Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT)

The IMPACT Trial Centers Kalden/AntoniErlangen, Germany Burmester/SchneiderBerlin, Germany Smolen/EbnerVienna, Austria Kirkham London, United Kingdom Keystone/GladmanToronto, Canada Kavanaugh/TutuncuSan Diego, California Weisman/WallaceLos Angeles, California Furst/MolitorSeattle, Washington WassenbergRatingen, Germany

Multi-center, randomized, double-blind placebo controlled study in patients with active psoriatic arthritis 104 patients at 9 sites in Canada, Europe and USA Study Design

Dosing: –Placebo vs. Infliximab 5 mg/kg at weeks 0, 2, 6 and 14, open label q 8 week in follow-up Endpoints (week 16): –Primary: ACR 20 –Secondary: PsARC, PASI, ACR 50, ACR 70, dactylitis, enthesiopathy, Schober index, DAS On-going open-label follow-up through 1 year and a 2 year extension

IMPACT Inclusion Criteria > 18 years old PsA with peripheral polyarticular involvement for >6 months Typical psoriatic arthritis presentation with /without active skin lesions

IMPACT Inclusion Criteria Negative for RF Active disease (5 joints and ESR>28, or CRP> 15, or morning stiffness > 45 minutes) At least 1 DMARD failure Stable DMARD dosing > 4 weeks, if applicable Stable prednisone <10 mg/day for 2 weeks Stable NSAIDS for 2 weeks

IMPACT Exclusion Criteria Pregnant, nursing, planning pregnancy in 6 months Other confounding conditions/ uncontrolled diseases Parenteral corticosteroids within 4 weeks of screening Prior treatment with monoclonal antibody Chronic infections Active TB within 3 years, opportunistic infection within 2 months Malignancy within 5 years

ControlledOpen-label Week * Group IPPPPInInIn In InIn Group IIIn In InInPPIn In InIn P= Placebo In= Infliximab (5mg/kg) 1:1 randomisation *At Week 16, group I received an induction regimen of infliximab 5 mg/kg and group II received a placebo induction regiment to maintain blind of original treatment randomization throughout the open label phase Treatment Regimens

Patient Population PlaceboInfliximab Disease duration (years) Skin Involvement (%) Concomitant DMARDs (%) Concomitant MTX (%) Concomitant NSAIDs (%) Concomitant Corticosteroids (%)

Mean Baseline Activity PlaceboInfliximab Tender Joint Count Swollen Joint Count Physician Global (0-100) Patient Global (0-100) Patient Pain (0-100) HAQ Disability Index (0-3) CRP (mg/L)

Safety Findings

Patient Discontinuations WeekReason for WithdrawalTreatment Week 14Acute chest infection, asthmaInfliximab Week 16Joint infectionInfliximab Week 18Withdrew consent*Placebo Week 22StomatitisPlacebo/Inflix. Week 22Elevated liver enzymesInfliximab Week 22Withdrew consent*Infliximab Week 30Withdrew consent*Placebo/Inflix. Week 38Infusion reactionPlacebo/Inflix. Week 50Fall, MeningiomaInfliximab * Treatment failure

Non-Serious Adverse Events at Week 16 Adverse EventInfliximabPlacebo Common Cold/Flu/Cough1012 UTI86 URI37 Bronchitis24 Headache12 Rash22 Pruritus10 Diarrhea21 Vaso-vagal Reaction20 Hypertension02 Oral Ulcers01 Dizziness03

Serious Adverse Events GroupWeekDiagnosisOutcomeStatus Placebo14DiverticulitisResolvedContinued Placebo16Urethral StrictureResolvedContinued Placebo/Inf30Rule out MIResolvedDiscontinued* Placebo/Inf30FeverResolvedContinued Placebo/Inf 38Infusion reactionResolvedDiscontinued* *treatment failure PlaceboPlacebo

Serious Adverse Events Group WeekDiagnosisOutcomeStatus Infliximab3Atrial fibrillation ResolvedContinued Infliximab47Atrial fibrillation ResolvedContinued Infliximab 26Achilles Resolved Continued tendon rupture Infliximab22StrokeResolvedDiscontinued Infliximab16Joint infectionResolvedDiscontinued Infliximab38Angina PectorisResolvedContinued Infliximab44Inguinial HerniaResolvedContinued Infliximab50Fall, MeningiomaOngoingDiscontinued *treatment failure InfliximabInfliximab

Summary of Safety Findings No TB No opportunistic Infections One infusion reaction One infected joint Safety profile similar to previously reported

Efficacy Results

Week 16 Results PsARC *p< Percent of Patients

Week 50 Results PsARC Percent of Patients

Week 16 Results Proportion of DAS 28 Responders Patients with a Good or Moderate DAS28 Response at Week 16 Percent of Patients

Week 50 Results Proportion of DAS 28 Responders Patients with a Good or Moderate DAS28 Response at Week 50 Percent of Patients

Proportion of DAS28 Responders Over Time Percent of Patients Responding Patients with a Good or Moderate DAS28 Response Week

DAS28 Score Over Time Mean Values Mean DAS 28 Score <3.2 Good Response >5.1 Non-responders Week

DAS28 Score Over Time Median Values Week Median DAS 28 Score <3.2 Good Response >5.1 Non-responders

DAS Original Score Over Time Mean Values Mean DAS Score <2.4 Good Response >3.7 Non-responders Week

DAS Original Score Over Time Median Values Median DAS Score <2.4 Good Response >3.7 Non-responders Week

Week 16 Results Proportion of DAS Original Responders Patients with a Good or Moderate DAS Response at Week 16 Percent of Patients

Week 50 Results Proportion of DAS Original Responders Patients with a Good or Moderate DAS Response at Week 50 Percent of Patients

Proportion of DAS Original Responders Over Time Percent of Patients Responding Patients with a Good or Moderate DAS Response Week

Week 16 Results: ACR 20, 50, 70 Percent of Patients Responding *p<0.0001

Week 50 Results: ACR 20, 50, 70 Percent of Patients Responding

Week 50 Results: ACR 20 by ESR Subgroups Percent of Patients Responding

Week 50 Results: ACR 50 by ESR Subgroups Percent of Patients Responding

Week 50 Results: ACR 70 by ESR Subgroups Percent of Patients Responding

Week 50 Results: ACR 20 by CRP Subgroups Percent of Patients Responding

Week 50 Results: ACR 50 by CRP Subgroups Percent of Patients Responding

Week 50 Results: ACR 70 by CRP Subgroups Percent of Patients Responding

Proportion of Patients Achieving ACR 20 Over Time Percent of Patients Responding Week

Proportion of Patients Achieving ACR 50 Over Time Percent of Patients Responding Week

Proportion of Patients Achieving ACR 70 Over Time Percent of Patients Responding Week

Enthesitis Over Time *p=0.05 vs placebo Number of Patients with Enthesitis * * Week

Enthesitis Over Time Number of Patients with Enthesitis *p=0.05 vs placebo

Dactylitis Score

Week

Baseline PASI PlaceboInfliximab n = 52n = 52 Subjects with Any Skin n= 42n= 42 Involvement Subjects with PASI >2.5n = 18n = 21 Mean Baseline 7.96 ( ) 8.88 ( )

Week 16 Results: PASI PlaceboInfliximab Mean PASI Baseline Mean PASI Week % Change of Mean-29.6%81.5%* > 75% Improvement1 subjects 14 subjects (0.05%) (67%)**

Week 50 Results: PASI Placebo Infliximab Mean PASI Baseline Mean PASI Week % Change of Mean47.6%72.1%* > 75% Improvement8 subjects 12 subjects (44%) (57%)

Conclusions Infliximab treatment is effective in PsA –Reduction in synovitis and psoriatic lesions at Week 16 81% Mean reduction in PASI in infliximab group 67% achieved >75% Improvement in PASI –Week 50

Conclusions Infliximab treatment is effective in PsA –Reduction in ACR at Week % of subjects achieved ACR % of subjects achieved ACR % of subjects achieved ACR 70 78% of subjects achieved Clegg (PsARC) Criteria Infliximab was well-tolerated with similar profile to other indications Low drop out rate