ACT-RAY and MRI substudy

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

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

Professor Philip Conaghan

Professor of Musculoskeletal Medicine, University of Leeds

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}

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.

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):609-621. 2. Fleischmann R, et al. EULAR 2010. Abstract FRI0205. 3. Kremer J, et al. EULAR 2011. Abstract FRI0367. 4. Ostergaard M, et al. Arthritis Rheum. 1999;42(5):918-929.

5. Conaghan PG, et al. Arthritis Rheum. 2003; 48(1):64-71. 6. McQueen FM, et al. Ann Rheum Dis. 2007; 66(12):1581-7.

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

®

Baseline

Week 24

Week 52

Randomised study

TCZ + MTX

TCZ + PBO

Every 12 weeks

Week 104

Treatment intensity unchanged

12

Maintenance

ACT-RAY study design

MRI visits

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, 0-250

– No gadolinium enhancement was used

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)

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) 21.23 (25.48) 19.01 (24.99) -

Joint space narrowing 10.48 (13.70) 7.94 (12.20) -

Erosions 10.76 (12.20) 11.07 (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) 11.06 (14.80) 9.44 (13.60)

Erosion 19.37 (14.44) 15.97 (12.56) 17.64 (13.52)

a _{Wrist + 1-5 MCP}

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 7.2 7.1 –0.1 (–0.5, 0.3) 6.3 –0.9 (–1.6, –0.2) p ≤ 0.01 7.4 6.5 –0.9 (–1.5, -0.4) p ≤ 0.001 5.7 –1.9 (–2.8, –1.0) p ≤ 0.0001 OST 7.8 7.6 –0.2 (–1.3, 0.9) p ≤ 0.01 4.4 –3.6 (–6.5, –0.7) p ≤ 0.001 11.1 10.3 –0.7 (–1.8, 0.3) 5.5 –5.1 (–8.6, –1.6) p ≤ 0.01 ERO 19.4 19.4 0.0 (–0.4, 0.5) 19.2 –0.3 (–1.2, 0.6) 16.0 16.2 0.2 (–0.0, 0.5) 16.6 0.0 (–0.6, 0.6)

Cumulative probability plot of change from

baseline to week 12 in total synovitis score

Changes outside of the shaded region exceed SDC < -1.71 = improvement; > +1.71 = worsening

TCZ + MTX (n =31) TCZ + PBO (n =31)

Cumulative probability plot of change from

baseline to week 12 in total osteitis score

Changes outside of the shaded region exceed SDC < -4.27 = improvement; > +4.27 = worsening

TCZ + MTX (n =31) TCZ + PBO (n =31)

Cumulative probability plot of change from

baseline to week 12 in total erosion score

Changes outside of the shaded region exceed SDC < -1.51 = improvement; > +1.51 = worsening

TCZ + MTX (n =31) TCZ + PBO (n =31)

Baseline Week 2 MCP 2

Radiocarpal Joint

SDC-based classifications of

RAMRIS change scores

TCZ + MTX (n = 30) n (%) TCZ + PBO (n = 29) n (%) Classification Derived From SDCa _{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}

Summary of new location involvement (MRI)

Patients With New Locations n (%) New Locations n TCZ + MTX TCZ + PBO TCZ + MTX TCZ + PBO Erosions Baseline to week 2 2 (6.5) (n=31) 0 (0) (n=32) 2 0 Baseline to week 12 1 (3.3) (n=30) 0 (0) (n=29) 1 0 Synovitis Baseline to week 2 0 (0) (n=31) 0 (0) (n=32) 0 0 Baseline to week 12 0 (0) (n=30) 0 (0) (n=29) 0 0 Osteitis Baseline to week 2 1 (3.2) (n=31) 2 (6.3) (n=32) 6 4 Baseline to week 12 0 (0) (n=30) 4 (13.8) (n=29) 0 5

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

Mean DAS28 over time

TCZ + MTX (n = 31) TCZ + PBO (n = 32) TCZ + MTX: n = 31 31 29 31 TCZ + PBO: n = 32 30 31 29 3.44 3.44 Week

Error bars = standard error of the means

> 5.1 = high disease activity

Mean CRP levels over time

TCZ + MTX TCZ + PBO TCZ + MTX: n = 31 30 29 31 TCZ + PBO: n = 32 30 31 29 0.20 0.11 Week ULN = 0.3 mg/dL

Error bars = standard error of the means ULN = upper limit of normal

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

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