Rituximab in Myositis (RIM) Study Muscle Study Group September 28, 2012 Chester V. Oddis, MD Division of Rheumatology and Clinical Immunology University of Pittsburgh

Disclosures Genentech: Grant support and supply of study drug; Advisory Board

Where Were We in 2000? Lack of consistent design in published trials 26 prospective myositis trials reviewed 14 adult PM-DM; 5 adult IBM; 5 JDM; 2 adult PM/DM/IBM Problems with ‘current’ trials different myositis classification criteria used lack of uniformity with inclusion/exclusion criteria variability in concomitant therapies variability in trial durations and subsequent follow-up different intervals of assessment lack of uniformity in measures for outcome assessments

Myositis Clinical Trials: “Pieces of the Puzzle” Establishment of IMACS Adult/pediatric/multidisciplinary/international Agreed upon outcome measures [Miller] Definition(s) of improvement for myositis clinical trials [Rider] Consensus on conduct of adult and juvenile myositis clinical trials [Oddis/Rider] Assessment of disease activity and damage [Sultan/Isenberg]

Preliminary DOI for IIM Clinical Trials 3 of any 6 CSM improved by ≥ 20%, with no more than 2 CSM worsening by ≥ 25% (cannot include MMT) Rider, Arth Rheum, 2004 DOI not just a consensus definition, but partially validated using previous adult trial data (n=4) and pediatric natural history data

Rituximab in Myositis Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis Chester V. Oddis, MD Ann M. Reed, MD and the RIM Study Group

RIM Study: Aim To examine the efficacy of rituximab, a B cell depleting agent, in refractory adult and juvenile myositis patients in a multicenter 44-week clinical trial enrolling 76 adult PM, 76 adult DM and 50 JDM patients

Inclusion Criteria Definite or probable PM or JDM/DM (by Bohan and Peter criteria) All patients with PM required verification of diagnosis by a 3-member Adjudication Committee Included medical record review and muscle biopsy review by a neuropathologist Problem of PM mimics and to exclude IBM

Inclusion Criteria Refractory myositis = Intolerance to or an inadequate response to corticosteroids plus at least one other immunosuppressive (IS) agent Adult PM or DM required Manual Muscle Testing-8 (MMT-8) score ≤ 125/150 and 2 other abnormal Core Set Measures (CSM) JDM could enter by the same criteria as adults or if MMT-8 >125 then they required 3 other abnormal CSM

Manual Muscle Testing-8 (MMT-8) Muscle Groups Right (0 – 10) Left (0 – 10) Axial (0 – 10) Axial Muscles (0 – 10) Neck Flexors 0-10 Proximal Muscles (0 – 100) Deltoid Biceps brachii Gluteus maximus Gluteus medius Quadriceps Distal Muscles (0 – 40) Wrist Extensors Ankle dorsiflexors MMT-8 score (0 – 150) 0-70 Set of 8 muscle groups with a maximum score = 150

Extramuscular Disease RIM Study: 5 Additional Core Set Measures Domain Core Set Measures Global Activity Physician global VAS ≥ 2.0 on 10cm scale Patient/Parent global VAS ≥ 2.0 on 10cm scale Physical Function CHAQ/HAQ disability index ≥ 0.25 Laboratory Assessment At least one muscle enzyme (CK/AST/ALT/LDH/aldolase) ≥ 1.3x ULN Extramuscular Disease Global extramuscular disease activity VAS ≥ 1.0 on the Myositis Disease Activity Assessment Tool (MDAAT) – constitutional, cutaneous, articular, GI, pulmonary, cardiac

Inclusion Criteria Stable prednisone dose for 4 weeks prior to screening visit Background therapy with at least 1 other IS agent at stable dose for at least 6 weeks prior to screening visit was encouraged

Randomized Placebo Phase Design (RPPD) Wk 0 Wk 1 Wk 8 Wk 9 Wk 4 Wk 12 Wk 44 Screen Rituximab Placebo Rtx Early Placebo-controlled Double Blind Phase Wks 12 – 44 (8 additional visits) Rtx Late Placebo Rituximab Subjects randomly assigned, double-blind, to ‘Rtx Early’ or ‘Rtx Late’ ½ subjects receive drug early and ½ subjects receive drug 8 wks later Week 8: reflects a ‘randomized placebo-controlled trial’ No corticosteroids at time of the 4 infusions 14 visits (specimens/CSM) over 44 weeks

Participant Flow Diagram MMT>125 Low IgG/IgM 200 randomized and 195 included in final analysis

Rituximab Dosing Children received 575mg/m2 up to a maximum dose of 1gm 1 week apart Adults received 750mg/m2 BSA up to a maximum dose of 1gm 1 week apart

. Patient Baseline Demographic and Clinical Characteristics Early Rituximab (n=96) Late Rituximab (n=104) p value Caucasian race (%) 62 (65) 81 (78) 0.05 Mean age (SD) 43 (18.2) 40 (18.4) 0.36 Female sex (%) 68 (71) 78 (75) 0.61 IIM subset (PM/DM/JDM) 37/36/23 (n=96) 39/40/25 (n=104) 0.99 Mean disease duration (SD) 5.2 yrs (6.5) 5.4 years (6.0) 0.78 Mean prednisone dose (SD) 19.7 (12.1) 21.4 (14.4) 0.39 Non-corticosteroid immunosuppressive use (%) 84 (88) 89 (86) 0.85 Myositis autoantibody positivity (%) Anti-synthetase Anti-SRP DM-associated* Other autoantibody# None of the above Undefined autoantibody+ 16 (17.8) 13 (14.4) 33 (36.7) 8 (8.9) 20 (22.2) 6 16 (15.8) 12 (11.9) 38 (37.6) 19 (18.8) 3 0.65

Baseline Core Set Measures (Mean/SD) Characteristic Early Rituximab (n=96) Late Rituximab (n=104) p value MMT-8 ratio 71 (11.4) 71.7 (13.0) 0.70 MD Global VAS (0-100 mm) 51.4 (17.6) 49.2 (17.4) 0.37 Patient/Parent Global VAS (0-100mm) 65.4 (20.3) 65.6 (21.7) 0.94 HAQ/CHAQ Disability Index (0-3) 1.55 (.7) 1.53 (0.8) 0.84 Muscle enzyme x ULN 9.5 (14.9) 5.5 (9.0) 0.03 Extramuscular Score VAS 27.4 (20.4) 30.7 (19.5) 0.25 MMT-8 ratio refers to recorded MMT-8/total possible score for muscles tested

Data Quality Very low patient dropout Excellent quality of data 5 pts with baseline visit and no subsequent measurements 195 randomized pts included in analysis Excellent quality of data Very little missing data Percentage of missing values = 1.2%

B cell Numbers Before and After Rituximab Early Rtx LateRtx

To meet DOI subjects had to satisfy criteria on 2 consecutive visits DOI for RIM Study ≥ 20% improvement in 3 of any 6 CSM, no more than 2 CSM worsening by ≥ 25% (excluding MMT) To meet DOI subjects had to satisfy criteria on 2 consecutive visits

Primary Endpoint and Hypothesis Primary Endpoint: Compare the time to DOI between the ‘Rtx Early’ and ‘Rtx Late’ groups Hypothesis: The time to DOI will be statistically less (shorter) in early vs. late treatment groups

Primary Outcome: Entire Cohort Median time to DOI: Early Rtx = 20.0 weeks Late Rtx = 20.2 weeks p = 0.74 (log rank)

Primary Outcome: Adult PM Median time to DOI: Early Rtx = 21.8 weeks Late Rtx = 24.0 weeks p = 0.43 (log rank) Primary Outcome: Adult DM Median time to DOI: Early Rtx = 20.4 weeks Late Rtx = 20.3 weeks p = 0.70 (log rank)

Primary Outcome: JDM Median time to DOI: Early Rtx = 11.7 weeks Late Rtx = 19.6 weeks p = 0.32 (log rank)

Secondary Endpoints and Hypotheses Secondary Endpoint II: Compare the response rates (proportion of patients achieving DOI) at week 8 in early vs. late groups Hypothesis: The response rate will be significantly higher in the early group at week 8

Proportions of Patients Meeting DOI at Week 8 Secondary Endpoint II Proportions of Patients Meeting DOI at Week 8 Early Rtx Late Rtx 20.6% 15% 26

Patients Meeting DOI During Trial Early Rtx Late Rtx 85% 80% Overall, 83% (161/195) of subjects met the DOI during the course of the 44-week clinical trial 27

Corticosteroid Sparing Effect There was a significant difference in the mean corticosteroid dose at baseline compared to the final visit 28

Retreatment With Rituximab 10 subjects (9 evaluable) met criteria for re-treatment with Rtx 4 were in ‘Early’ and 5 in ‘Late’ Rtx groups Weeks to Initial DOI (mean, n=9) Weeks from DOI to DOW Weeks to Re-treatment DOI (mean, n=8) 12.4 16.5 19.9

Adverse Events 52/200 (26%) subjects had 68 serious adverse events (SAE) 40% of those were reported as related to treatment Most common SAEs included: infection (25%) musculoskeletal (18%) GI (12%) cardiac (7%) 1 death (unrelated to drug) No cases of PML

Summary The primary and secondary endpoints were not achieved in the RIM Study 83% of refractory adult and juvenile myositis patients met the DOI in this trial There was a significant corticosteroid sparing effect noted in this trial between the baseline dose and the dose at study conclusion Rituximab was generally well tolerated

RIM Study Conclusions Overestimate of the rituximab effect SC postulated >50% would meet DOI by 8 weeks One-half responded by 20 weeks (lower potency) Underestimate of placebo effect Short placebo phase of 8 weeks Heterogeneity of myositis Increased variance around time to DOI in both arms Subjective CSM (partially validated)

What about more stringent criteria for improvement? At least 4 CSM improving by 40%

Entire Cohort: Time to Stringent DOI Early Rtx Late Rtx p=0.13 (Peto-Peto test) p=0.18 (log rank)

RIM Study Autoantibodies Autoantibody Number (%) Synthetase 32 (16%) - 28 Jo-1 SRP 25 (13%) DM-associated 71 (35%) - 26 Mi-2 - 23 TIF1-gamma - 22 MJ Overlap/other autoAb 24 (12%) No MAA 40 (20%) Undefined 9 (4%) Total 200

Baseline Autoantibodies Predict Outcome Autoantibody subsets anti-SynAb - HR 2.3 (1.3 – 4.2), p value = 0.01 DM Abs: TIF-1/MJ/Mi-2 - HR 1.9 (1.2 – 3.1), p value = 0.01 no autoAb (21%) anti-SRP (13%) other autoAb (14%) DM:TIF-1/MJ/Mi-2 (33%) anti-syn Ab (14%) Survival distribution function Time in weeks Anti-syn & DM Abs predicted a better outcome, but anti-SRP and those without MAAs had a worse outcome

Median Time to Stringent DOI: Jo-1 vs non-Jo-1 Median time to stringent DOI in Early = 27.9 weeks Early vs Late p=0.12 (log rank)

Other Univariate Predictors Caucasians showed a better response (p=0.04) Higher baseline VAS for extramuscular activity was only CSM predictive of better response (p=0.02) Higher baseline VAS muscle damage score predicted a poor response (p=0.05) Aggarwal, Arth Rheum 62: S385, 2010

Future Directions Study the ‘immunology’ of the response in the specimens obtained from RIM and correlate this to the clinical outcomes Assess other biomarkers from the specimen repository Re-examination of the DOI and the response criteria

Participating Centers

Foreign Centers

Participating Centers Adult Sites Alabama (Fessler) Boston (Narayanaswami) Czechoslovakia (Vencovsky) Dallas (Olsen) Kansas City (Barohn/Latinis) Kentucky (Crofford) London (Isenberg) Mayo Clinic (Ytterberg) Miami (Sharma) Michigan (Seibold/Schiopu) Michigan State (Martin/Eggebeen) Milwaukee (Cronin) New York: North Shore (Marder) New York: HSS (DiMartino) NIH (Miller) Philadelphia (Kolasinski) Phoenix (Levine) Pittsburgh (Oddis/Ascherman) Stanford (Chung/Fiorentino) Sweden (Lundberg) UCLA (Weisman/Venuturupalli) Pediatric Sites Boston (Kim) Cincinnati (Lovell) Duke (Rabinovich) Mayo Clinic (Reed) Miami (Rivas-Chacon) Michigan State (Martin/Eggebeen) NIH (Rider) Nova Scotia (Huber) Philadelphia (Sherry) Pittsburgh (Kietz) Stanford (Sandborg) Toronto (Feldman) Our Patients!!! Made changes: Michigan should be changed to Seibold and Schiopu The 2 adult New York sites should be distinguished from each other – i.e. location ; Marder-North Shore; DiMartino: HSS Stanford is spelled wrong and should be Chung and Fiorentino UCLA should be Weisman and Venuturupalli 42

Acknowledgements Supported by: Coordinating Center Dana Ascherman, MD Rohit Aggarwal, MD Sherrie Pryber, Project Manager Diane Koontz, Project Manager Noreen Fertig, BS Kelly Reckley, BS Maureen Laffoon, BS Xinyan Gu IDS Pharmacy David Lacomis, MD Jonette Werley, BA, HT, HTL Christopher Bise, MS, PT Steering Committee Ann Reed, MD Steve Ytterberg, MD Dana Ascherman, MD David Lacomis, MD Brian Feldman, MD Fred Miller, MD, PhD Lisa Rider, MD Todd Levine, MD Steve Belle, PhD Howard Rockette, PhD Michael Harris-Love,MPT Data Center Howard Rockette, PhD Steven Belle, PhD Sharon Lawlor, MBA Stephanie Kelley, MS Other Collaborators The RIM Study Group RIM Study Coordinators David Isenberg, MD, FRCP Myositis Working Group The Myositis Association RIM Publication Committee IMACS Supported by: