ACT-RAY and MRI substudy

Transcription

1 Tocilizumab as Monotherapy or in Combination With Methotrexate associated with Early Reductions in Tissue Inflammation: 12-Week Results From a Magnetic Resonance Imaging Substudy of a Randomized Controlled Trial Professor Philip Conaghan Professor of Musculoskeletal Medicine, University of Leeds Philip G. Conaghan, 1 Charles Peterfy, 2 Julie DiCarlo, 2 Ewa Olech, 3 Alan Alberts, 4 Jeffrey Alper, 5 Jenny Devenport, 6 Andrew Anisfeld, 6 Orrin Troum 7 1 University of Leeds, Leeds, United Kingdom; 2 Spire Sciences LLC, San Francisco, CA, USA; 3 Oklahoma Medical Research Foundation, O City, OK, USA; 4 West Broward Rheumatology Associates, Inc., Tamarac, FL, USA; 5 Jeffrey Alper MD Research, Naples, FL, USA; 6 Genentech, South San Francisco, CA, USA; 7 USC Keck School of Medicine, Santa Monica, CA, USA

2 Author disclosures 1. Philip Conaghan: Research Grants: Centocor Inc., Merck Pharmaceuticals, Pfizer Inc. Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Pfizer Inc. 2. Charles Peterfy: Employment: Spire Sciences LLC, providing central image analysis services to multiple pharmaceutical companies 3. Julie DiCarlo: Employment: Spire Sciences LLC, providing central image analysis services to multiple pharmaceutical companies 4. Ewa Olech: Research Grants and Consulting fees: Genentech Inc. 5. Alan Alberts: Research Grants: Centocor Inc., Pfizer Inc., Bristol-Myers Squibb, F. Hoffmann- La Roche Ltd, UCB, Inc., Eli Lilly and Company, Novartis 6. Jeffrey Alper: Speakers Bureau: Abbott 7. Jenny Devenport: Employment: Genentech Inc. 8. Andrew Anisfeld: Employment: Genentech Inc. 9. Orrin Troum: Research Grants: Abbott, Amgen, Bristol-Myers Squibb, Centocor, F. Hoffmann- La Roche Ltd, Genentech, Novartis, Pfizer Inc. Speakers Bureau: Abbott, Amgen, Bristol- Myers Squibb, F. Hoffmann-La Roche Ltd, Genentech, UCB, Pfizer Inc. Consulting: Abbott, Amgen, Centocor, F. Hoffmann-La Roche Ltd, Genentech, Pfizer Inc. 10.ACT-RAY was funded by Roche and support for presentations was provided by Roche Products Ltd and Chugai Pharma UK Ltd.

3 Introduction Interleukin-6 receptor (IL-6R) inhibition with tocilizumab (TCZ) + methotrexate (MTX) has successfully inhibited the progression of radiographic joint damage in patients with rheumatoid arthritis 1-3 MRI is a highly sensitive measure of inflammation and structural damage MRI synovial inflammatory findings correlate well with histopathological features of inflammation 4 Time integrated synovitis has predicted progression of erosions 5 MRI-detected bone marrow oedema or osteitis is a strong predictor of subsequent bone erosions 6-8 Office-based low-field MRI is an accessible method to detect the earliest benefit of treatment and enhance insight into patient status 1. Kremer J, et al. Arthritis Rheum. 2011; 63(3): Fleischmann R, et al. EULAR Abstract FRI Kremer J, et al. EULAR Abstract FRI Ostergaard M, et al. Arthritis Rheum. 1999;42(5): Conaghan PG, et al. Arthritis Rheum. 2003; 48(1): McQueen FM, et al. Ann Rheum Dis. 2007; 66(12): Haavardsholm EA, et al. Ann Rheum Dis. 2008; 67(6): Hetland ML, et al. Ann Rheum Dis. 2009; 68(3):

4 ACT-RAY and MRI substudy ACT-RAY main trial 2-year study of tocilizumab 8 mg/kg (TCZ) monotherapy vs. with MTX Double-blind, randomised, active-control Clinical endpoints Radiographic assessment of inhibition of joint destruction To assess potential of TCZ to achieve drug-free remission Adult patients with erosive RA; inadequate response to MTX 556 patients from 125 sites in 20 countries ACT-RAY MRI substudy MRI substudy: 63 patients from 18 sites in the USA To examine early effects of TCZ on synovitis, osteitis, erosions Planned 12 week interim analysis to assess endpoints at 2 and 12 weeks using 0.2T MRI

5 ACT-RAY study design Randomised study Every 12 weeks TCZ + MTX 12 Treatment intensity unchanged TCZ + PBO Baseline Week 24 Week 52 Week 104 MRI visits Week Maintenance

6 MRI substudy methods 0.2T extremity MRI of a hand (metacarpophalangeal joints 1-5) and wrist was acquired at baseline and at weeks 2 and 12 MRI images were quality controlled and scored by 2 radiologists blinded to treatment assignment and visit order A modified OMERACT RAMRIS method was used: Synovitis (based primarily on coronal and axial STIR scans): 8 regions in hand and wrist assessed; total score, 0-24 Osteitis (based primarily on coronal STIR scans): 25 regions in hand and wrist assessed; total score, 0-75 Erosion: 25 regions in hand and wrist assessed; total score, No gadolinium enhancement was used

7 MRI substudy baseline RA characteristics TCZ + MTX n = 31 TCZ + PBO n = 32 All TCZ n = 63 Mean RA duration, y (SD) 7.8 (7.23) 6.5 (8.07) 7.1 (7.63) RA duration category, n (%) < 2 y 10 (32.3) 13 (40.6) 23 (36.5) 2 to < 5 y 4 (12.9) 7 (21.9) 11 (17.5) 5 to < 10 y 6 (19.4) 4 (12.5) 10 (15.9) 10 y 11 (35.5) 8 (25.0) 19 (30.2) CRP, mean mg/dl (SD) 1.00 (1.38) 1.18 (1.85) 1.09 (1.63) Oral steroid use, n (%) 15 (48.4) 13 (40.6) 28 (44.4) Number of previous DMARDs, mean (SD) 1.5 (1.18) 1.5 (0.62) 1.5 (0.93) DAS28, mean (SD) 6.4 (1.03) 6.5 (1.13) 6.5 (1.08) CRP = C-reactive protein

8 MRI substudy baseline RA characteristics TCZ + MTX n = 31 TCZ + PBO n = 32 All TCZ n = 63 Sharp scores, mean (SD) Total sharp score (JSN+GSS-ERO) (25.48) (24.99) - Joint space narrowing (13.70) 7.94 (12.20) - Erosions (12.20) (13.99) - Mean RAMRIS score, mean (SD) a Synovitis 7.23 (4.60) 7.42 (4.16) 7.33 (4.35) Osteitis 7.77 (12.26) (14.80) 9.44 (13.60) Erosion (14.44) (12.56) (13.52) a Wrist MCP CRP = C-reactive protein; GSS = Genant modified sharp scores

9 MRI substudy: mean MRI scores TCZ + MTX (n = 31) TCZ + PBO (n = 32) RAMRIS BL (n = 31) Wk 2 (n = 31) BL to Wk 2 (95% CI) (n = 31) Wk 12 (n = 30) BL to Wk 12 (95% CI) (n = 30) BL (n = 32) Wk 2 (n = 32) BL to Wk 2 (95% CI) (n = 32) Wk 12 (n = 29) BL to Wk 12 (95% CI) (n = 29) SYN ( 0.5, 0.3) ( 1.6, 0.2) p ( 1.5, -0.4) p ( 2.8, 1.0) p OST ( 1.3, 0.9) p ( 6.5, 0.7) p ( 1.8, 0.3) ( 8.6, 1.6) p 0.01 ERO ( 0.4, 0.5) ( 1.2, 0.6) ( 0.0, 0.5) ( 0.6, 0.6) p-value from Wilcoxon Signed Rank test for no change from BL within group. Percentile interval: 95% CI of mean change from BL within group

10 Cumulative probability plot of change from baseline to week 12 in total synovitis score TCZ + MTX (n =31) TCZ + PBO (n =31) * Changes outside of the shaded region exceed SDC < = improvement; > = worsening

11 Cumulative probability plot of change from baseline to week 12 in total osteitis score TCZ + MTX (n =31) TCZ + PBO (n =31) * Changes outside of the shaded region exceed SDC < = improvement; > = worsening

12 Cumulative probability plot of change from baseline to week 12 in total erosion score TCZ + MTX (n =31) TCZ + PBO (n =31) * Changes outside of the shaded region exceed SDC < = improvement; > = worsening

13 Example: synovitis regression in 2 weeks MCP 2 Radiocarpal Joint Baseline Week 2

14 SDC-based classifications of RAMRIS change scores TCZ + MTX (n = 30) n (%) TCZ + PBO (n = 29) n (%) Classification Derived From SDC a at Week 12 Regressors (Change -SDC) Progressors (Change SDC) Regressors (Change -SDC) Progressors (Change SDC) SYN 7 (23.3) 1 (3.3) 11 (37.9) 0 OST 6 (20.0) 0 (0.0) 9 (31.0) 1 (3.4) ERO 3 (10.0) 2 (6.7) 3 (10.3) 2 (6.9) a SDC values at week 12: SYN: 1.71; OST: 4.27; ERO: 1.51 SDC = smallest detectable change

15 Summary of new location involvement (MRI) Erosions Synovitis Osteitis Baseline to week 2 Baseline to week 12 Baseline to week 2 Baseline to week 12 Baseline to week 2 Baseline to week 12 Patients With New Locations n (%) TCZ + MTX 2 (6.5) (n=31) 1 (3.3) (n=30) 0 (0) (n=31) 0 (0) (n=30) 1 (3.2) (n=31) 0 (0) (n=30) TCZ + PBO TCZ + MTX 0 (0) (n=32) 0 (0) (n=29) 0 (0) (n=32) 0 (0) (n=29) 2 (6.3) (n=32) 4 (13.8) (n=29) New Locations n TCZ + PBO

16 Summary of MRI findings Decreases in synovitis and osteitis scores were observed at week 2 and were statistically significant in both groups by week 12 No significant changes from baseline in mean erosion score were observed The proportion of patients who experienced improvements SDC for both synovitis and osteitis was numerically higher in the PBO group Similar numbers of patients experienced ERO progression vs. regression in each group At week 12, only one patient (TCZ + MTX group) developed a newly eroded bone

17 Mean DAS28 over time TCZ + MTX (n = 31) TCZ + PBO (n = 32) > 5.1 = high disease activity Week TCZ + MTX: n = TCZ + PBO: n = Error bars = standard error of the means

18 Mean CRP levels over time TCZ + MTX TCZ + PBO ULN = 0.3 mg/dl Week TCZ + MTX: n = TCZ + PBO: n = Error bars = standard error of the means ULN = upper limit of normal

19 Conclusions These MRI data demonstrate that TCZ is associated with early suppression of synovitis and osteitis, with no statistically significant mean increase in erosion score observed through week 12 The similarities in MRI findings between the TCZ + PBO and TCZ + MTX groups suggest that continuation of MTX in combination with TCZ and switching to TCZ monotherapy are equally beneficial for early suppression of joint inflammation These findings are consistent with clinical findings at 24 weeks in the ACT-RAY clinical trial 1 TCZ monotherapy may be an appropriate alternative to TCZ + MTX in patients who are intolerant or unwilling/unable to take MTX Further analyses will examine whether these trends are consistent through 52 weeks of treatment 1. Dougados M, et al. BSR oral presentation 2012

20 ACT-RAY MRI Substudy: Investigators Alan Alberts Jeffrey Alper Michael Borofsky Antony Hou Jeffrey Kaine Timothy Kelly Robert P. LaGrone Jeffrey G. Lawson Ewa Olech Meera Oza Samuel Pegram David Ridley Joshua Stolow Orrin Troum Michael Weitz Darice Yang