasms was low and not considered to be treatment-related.

Questions and Answers with Dr. Elena Fisheleva, Welwyn, UK

Q: How would you characterize the safety profile of tocilizumab?

A: The highest proportion of patients with adverse events were the infection adverse events, and that is what you would expect with biological therapies anyway. The next type of adverse events would be related to headaches and nausea, things like that, so that is also quite straightforward and manageable. We do see some liver enzyme elevations, which occur, not as a clinical event but usually a laboratory abnormality, and cholesterol elevations as well, in about 6% of patients.

Q: To what extent do the adverse events observed affect treatment with tocilizumab?

A: The actual rate of serious adverse events was very low, and you could see also by the amount of patients who discontinued from the studies which is also very low, which means that even if they had a serious adverse event, they could manage it and continue on trial.

Q: Do you think that the observed level of safety will continue with long-term tocilizumab therapy?

A: We have data for 1.5 years of exposure because our long-term studies are currently ongoing, and we don’t see any evidence of increase in any types of adverse events compared to what has been seen in the first six months.

ABSTRACT 1670 - Safety of Tocilizumab in Patients with Rheumatoid Arthritis: An Interim Analysis of Long-Term Extension Trials with a Mean Treatment Duration of 1.5 Years

R. F. van Vollenhoven, J. Smolen, H. P.T. Tony, C. Codding, E. C. Keystone, T. Woodworth, E. Alecock, R. Alten

Purpose: The efficacy and safety of tocilizumab (TCZ) has been demonstrated in patients with rheumatoid arthritis (RA) in phase 3 clinical trials. To further assess the safety and tolerability of TCZ, an interim analysis of long-term extension studies was performed to evaluate safety outcomes.

Methods: Patients with RA who completed the four international, randomized, double-blind, placebo-controlled, 24-week, phase 3 trials (OPTION, TOWARD, AMBITION, and RADIATE) could transition into two ongoing, openlabel, extension studies assessing the long-term safety of TCZ (8 mg/kg; every 4 weeks). Safety outcomes were evaluated up to the cut-off date, October 1, 2007.

Results: A total of 2562 patients (94.3%) transitioned into the extension studies, with a median TCZ exposure of 1.5 years, and a total cumulative duration of observation of 3693.0 patient years. The rate of withdrawals due to AEs remained low with a total of 6.2% of patients withdrawn due to an AE by the cut-off date. The most common adverse events (AEs) leading to withdrawal were neoplasms (1.1%), elevations of liver enzymes (1.0%), and infections (0.9%). The rate of serious AEs was 13.5 (95% CI: 12.4-14.8) and serious infections was 3.9 (95% CI: 3.3-4.6) per 100 patient years, with no evidence of increased risk with continued TCZ exposure. A decrease in the mean neutrophil count (<1x109 cells/L) was reported in 3.8% of patients; however, these decreases were not sustained and no clear association with serious infections were detectable. Alanine and aspartate aminotransferases (AST and ALT) were elevated >3x the upper limit of normal in 7.6% and 2.4% of patients, respectively. In most cases, elevations were single occurrences and there was no association with clinically relevant changes in direct bilirubin. The mean total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride values were elevated from the first measurement at Week 6, and remained elevated with continued TCZ treatment, but without further increases with continued treatment. The overall rate of myocardial infarction was low at 0.27 (95% CI: 0.1-0.5) per 100 patient years, and the rate was stable over 6-monthly intervals.

Conclusions: TCZ showed a favorable safety profile over the extended treatment period with a low discontinuation rate. The results of the continuing extension studies will provide further insight into TCZ as a long-term treatment option.

Commentary on abstract 1670

One of the most important things to know about medications used in chronic disease is how their efficacy and safety may change with time, e.g., if there are cumulative toxicities or if new problems will arise due to prolonged exposure. This analysis of the ongoing open-label extension studies of patients who participated in the original phase III trials provides data to 18 months. Withdrawal rates remained low with a total of 6.2% of patients having withdrawn due to an adverse event, the major reasons being neoplasms, liver enzyme elevations and infections. Overall, the incidence of adverse events, including serious adverse events, did not increase with continued treatment. The rate of serious adverse events was 13.54 per 100 patient-years of tocilizumab use, and the most common type of serious adverse event continued to be serious infection. Liver enzyme elevations continued to be manageable by interruption of treatment or dose modification. Lipid levels remained at the levels observed at week 6.

Questions and Answers with Dr. Elena Fisheleva, Welwyn, UK

Q: Is there any evidence that any of the neoplasms seen may be treatment-related?

A: No, we don’t see any evidence of a relationship, although we don’t have enough duration of observation or enough patients exposed yet. But we are constantly monitoring our patients for malignancies and we will be doing it accordingly with regulations for biological therapies as needed, but we currently see no evidence of increasing risk.

Q: Do any of the serious adverse events seen mandate termination of tocilizumab therapy?

A: Actually in our clinical trials, especially in the long-term clinical trials, we did not mandate termination of tocilizumab under any circumstances except when the liver enzymes were really high. In the short-term studies, we also mandated discontinuation if the neutrophils dropped below 0.5, which happened very infrequently, a total of 12 patients in the whole clinical program.

Q: Were there any problems with infusion reactions?

A: There were very few infusion-related events, such as pyrexia, and they tend to be transient, so I doubt if many were even reported. Anaphylaxis was seen in six patients in the whole program.

ABSTRACT 1667 - Hepatic Aminotransferases and Bilirubin Levels During Tocilizumab Treatment of Patients with Rheumatoid Arthritis: Pooled Analysis of Five Phase III Clinical Trials

J. M. Kremer, A. K. John, R. Malamet, E. C. Keystone

Purpose: In five phase 3 clinical trials, tocilizumab (TCZ), an IL-6 receptor inhibitor, significantly improved signs and symptoms and was well tolerated in moderate-to-severe rheumatoid arthritis (RA). Liver enzymes are routinely monitored in patients taking DMARDs, and this pooled analysis evaluated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin during these trials.

Methods: Five international, randomized, double-blind, placebo-controlled, 24-week trials included patients with RA who received TCZ 4 mg/kg or 8 mg/kg or placebo (control) via intravenous infusion every 4 weeks, in combination with DMARDs (OPTION, TOWARD, RADIATE, and LITHE), or who received TCZ 8 mg/kg or methotrexate (MTX; control) monotherapy (AMBITION). An exploratory post-hoc analysis of liver enzyme levels recorded at Week 2, then every 4 weeks for 24 weeks, was performed.

Results: Mean baseline ALT (28.0-31.0 U/L), AST (22.0-24.0 U/L), and total bilirubin (0.3-0.4 mg/dL) were comparable across studies and treatments. The incidence of shifts in ALT and AST from normal at baseline to >upper limit of normal (ULN) during treatment was higher with TCZ+DMARD vs control, and similar with TCZ monotherapy vs MTX (Table). Amongst patients with elevations 1-3xULN in ALT and AST, 33.3% and 45.6% of TCZ-treated patients experienced this as a single occurrence, respectively, compared with 40.7% and 56.7% of MTX-only patients. The majority of these patients (82.0% ALT and 80.2% AST for TCZ-treated patients vs 74.3% ALT and 79.0% AST for MTX-only patients) did not require dose modification to achieve =ULN. Few TCZ+DMARD and TCZ patients had >1 elevation >3xULN in ALT (2.1% and 0.4%) or AST (0.4% and 0%), and there were no sustained ele
ferase elevations were not associated with clinically relevant increases in total bilirubin; changes in total bilirubin were driven by indirect bilirubin. Although no patients experienced clinical signs or symptoms of hepatitis or hepatic dysfunction, per protocol, 25 patients discontinued treatment due to ALT/AST >5×ULN with TCZ+DMARD.

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Conclusions: In patients with RA and a range of differences in disease duration and DMARD use, the incidence of elevations of hepatic transferases (>3×ULN) was <5% with TCZ+DMARD, <2% with TCZ monotherapy, and <3% with MTX monotherapy and these elevations were not associated with clinical signs or symptoms of liver disease. The majority of elevations 1-3xULN returned to normal limits without any adjustment in TCZ therapy.

Commentary on abstract 1667

The monitoring of serum transaminase levels during the phase III tocilizumab trials stems from the known hepatotoxicity of some DMARDs, including MTX. The most serious findings were per-protocol treatment discontinuations in 25 of 4098 patients due to ALT/AST increases of >5x ULN. These were all seen in patients on regimens that included both tocilizumab and a DMARD. There was evidence of possible additive toxicity; higher increases were seen in combination therapy populations than in either agent as monotherapies. However, increases above 3x ULN were both infrequent (approximately 6% for ALT in combination therapy patients) and transient; most patients who experienced such elevations did so only once, and levels decreased after treatment interruption. Below 3x ULN, elevations were transient and normalized in most cases without dose modification. Bilirubin showed similarly low rates of elevation, although they tended to be higher with tocilizumab than with DMARDs. As yet, there has been no evidence of liver pathology associated with these findings.

Questions and Answers with Dr. Joel Kremer, Albany Medical College, New York

Q: Are there predictors of which patients are likely to experience significant transaminase elevations?

A: No. Those patients who had a slight transaminase at baseline—they accepted up to 1.5x normal at baseline—were not necessarily more likely to have an increased delta. But honestly, what I would like to see in that population is a really good history of alcohol intake, not only contemporaneous history, but historical history about alcohol intake. What about other confounders—acetaminophen intake, hydrocodone intake, BMI, obesity, adiposity associated with fatty liver? Keeping all those things in mind, I think we just need to be vigilant and manipulate one of the interventions so as to keep the enzymes closer to the normal range.

Q: In clinical practice, what options would you consider given a significant elevation?

A: You have a variety of opportunities. Should they be on a contemporaneous hepatotoxic drug, MTX? You’re on seven pills, you go to four or five pills; then repeat the enzymes and see what happens. I ask, were you drinking? Half the time I hear yes, I went to a wedding. I tell them this was the result, and all of a sudden you get a focusing of the patient.

Q: Again in clinical practice, if you get to 5x ULN, would it be mandatory to discontinue, as was done in the study?

A: I don’t think there’s anything mandatory, there’s just wise and unwise in clinical practice. I would not tolerate 5x ULN, that’s for sure. I don’t think there’s going to be a black box [warning] that 5x ULN means you have to jettison the drug, but clearly you have to be careful.

ABSTRACT 993 - Low Immunogenic Potential of Tocilizumab in Patients with Rheumatoid Arthritis: Analysis of Four Phase III Clinical Trials

C. Ramos-Remus, M. C. Genovese, R. A. Harrell, T. Woodworth, E. Alecock

Purpose: Biologic therapies may induce anti-drug antibodies that reduce efficacy or cause adverse reactions. Tocilizumab (TCZ), a humanized interleukin-6 receptor-blocking monoclonal antibody, significantly improved the signs and symptoms in patients with rheumatoid arthritis (RA) in phase 3 clinical trials. The potential development of anti-TCZ human anti-human antibodies (HAHAs) and their effect on both efficacy and allergic type adverse event (AE) incidence was also evaluated in these studies.

Methods: In four international, randomized, double-blind, placebo-controlled, 24-week trials, patients with moderate-to-severe RA who were inadequate responders to DMARDs (OPTION and TOWARD) or anti-TNF biologic therapy (RADIATE) received combination treatment with DMARDs plus TCZ 8 mg/kg (TCZ8+DMARD) or TCZ 4 mg/kg (TCZ4+DMARD) via intravenous infusion every 4 weeks. Patients who were methotrexate (MTX) naïve or not inadequate responders (AMBITION) received TCZ 8 mg/kg monotherapy (TCZ8). Serum samples were obtained during scheduled visits, prior to dosing to minimize TCZ interference, and immunogenicity testing was performed using four validated assays: HAHA screening and confirmation, inhibition ELISA for neutralizing antibodies, and BiaCore for Ig antibodies.

Results: A total of 1747 TCZ-treated patients were screened, and 24 patients developed neutralizing (n=18), Ig class (n=9), or uncharacterized (n=4) HAHAs, with some patients appearing in multiple categories. More than 70% of patients with neutralizing HAHAs were detected by Week 8, and their incidence was highest in patients treated with TCZ8+DMARD (n=16), compared with TCZ4+DMARD (n=1) or TCZ8 (n=1). In patients with neutralizing HAHAs, efficacy assessed by CRP levels and DAS28 was maintained, with no withdrawals due to lack of efficacy. Du
patients had 12 AEs of allergic nature; however, 4 of these patients developed HAHAs prior to the allergic AE: 1 severe anaphylactic reaction with TCZ4+DMARD leading to withdrawal, 2 mild-to-moderate infusion-related reactions with TCZ8+DMARD leading to 1 withdrawal, and 1 moderate infusion-related reaction with TCZ8 leading to withdrawal. In all cases, the allergic AEs were resolved.

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Conclusions: TCZ monotherapy or combination treatment is associated with a low immunogenic potential in patients with RA.

Commentary on abstract 993

A potential concern with the use of therapeutic monoclonal antibodies is the development of antibodies, which may reduce the efficacy of the agent and potentially lead to the appearance of allergic adverse events. For example, such responses have been observed with adalimumab and infliximab. This analysis examined data from 2553 patients who had been given tocilizumab in five phase III trials (including interim 24-week data from the LITHE study). A total of 46 patients developed HAHAs. However, only five patients with anti-tocilizumab HAHAs withdrew from the trials due to adverse events, and there was no overall difference in the adverse event profile of patients who developed HAHAs compared with the total patient population. There was a higher incidence of anti-tocilizumab production among patients treated with the MTX/tocilizumab 4 mg/kg dose than among those treated with 8 mg/kg either with a DMARD or as monotherapy. No reductions of efficacy due to HAHAs were reported.

Questions and Answers with Dr. Mark Genovese, Stanford University School of Medicine, Palo Alto, California

Q: What is the most important message from these data?

A: They confirm what we have heard from the preliminary results of each of the individual trials: that we have not seen a great deal of immunogenicity associated with tocilizumab, and when immunogenicity has been observed, it has not correlated with either response or lack of response, or with a safety issue developing, so it is reassuring.

Q: Is there a likelihood immunogenic potential may increase over time?

A: You are never certain, but I think it’s unlikely. We’ve got 24-week plus data about immunogenicity, and we have not seen any change there. I know the company’s continuing to look at it in open-label extensions. It is always a possibility, but I suspect it’s not going to prove to be a real issue.

Q: Would you say that the immunogenicity testing was comprehensive?

A: Yes, I think the assays that were set up to assess immunogenicity were quite rigorous, and were appropriate to really get at the issue as to whether or not immunogenicity was occurring, and if so, whether it was correlating with any negative events.

ABSTRACT 1668 - Relationship Between Patient Characteristics and the Development of Serious Infections in Patients Receiving Tocilizumab: Results from Long-term Extension Studies with a Follow-up Duration of 1.5 Years

J. M. Kremer, R. F. van Vollenhoven, D. J. Ridley, W. Rizzo, E. Fisheleva, E. Alecock, P. Mease

Background: The immunomodulatory effects of biologic therapies used to treat rheumatoid arthritis may lead to the development of serious infections. Susceptibility to serious infections may also be determined by comorbid conditions or other predisposing factors, whose identification may help guide treatment decisions. In recently completed clinical trials, the interleukin-6 receptor inhibitor, tocilizumab (TCZ), has been shown to be effective and well tolerated, with a low incidence of serious infections.

Purpose: To determine the association between patient characteristics and the development of serious infections during TCZ treatment.

Methods: Patients completing one of four phase 3 clinical studies, OPTION, TOWARD, RADIATE, or AMBITION, were eligible to enter one of two long-term extension (LTE) studies with open-label TCZ 8mg/kg as monotherapy or combined with a DMARD. In this post-hoc exploratory analysis, data from the clinical and LTE studies were pooled, and outcomes evaluated from initial treatment dose until the LTE study cut-off date, October 1, 2007. Logistic regression analysis was used to determine the effects of specific, clinically-relevant patient characteristics, as well as neutrophil counts <1x109/L during the observation period, on the probability of developing a serious infection (leading to death or hospitalization or requiring intravenous antibiotics), presented as odds ratios (OR) with 95% confidence intervals (CI).

Results: The analysis population comprised 2562 patients (OPTION n=537; TOWARD n=1059; AMBITION n=566; RADIATE n=400), with a median TCZ exposure time of 1.5 years. There were 133 patients (5.2%) who experienced 145 serious infections (incidence rate: 3.9 per 100 patient-years [95% CI: 3.3-4.6]). Neutrophil counts <1x109/L post-baseline and c
monary disease were not significantly associated with developing a serious infection; all other assessed characteristics were associated (Table).

Conclusions: During treatment with TCZ 8mg/kg, diabetes, age =65 years, a history of infection, and corticosteroid use were associated with an increased probability of developing a serious infection. No association was observed between low neutrophil counts and serious infections.

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Commentary on abstract 1668

Because biologic treatments are immunodulatory by nature, the risk of serious infections is a concern. Experience with TNF inhibitors has shown that this risk is significant. IL-6 plays a key role in immune response, including inflammatory response and leukocyte activity. Accordingly, tocilizumab, an IL-6 inhibitor, is likely to degrade immune responses. By pooling data from four phase III studies and their extension phases, this analysis was able to access data from 2562 patients with a median duration of tocilizumab usage of 1.5 years. The risk factors identified—age =65 years (OR 1.9), diabetes (OR 2.0), history of infection (2.2), and baseline corticosteroids (OR 1.8)—were perhaps not unexpected, but the absence of association with chronic obstructive pulmonary disease and low neutrophils during therapy was somewhat surprising. Data from the extension phases of the trials provided evidence that the risk of serious infection does not continue to rise beyond the first six months.

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