IL-6 Inhibition in RA An Emerging Role for Tocilizumab HIGHLIGHTS FROM EULAR 2008 PRESENTATIONS

IL-6 Inhibition in RA

An Emerging Role for Tocilizumab

HIGHLIGHTS FROMEULAR 2008 PRESENTATIONS

Three-year extension of the Samurai study: Radiographic findings

Nishimoto et al. EULAR 2008, abstract FRI0153

The Samurai study was a randomized trial designed to evaluate the effect of tocilizumab (TCZ) on radiographic progression at one year vs. conventional DMARDs in patients with early RA

At the end of the one-year randomized study• 128 patients continued to receive TCZ 8 mg/kg• 113 patients on conventional DMARDs also received TCZ

The 3-year radiographic analysis was based on 212 patients who had radiographic data from baseline, 1 and 3-year visits



Patient Disposition




• In the TCZ group, 37.5% of patients at 1 year, and 38.3% at 3 years, had no radiographic progression (TSS change equal to or <0.5)

• In the DMARDs/TCZ group, 20.7% at 1 year, and 18.5% at 3 years, had no radiographic progression

• The yearly progression rate during the 2nd and 3rd year was significantly suppressed in both groups compared with that seen during the randomized trial in the first year

• The mean radiographic score changes over 3 years were all significantly lower in the TCZ group than in the DMARDs/TCZ group

• Switch from DMARDs to TCZ significantly suppressed radiographic progression but efficacy was less than that in the TCZ group




• TCZ significantly suppressed radiographic progression in this 3-year long-term study

• The mean erosion score did not increase at all in the second and third year of TCZ treatment

• Early as opposed to late introduction of TCZ was more effective in preventing joint damage




Radiographic changes from baseline [Mean (95% CI)]

TCZ (n=120) DMARDs/TCZ (n=92)

1-year 3-year 1-year 3-year

TSS 4.93 (3.08, 6.79) ‡ 7.42 (4.26, 10.58) ‡ 11.38 (7.56, 15.19) 16.32 (10.99, 21.65)

Erosion 1.83 (0.95, 2.70) ‡ 2.23 (0.74, 3.73) ‡ 5.76 (3.87, 7.65) 7.72 (4.81, 10.64)

JSN 3.18 (2.04, 4.32) 5.38 (3.35, 7.42) † 5.62 (3.49, 7.76) 8.58 (5.94, 11.21

‡ P<0.001, † P<0.01, vs. DMARDs/TCZ analyzed with a rank transformed analysis of covariance (ANCOVA)

SAMURAI study: Conclusions

• TCZ significantly suppressed radiographic progression in this 3-year long-term study

• The mean erosion score did not increase at all in the second and third year of TCZ treatment

• Early as opposed to late introduction of TCZ was more effective in preventing joint damage


Rapid Improvement in Signs and Symptoms of RA with Tocilizumab: Pooled Analysis of OPTION & TOWARD Trials

Pooled analysis (ITT population) from 1625 patients

Treatment regimens

OPTION• TCZ 8 mg/kg every 4 weeks + MTX 10 to 25 mg/week• or PBO + MTX 10-25 mg/week

TOWARD• TCZ 8 mg/kg every 4 weeks + stable DMARD therapy• or PBO + stable DMARD therapy

Beaulieu et al. EULAR 2008, abstract THU0184

Pooled Analysis of OPTION & TOWARD: Results

Week 2 Week 4 Week 8 Week 24

ACR20 14% 21% 27% 34%

ACR50 4% 9% 14% 29%

ACR70 1% 3% 6% 18%


Mean ACR Response differences for TCZ vs. PBO

Week 2 Week 24

DAS28 -1.16 6% (week 4)

DAS28 remission (<2.6) -1.95 25%

Good or moderate EULAR response

47% 42%

C-reactive protein -2.25 mg/dL -1.59 mg/dL

Hemoglobin 0.80 g/dL 1.16 g/dL


Pooled Analysis of OPTION & TOWARD: Results

Mean treatment response differences for TCZ vs. PBO

Summary

• TCZ 8 mg/kg + DMARD therapy produced early, sustained and clinically significant improvements in signs and symptoms of RA compared with controls

• Improvement was accompanied by early, rapid and sustained reductions in CRP, suggesting an early and significant effect on inflammation

• Rapid increases in hemoglobin suggest that the beneficial effects of TCZ therapy may extend beyond those associated with the joints


Changes in liver enzymes & Bilirubin:Pooled analysis of OPTION & TOWARD

• It is crucial to know whether the addition of tocilizumab (TCZ) to DMARD therapy, especially MTX, increases hepatic toxicity over that seen with DMARDs alone

• ALT, AST and bilirubin values were pooled from 2, phase III RCT of TCZ, given with stable DMARD therapy, in patients with inadequate response to DMARDs

• ALT, AST and bilirubin were monitored throughout the 24-week study

Beaulieu et al. EULAR 2008, abstract FRI0173

Results

• More patients in the TCZ + DMARD arm had an increase in liver enzymes than in controls during study treatment

• Most patients had increases of >1-3 upper limit of normal (ULN) in both treatment groups, with fewer shifts to 3x ULN

• A greater proportion of TCZ + DMARD patients with liver enzyme elevations had ≥2 consecutive ALT or AST elevations than controls

• Most patients in both treatment groups had normalization of liver enzymes after a single elevation of AST or ALT, with no dose interruption


Results

• Most liver enzymes had returned to baseline by last study observation in patients withdrawn from study because of liver enzyme elevations

• One patient in the PBO + DMARD arm discontinued therapy because of an ALT increase >5x ULN

• Shifts in total bilirubin to <3x ULN occurred in 9% of TCZ + DMARD vs. <1% for PBO + DMARD


Results

• No patients in the TCZ + DMARD group experienced a simultaneous increase in ALT and AST to 3x ULN or greater and an increase in total bilirubin ≥ 2x ULN

• No clinical signs of hepatic injury were observed in patients with increases in ALT, AST and total bilirubin


Efficacy Data Based on ACR Criteria:Pooled analysis of OPTION & TOWARD Trials

This pooled ITT analysis included 1625 patients: • 1008 treated with TCZ + DMARD• 617 treated with PBO + DMARD

Efficacy according to ACR20, ACR50 and ACR70 responses

Adjusted mean changes from baseline in core ACR response criteria were also evaluated at each visit

Genovese et al. EULAR 2008, abstract THU0185

ACR Response Rates at Week 24

34%

29%

18%


Pooled analysis of OPTION & TOWARD: Efficacy Mean treatment differences at week 24 (All in favor of TCZ + DMARD)

Tender joint count

Swollen joint count

Patient

global VAS

MD global VAS

Patient pain VAS

HAQDI CRP ESR

-7.8 -5.5 -15.1 -12.3 -15.2 -0.26 -1.6 -31.0


Summary

• TCZ + DMARD produced clinically significant reductions in signs and symptoms of RA vs. DMARD alone in patients with an inadequate response to previous DMARD therapy

• There were significant improvements from baseline in all core ACR response criteria and this effect improved throughout the 24-week study

• Pooled data support the use of TCZ for DMARD- unresponsive patients with moderate to severe RA


A PK/PD analysis of the relationship between tocilizumab concentration and efficacy

• This analysis described the relationship between TCZ concentrations and efficacy, as assessed by DAS28 over 24 weeks using a population PK/PD model

• The PK/PD model was used to simulate DAS 28 time profiles in patients treated with TCZ 8 mg/kg or 4 mg/kg for 24 weeks

• 12,618 DAS28 observations from 1703 patients were used for model development

– OPTION (4153 observations from 572 patients)– TOWARD (8465 observations from 1131 patients

Levi et al. EULAR 2008, abstract THU0174

For external validation, 2350 observations from 443 patients in the RADIATE Trial were used.

• Relationships between cumulative TCZ exposure for serum concentration-time profiles and DAS28 time course were assessed and stratified into low, medium and high exposure categories.

• An exposure-response relationship was observed between TCZ treatment and DAS28 reduction, with clear differences between the lowest and medium TCZ exposure categories



• The maximal effect of TCZ was estimated at 72.5%, corresponding to a maximum 5-point DAS reduction for a typical initial baseline DAS28 of 6.8, with low inter-patient variability

• The effect of DMARD background therapy represented only a small fraction of the total effect on DAS28 observed for the two TCZ doses (estimated 0.8 point DAS reduction from baseline)




Effect of tocilizumab (TCZ) exposure on mean DAS28 response


Proportion of patients achieving DAS28 remission and good EULAR response according to tocilizumab dosage: Simulation results

Conclusions

• TCZ serum concentration levels were predictive of reduction in DAS28

• Serum concentrations corresponding to TCZ 8 mg/kg were more effective in reducing disease activity than those corresponding to 4 mg/kg


Improvement in hemoglobin and FACIT-fatigue score: Pooled analysis of OPTION & TOWARD

• A common type of anemia in RA is anemia of chronic inflammation

• IL-6 is a key mediator of this anemia, stimulating production of acute phase proteins including hepcidin, a hormone that blocks iron transport

• Inhibition of hepcidin production by tocilizumab (TCZ), an IL-6 inhibitor, should improve iron transport from the gut

Smolen et al. EULAR 2008, abstract THU0168

• A total of 1008 TCZ + DMARD patients and 617 controls were included in this ITT pooled analysis

• In patients with Hb below the lower limit of normal (LLN) at baseline, TCZ + DMARD rapidly increased Hb levels and they remained stable and within the normal range across time

• In patients with Hb above the LLN at baseline, TCZ + DMARD slightly increased Hb at treatment onset and they remained stable within the normal range across time

• In patients with very low baseline Hb (8.5-10 g/dL) mean change in Hb at week 24 was significantly greater with TCZ + DMARD at 2.55 g/dL vs 0.34 g/dL for controls


Improvement in Hb and FACIT-fatigue score: Pooled analysis of OPTION & TOWARD

TCZ + DMARD Controls Treatment difference

Mean change in Hb from BSE at week 24

1.04 g/dL -0.11 g/dL 1.16 g/dL

Mean change in Hb from BSE at week 2

0.68 g/dL -0.14g/dL 0.81 g/dL

Proportion of patients who achieved a Hb of 1.0 g/dL or more at week 24

51.7% 17.1% P<0.0001


Improvement in Hb and FACIT-fatigue score: Pooled analysis of OPTION & TOWARD


Changes from baseline in FACIT fatigue scoreaccording to improvements in Hb from baseline to Week 24 of <1.0 g/dL and ≥1.0 g/dL


Hb levels over time (g/dL)


Changes from baseline in DAS28 score according to improvements in Hb from baseline toWeek 24 of <1.0 g/dL and ≥1.0 g/dL

Improvement in Hb and FACIT-fatigue Score: Pooled Analysis of OPTION & TOWARD

• Mean change in FACIT-fatigue scores at week 24 were significantly greater in TCZ + DMARD patients than controls, especially in patients who experienced at 1.0 g/dL or greater increase in Hb over BSE

• TCZ + DMARD patients with a 1.0 g/dL or greater increase in Hb at week 24 had significantly greater improvements in FACIT-fatigue scores than those with <1.0 g/dL increase in Hb

• Control patients with a 1.0 g/dL or greater increase in Hb at week 24 experienced greater FACIT-fatigue improvements compared with those with < 1.0 g/dL increase but the difference was not significant.


Improvement in Hb and FACIT-fatigue Score: Pooled Analysis of OPTION & TOWARD

• In both treatment groups, patients who achieved a greater improvement in DAS28 score tended to experience a greater improvement in Hb

• This observation suggests that a reduction in disease activity may be associated with improved Hb levels

• Normalization of Hb in anemic RA patients may be a suitable marker of disease activity

• Fatigue improves along with improving Hb levels and reduced disease activity


Pooled analysis of OPTION & TOWARD: Baseline neutrophil counts and serious infections

• The immunomodulatory effects of biologic therapies may increase the risk of serious infections

• IL-6 also plays a pivotal role in regulating the immune system

• This analysis examined baseline characteristics and neutrophil counts in patients who developed serious infections in OPTION & TOWARD



• Serious infections were defined as those leading to death or hospitalization or requiring iv antibiotics

• Neutrophil counts were determined at baseline, and then every 2 weeks until week 16 then every 4 weeks until week 32

• A total of 1008 patients on TCZ + DMARD and 618 PBO + DMARD controls were included in this analysis



Patients with serious infections

Infection rate/100 patient-years

Total number of events

TCZ + DMARD 28 patients (2.8%) 5.9 29

PBO + DMARD 10 patients (1.6%) 4.0 11



Neutrophil count (at least 1 count below the LLN at any time)

TCZ + DMARD PBO + DMARD

1.5 - <2.0 x 109/L 195 patients (19.3%) 19 patients (3.1%)

1.0 - <1.5 x 109/L 115 patients (11.4%) 5 patients (0.8%)

0.5 - < 1.0 x 109/L31 patients (3.1%)

0

<0.5 x 109/L0 0



• The proportion of patients with diabetes at BSE was higher among those who developed a serious infection

• Patients receiving corticosteroids were also over-represented among those who developed serious infections

• There was no indication that a low neutrophil count increased the risk of serious infections


Reduction in inflammatory biomarkers with increasing exposure to tocilizumab: Pooled data

• Data were pooled from 4 RCTs evaluating tocilizumab (TCZ) ± DMARD therapy

• A total of 2243 patients were included in the graphic analysis: – 833 controls

– 201 in low TCZ exposure

– 539 in medium TCZ exposure

– 670 in high TCZ exposure

• The purpose of this analysis was to investigate treatment effect on main biomarkers of inflammation



Study design and treatment of four phase III clinical trials of tocilizumab in patients with moderate-to-severe RA

Trial Patients Treatment regimensTreatment duration

Combination therapy

Rescue therapy

OPTIONInadequate response to MTX

TCZ 8 mg/kg q. 4 weeks TCZ 4 mg/kg q. 4 weeks Placebo q. 4 weeks

24weeksMTX 10-25 mg(oral or iv) weekly

TCZ 8 mg/kg starting at week 16

TOWARD*Inadequate response to current DMARD therapy

TCZ 8 mg/kg q. 4 weeks Placebo q. 4 weeks

24 weeksStable anti-rheumatic therapy, including DMARDs

DMARD and/or corticosteroid starting at week 16

AMBITION

Not treated with MTX within 6 months prior to randomization; never discontinued MTX for inadequate response or toxicity

TCZ 8 mg/kg q. 4 weeks MTX 7.5-20 mg (oral) weekly Placebo q. 4 weeks

24 weeks NoneTCZ 8 mg/kg up to but not including week 8

RADIATEInadequate response to previous anti-TNF therapy

TCZ 8 mg/kg q. 4 weeks TCZ 4 mg/kg q. 4 weeks Placebo q. 4 weeks

24 weeksMTX 10-25 mg(oral or iv) weekly

TCZ 8 mg/kg starting at week 16

*Permitted DMARDs in TOWARD included MTX, chloroquine, hydroxychloroquine, parenteral gold, sulfasalazine, azathioprine and leflunomide.



• Across all 4 studies, increased exposure to TCZ was associated with a decrease in CRP, ESR and SAA levels

• High TCZ exposure was associated with a pronounced reduction in CRP levels by week 2

• The effect of TCZ on CRP persisted throughout the 24-week trials


• Upper limit of normal levels of CRP, ESR and SAA were more likely to be sustained between consecutive infusions with increasing TCZ exposure

• TCZ 8 mg/kg led to more persistent reductions in inflammatory biomarkers compared with 4 mg/kg

• TCZ’s consistent effect on CRP from week 2 likely reflects not only a decrease in inflammation but also inhibition of hepatic IL-6R signaling and consequent decrease in CRP synthesis



IL-6 Inhibition with tocilizumab:Summary of findings

Radiographic

Tocilizumab significantly suppressed radiographic progression for 3 years of follow-up and the mean erosion score remained stable

Early introduction of TCZ protects joints more effectively than late introduction


Safety Profile

More pts on TCZ/DMARD arm had liver enzyme increases, however, in most AST and ALT levels normalized during continued therapy, with few patients having dose interruptions

No drug-induced hepatic injury observed

Patients with diabetes as well as those receiving corticosteroid were over-represented among those who are at risk for serious infection

There was no indication that a low neutrophil count increases the risk of serious infections

Efficacy

Tocilizumab produced significant improvements in all core ACR response criteria

In patients with an inadequate response to previous DMARD therapy, the TCZ/DMARD combination produced clinically significant reductions in signs and symptoms of RA vs. DMARD alone

More patients achieved DAS28 and DAS28 < 2.6 with TCZ + DMARD than DMARD alone

Pooled data support the use of the TCZ/DMARD combination for DMARD-unresponsive patients with moderate to severe RA



PK/PD profile

TCZ serum concentration levels were predictive of reduction in DAS28

Serum concentrations corresponding to TCZ 8 mg/kg were more effective in reducing disease activity than at 4 mg/kg

Across all 4 studies, increased exposure to TCZ was associated with a decrease in CRP, ESR and SAA levels

High TCZ exposure was associated with a pronounced reduction in CRP levels by week 2

Upper limit of normal levels of CRP, ESR and SAA were more likely to be sustained between consecutive infusions with increasing TCZ exposure


Systemic

A reduction in disease activity may be associated with improved Hb levels

Normalization of Hb in anemic RA patients may be a suitable marker of disease activity

Fatigue improves along with improving Hb levels and reduced disease activity

Rapid increases in Hb suggest that the beneficial effects may extend beyond those associated with the joints


Inflammation

Early rapid and sustained reductions in CRP

TCZ 8 mg/kg led to more persistent reductions in inflammatory biomarkers compared with 4 mg/kg

TCZ’s consistent effect on CRP from week 2 likely reflects not only a decrease in inflammation but also inhibition of hepatic IL-6R signaling and consequent decrease in CRP synthesis

Documents

IL-6 Inhibition in RA An Emerging Role for Tocilizumab HIGHLIGHTS FROM EULAR 2008 PRESENTATIONS