CROHN'S DISEASE/ULCERATIVE COLITIS TREATMENT ALGORITHM

CROHN'S DISEASE/ULCERATIVE COLITIS TREATMENT ALGORITHM Crohn's Disease Ulcerative Colitis Steroids x 2 No prior AZA/6-MP Biologic Agent AZA/6-MP

STEP-UP MANAGEMENT APPROACH Advantages Patients attain remission with less toxic therapies Potentially more toxic therapies reserved for more severe or refractory disease Minimizes risk of adverse events Cost sparing (short-term?) Disadvantages Patients have to "earn" most effective treatments Decrease in quality-of-life before patients obtain optimal therapy Likelihood of surgery is high Disease is not modified

CURRENT AND FUTURE THERAPEUTIC PARADIGMS Current Future Bottom-up approach Conservative use of immunomodulators Goals Induce remission Maintain remission Prevent complications Optimize surgical outcomes Early aggressive approach Earlier use of immunomodulators Additional goals Disease modification Mucosal healing Pharmacoeconomics Disease prevention!

INFLAMMATORY DISEASE IS MORE FREQUENT IN EARLY CROHN S 100 90 Cumulative Probability (%) 80 70 60 50 40 30 20 10 INFLAMMATORY PENETRATING STRICTURING 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk: N = 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis. 2002;8:244

CUMULATIVE RELAPSE RATES IN PATIENTS WITH CD 60 50 Percent of Patients 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Months After Diagnosis Between diagnosis and follow-up (mean, 16.2 mo) Mourn B et al. Scand J Gastroenterol. 1997;32:1005

CUMULATIVE PROBABILITY OF SURGERY IN CD 100 80 Percent of Patients 60 40 20 0 0 5 10 15 20 25 30 35 Years After Onset Kaplan-Meier analisys Mekhjian HS et al. Gastroenterology. 1979;77:907

CROHN`S DISEASE: CUMULATIVE INCIDENCE OF SURGICAL RESECTION AFTER STARTING CORTICOSTEROIDS 100 Cumulative probability (%) 80 60 40 20 0 0 30 60 182 90 365 Days N=77 Faubion WA Jr et al. Gastroenterology. 2001;121:255-260

CROHN'S DISEASE PREDICTORS OF DISABLING DISEASE: REQUIREMENT FOR STEROIDS IS TURNING POINT 5-year clinicalcourse after diagnosis Variable Nondisabling, % (n = 166) Disabling, % (n = 957) P value Age at onset < 40 years 87.7.0004 > 40 years 12.3 Location of disease Small bowel only 44.6 32.8.002 Small bowel + colon 25.9 39.4 Colon only 29.5 27.8 Smoking status Smoker 50.3 57.4.09 Ex or nonsmoker 49.7 42.6 Perianal lesions at diagnosis Yes 17.5 26.4.01 No 82.5 Required steroids for first flare Yes 37.3 65.2.0001 No 62.7 34.8 Beaugerie L et al. Gastroenterology2006;130:650-656.

CORTICOSTEROIDS: SHORT- AND LONG - TERM EFFICACY IN CROHN'S DISEASE 30 Day Responses n=74 Complete 58% (n=43) Partial 26% (n=19) None 16% (n=12) 1 Year Responses n=74* Prolonged response 28% (n=21) Steroid dependent 32% (n=24) Surgery 38% (n=28) * 1 patient lost to follow-up Faubion WA Jr. et al. Gastroenterology. 2001 ;121 255.

When should biologics be used?? Time comes to be the first choice?? Still the last resort?? Somewhere in between?? Severity of disease Extent or location of disease The presence of extraintestinal complications Growth and nutrition Functional ability...

BIOLOGIC AGENTS Differences in Molecular Structure

COMPARING ACCENT I, CHARM, AND PRECISE 2 RESULTS 80 ACCENT I* (infliximab) Patients (%) 58.5 39.0 22.8 Week 2 Respons Week 30 Remission Overall Remission Week 30 100 Patients (%) 60 CHARM** (adalimumab) 40 24 80 Patients (%) 64.1 PRECISE 2 (certolizumab pegol) 47.9 30.7 Week 4 Respons Week 26 Remission Overall Remission Week 26 Week 6 Respons Week 26 Remission Overall Remission Week 26 * 5 mg/kg dose. **Maintenance trial with 80/40 mg induction dosing. Randomized responders = CR-70 at week 4. Week 26 remission among randomized responders on 40 mg every other week dosing.

STEROID-FREE REMISSION: INFLIXIMAB vs ADALIMUMAB 100 ACCENTI Week 54 CHARM Week 56 24 32 29 23 0 Infliximab 5 mg/kg Infliximab 10 mg/kg Adalimumab 40 mg EOW Adalimumab 40 mg/wk Hanaueretal, Lancet 2002; 359: 1541-9 Colombel et al, Gastroenterology 2007; 132: 52-65

ACCENT I INFLIXIMAB MAINTENANCE THERAPY RESULTED IN LESS SURGERIES/PROCEDURES ACCENT I ACCENT II 140 126 Surgeries/procedures 100 patients 120 100 80 60 40 20 81 61 56 65 0 Episodic strategy (n=188) IFX5mg/kg scheduled (n=192) IFX10mg/kg scheduled (n=193) PBO maintenance (n=99) IFX maintenance (n=96) Rutgeerts, P et al. Gastroenterology.2004; 126:402-413. Lichtenstein, GR, et al. Gastroenterology. 2005;128:862-869. Data on File, Centocor, Inc.

ACCENT I & II MAINTENANCE THERAPY IS ASSOCIATED WITH FEWER CD SURGERIOS 50 P=0.01 Proportion of Patients with Surgeries 40 30 20 10 0 7.5 Episodic Strategy P=0.04 10 mg/kg Scheduled Strategy P=0.07 2.6 3.1 3.1 Week 54 5 mg/kg Scheduled Strategy Combined Scheduled Strategy Rutgeerts, etal. Gastroenterology 2004;126:402-413.

ACT 1 and ACT 2 NUMBER OF HOSPITALIZATIONS THROUGH Wk 30 30 *p<0.05 **p<0.01 Mean Number of Hospitalizations per 100 Patients 25 20 15 10 5 0 18 (44) N=244 Placebo 8** (19) N=242 5 mg/kg Infliximab 10* 9** (23) N=242 10 mg/kg Infliximab (42) N=484 Combined Infliximab The number in parentheses in each group represents the total number of hospitalizations. Data of File. Centocor. Inc.

TOP-DOWN vs STEP-UP: RESULTS CDAI < 150 AND no steroids AND no surgery Proportion of patients on immunosupressants 100 100 80 80 Patients (%) 60 40 * * ** Patients (%) 60 40 20 Step up Top down 20 Step up Top down 0 0 0 26 52 78 104 0 26 52 78 104 Week *p<0.01 **p<0.05 Week D`Haens et al. Lancet 2008; 371: 660-7

STEP-UP vs TOP-DOWN: COMPLETE ENDOSCOPIC REMISSION AT 2 YEARS 100 73** Patients (%) 30 0 Early aggressive treatment (n=26) Conventional treatment (n=23) **p=0.003 D`Haens et al. Lancet 2008; 371: 660-7

ACCENT 1 INFLIXIMAB IN CD: MUCOSAL HEALING Signicifant Benefit by Week 54 100 Percent Patients randomized as responders with mucosal healing at week 54 90 80 70 60 50 40 30 20 10 7 p=0.026 46 p=0.007 53 p=0.007 50 0 Eposodic (n=14) 5 mg/kg scheduled maintenance (n=11) 10 mg/kg scheduled maintenance (n=15) Combined scheduled maintenance (n=15) Rutgeers p. et al. Gastorintest/Endosc. 2006; 63:433

MUSIC TRIAL: ENDOSCOPIC IMPROVEMENT IN PATIENTS WITH ACTIVE CROHN'S DISEASE TREATED WITH CERTOLIZUMAB PEGOL (CZP) 100 Patients (%) 61.5 42.3 0 Endoscopic response, CDEIS decreased 5 Endoscopic remission, CDEIS <6 11.5 Complete endoscopic remission, CDEIS <3 Exploratory analysis (n=78) MUSIC demonstrates efficacy of CZP in achieving endoscopic response and endoscopic remission Colombelet al, Am J Gastroenterol 2008; 103: S-432 (No.1107)

ANSWERED QUESTIONS - MUCOSAL HEALING - Goals of treatment more ambitious Modification of the natural course has become the ultimate end point Good correlation betwen the severity of endoscopic lesions and clinical activity Mucosal healing may reduce complications, relapse/reccurence Reduction of cancer risk Crohn`s Disease: Mucosal healing occurs on o o o Corticosteroids NO AZA Infliximab

EARLY CROHN'S DISEASE SHOWS HIGH LEVELS OF REMISSION TO THERAPY WITH ADALIMUMAB Week 26 Week 56 100 100 Patients(%) 17 59* 25 40 41** Patients(%) 14 17 51 11 44+ 11 35** Years Years *p=0.002;**p<0.001; p=0.014; + p=0.001; all vs placebo <2 years: PBO n=23, adalimumab n=39 2to <5 years: PBO n=36, adalimumab n=57 5 years: PBO n=lll, adalimumab n=233 placebo ALL adalimumab Schreiber et al, Am J Gastroenterol 2007; (4 Suppl. 2): A-147

EFFICACY OF INFLIXIMAB (IFX) WITH AND WITHOUT IMMUNOMODULATORS (IMM): DATA FROM PIVOTAL IFX TRIALS 100 Ulcerative colitis Patients(%) 45 45 34 36 7.2 5.1 55 53 36 27 3.9 5.8 ACT I 54-wk Response ACT I 54-wk Remission ACT! 54-wk Hosp ACT II 30-wk Response ACT II 30-wk Remission ACT II 30-wk Hosp. 100 Crohn's disease IMM + Patients(%) 50 41 37 32 1.9 5.3 43 48 3.3 IMM - 4.4 ACCENTI 54-wk Response ACCENTI 54-wk Remission ACCENT I 54-wk Hosp. ACCENT II 54-wk Response ACCENT II 54-wk Response Lichtenstein et al, Gastroenterology 2007; 132: A-146

ACCENT I & II: COMPARABLE CLINICAL OUTCOMES WITH OR WITHOUT IMMUNOMODULATORS 100 OR 1.53 ACCENT I Patients(%) 63 53 50 41 52 39 37 32 100 Patients(%) Week 30 Week 54 Response 60 65 ACCENT II Week 30 Week 54 Remission 43 48 Infliximab with concomitant IMM Infliximab without concomitant IMM Week 30 Week 54 Maintenance of fistla closure Lichtenstein et al, Gastroenterology 2007; 132: A-146(No982)

CHARM: EFFECT OF CONCOMITANT ADALIMUMAB AND IMMUNOSUPPRESSIVE THERAPY ON REMISSION AT WEEK 56 100 Placebo Adalimumab 40 mg EOW, SC Adalimumab 40 mg qw, SC Patients in remission* (%) 12 37 39 13 33 50 0 n=131 n=136 n=121 n=39 n=36 n=36 *Remission defined as CDAI <150 With IMM Week 56 Without IMM Colombel et al, Gastroenterology 2007; 132: 52-65

Antibodies for biologics (ATIs) increase the risk of acute and delayed reactions shorten duration of response (eventually complete loss of response) ATIs detected in 39% when IFX was given episodically and 16% if scheduled ATIs are removing active drugs leading to lower response rate episodic therapy appears to induce ATIs If given episodically with IM 46% developed ATIs, without IM 73% Maser EA et all: association of trought serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn`s disease. Clin Gastroenterol Hepatol. 2006; IV (10): 1248-54 Beart F et all. Influence of immunogenicity on the long-term efficacy of Infliximab in Crohn`s disease. N Engl J Med. 2003; 348 (7): 601-8

ACCENT I: EFFECT OF CONCOMITANT IMMUNOMODULATORS ON THE INCIDENCE OF ATLS No immunomodulators (n=152) With immunomodulators (n=362) Patients with ATI (%) 50 45 40 35 30 25 20 15 10 5 0 p=0.003 38 16.1 10.9 p=ns p=ns 6.7 8 4.4 Episodic strategy Infliximab maintenance 5 mg/kg Infliximab maintenance 10 mg/kg 573 patients with Crohn's disease Hanauer et al. Clin Gastroenterol Hepatol 2004; 2: 542

DURATION OF RESPONSE TO INFLIXIMAB BY ANTIBODY LEVEL Days until subseqvent infusion 140 120 100 80 60 40 20 0 Undetectable 1.7 7.9 8 20 >20 Antibodies to infliximab (μg/ ml) Median duration of response higher for ATI titers < 8 μg/ ml vs ATI > 8 μg/ ml (p < 0.001) Beart et al. N Engl J Med 2003; 348:601

EFFECT OF IMMUNOMODULATORS ON MAINTENANCE OF RESPONSE TO INFLIXIMAB (IFX) 100 Started IMM >3 months prior to IFX Started IMM <3 months prior to IFX No IMM 50 0 12 24 36 48 Months Immunomodulators (IMM) started >3 months prior to IFX increased maintenance of response, p=0.027 n=198 Rudolph et a/. Gastroenterology 2006; 130: Abstract-142

ADJUSTMENT OF INFLIXIMAB THERAPY Episodic and episodic/scheduled (n=129) 14% n=18 25% n=32 11% n=14 50% n=65 5% n=6 20% n=25 4% n=5 Scheduled (n=123) 71% n=87 0 intervention 1 intervetion 2 intervetion 3 or more intervetion Intervention=increase in interval or reduction in IFX dose P=0.003 Hanauer S. : Gastroenterology amd Hepatology 2008.

CONTINUOUS vs INTERRUPTED USE OF IMMS IN THE LONG-TERM EFFICACY OF INFLIXIMAB: THE IMID TRIAL 1.0 0.8 0.6 0.4 No need for early "rescue" IFX: Primary endpoint Cumulative survival Log rank (Cox): 0735 Breslow: 0.906 Disontinued Continued Median IFX levels Week 8 to Week 104 combined IFX trough levels (μg) p<0.005 0.2 0.0 0 20 40 60 80 100 Time (weeks) Continued Disontinued 80 patients randomized to continue ( + CON, n=40) orto interrupt ( ++ DIS, n=40) immunomodulators (azathiopnne or methotrexate) 6 months afterthe start of infliximab (5 mg/kg IV) van Asche et al, Gastroenterology 2008; 134:1861-68

EFFICACY OF AZA AS CROHN'S DISEASE MAINTENANCE THERAPY AFTER STEROIDS* 100 n=63 pts with active disease 80 Patients not failing trial (%) 60 40 AZA 2.5 mg/kg per day 42% 20 Placebo 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 p=0.001 Duration of trial (months) 'Remission induced by prednisolone tapered over 12 wks Inclusion: Patients were not steroid dependent Candy et al. Gut 1995; 37: 674

CROHN'S DISEASE: NEWLY DIAGNOSED PATIENTS COMBINATION INDUCTION THERAPY 6-MP + PREDNISONE Remission 1.00 91% Pediatric CD within 8 wks of diagnosis (N=55 pts) Patients who required steroid therapy 6-MP at 1.5 mg/kg added as primary therapy Fraction steroid free 0.80 0.60 0.40 0.20 Initial Remission 89% = 6-MP = Controls Remission 53% p=0.0007 0.00 0 100 200 300 400 500 600 Markowitz J, et al. Gastroenterology. 2000;119:895-902. Deys Since Steroids Discontinued

DO IMMUNOSUPPRESSIVES CHANGE THE COURSE OF CROHN'S DISEASE? 50 No change in operative rates 40 Patients operated on (%) 30 20 10 0 0 12 24 36 48 60 p=0.81 Months after diagnosis 78-82 (n=34) 83-87 (n=46) 88-92 (n=102) 93-97 (n=176) 98-02 (n=102) Cosnes et al, Gut 2005; 54: 237

JACQUES COSNES - ISSUES - Retrospective, Single Center Not Population Cohort Study Assumption that all other factors remained similar Use of corticosteroids Dose of Azathioprine in all patients Did author use 2.5 mg/kg/day of AZA routinely on all patient: 0nly 8.4% needing surgery were taking AZA before surgery Indications for surgery Not standardized Based upon the physician discretion - not predetermined and uniform

COMMITT: MTX plus IFX in CD Patients with active CD on orticosteroids within last 6 weeks 1:1 randomization to IFX + PBO (n=63) IFX + MTX (n=63) Steroids withdrawn by Week 14 per protocol IFX at 0, 2, and 6 weeks then maintenance q8w Primary analysis: time to treatment failure CDAI <150, no prednisone by Week 14 and maintained to Week 50 Relapse: CDAI increase of 70 points Feagan B, et al. DDW 2008: #682C

COMMIT: METHOTREXATE (MTX) PLUS INFLIXIMAB (IFX) IN CROHN`S DISEASE Patients in remission off steroids Patients in treatment success 100 76.2 77.8 80 55.6 57.1 60 Patients(%) Patients(%) 40 p=0.63 20 0 Week 14 Week 50 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week since randomization Placebo + IFX MTX + IFX Placebo MTX Feagen et al. Gastroenterolpgy 2008; 135: 394-5

SONIC Induction + maintenance - steroid-free remission - mucosal healing IFX monotherapy vs IFX+AZA combination vs AZA monotherapy Moderate-to-severe CD No prior biologics/immunosuppressants

SONIC: CORTICOSTEROID FREE REMISSION AT WEEK 26 100 Primary endpoint p<0.001 p<0.022 Patients(%) p<0.009 44.4 56.8 30.6 Azathioprine + placebo n=170 Infliximab + placebo n=169 Infliximab + AZA n=169 Sandborn et al, Am J Gastroenterology 2008; 103(Suppl. 1): S436 (No. 1117)

SONIC: CORTICOSTEROID FREE REMISSION AT WEEK 50 100 Primary endpoint p<0.001 p=0.035 Patients(%) p=0.028 35 46 24 Azathioprine + placebo n=170 Infliximab + placebo n=169 Infliximab + AZA n=169 Sandborn et al, DDW 2009 : Abstract 750

SONIC MUCOSAL HEALING AT WEEK 26 100 Secondary endpoint p<0.001 Patients(%) p=0.023 p=0.055 44 30 17 18/109 28/93 47/107 Azathioprine + placebo Infliximab + placebo Infliximab + AZA Sandborn et al, Am J Gastroenterology 2008; 103(Suppl. 1): S436 (No. 1117)

COMMITT vs. SONIC COMMITT Steroid-induced patients IS Naive Steroid-Induced Forced steroid-taper by week 14 SONIC 40% Steroid-dependent (refractory CDAI>250) IS Naive Ad lib steroids to week 14 ( <-> ) then taper

Importance of treating with highly effective combination therapy early in the course SONIC has shown that combination is highly effective better than monotherapy COMMIT has shown that IM provided no additional benefit to biologics Whether patients on combinations can transition to a monotherapy for long-term?? Can we predict a high risk patient with multiple serological markers??

LOSS OF RESPONSE Individuals who achieve initial response to induction but subsequently relapse - Mechanisms for Loss of Response Include: Immunogenicity Other mechanisms of increased clearance Change in disease response to mechanism of action Non-inflammatory etiology of signs & symptoms

DEFINITIONS 250 CDAI Score 200 Primary failure 150 Loss of Response Remission 4 weeks 8 weeks 12 weeks 1 Year

FACTORS CONTRIBUTING TO PRIMARY LACK OF RESPONSE TO INFLIXIMAB No inflammation (IBS) Wrong end point structural damage (ie, stricture) inflammation better but bile-salt diarrhea celiac disease Mechanism of inflammation not TNF dependent Normal CRP panca positive (?) Polymorphism in IgG Fc receptor Ilia Smoking Louts et al Scand J Gastroenterol 2002:3/:818. Taylor el al. Gastroenterology. 2001; 120:1347. Esters el al. Am J Gastroenterol. 2002.9/: 1468. Louts et al Aliment Pharmacol Titer. 2004:19:511. Parti et al Gastroenterology. 2002:123:707.

SECONDARY NON-RESPONDER Individuals who respond to initial intervention but fail induction with second intervention May apply to induction or maintenance end-point criteria Usually applies to agents within therapeutic class Consider mechanisms for loss of response

DEFINITIONS 250 CDAI Score 200 Secondary Non-Response 150 Secondary Loss of Response Secondary Remission 4 weeks 8 weeks 12 weeks 1 Year

GAIN: ADALIMUMAB (ADA) MAINTAINS LONG-TERM REMISSION AND RESPONSE AFTER INFLIXIMAB FAILURE, 1-YEAR FOLLOW-UP 325 CD patients who failed IFX therapy enrolled in GAIN Patients (%) 100 90 80 70 60 50 40 30 20 10 0 92 75 60 57 51 35 n=310 ITT analysis n=126 Responder analysis Patients (%) 100 90 80 70 66 65 60 50 50 44 40 40 29 30 20 10 6 months 12 months 0 n=310 ITT analysis n=126 Responder analysis Remission (CDAI <150) Response ( 4 CDAI 100) Response ( CDAI >70) ADA shows sustained efficacy in maintaining clinical remission and response through 1 year of therapy in patients who failed prior IFX therapy Panaccione et al, Gastroenterology 2008; 134(4 Suppl. 1): A133 (920)

WELCOME: EFFICACY IN PATIENTS WITH PRIOR LOSS OF RESPONSE OR INTOLERANCE TO INFLIXIMAB Responce ( CDAI 100) Remission (CDAI 150) 70 60 61 PATIENTS(%) 50 40 30 39.3 n=539 20 10 0 WEEK 6 Results comparable to PRECiSE 2 (64.1% in overall population and 53.9% in patients previously exposed to infliximab) o prior infliximab exposure may not reduce response to certolizumab pegol (CZP) induction Patients with prior exposure to infliximab responded well to CZP Vermeire et a/, Gastroenterology 2008; 133: A67 (494)

ASSESSING LOSS OF RESPONSE TO A BIOLOGIC ASSESS FOR INFLAMMATION INFLAMMATION PRESENT NO INFLAMMATION CONSIDER IMMUNOGENICITY TREAT UNDERLYING MECHANISMS

ASSESSING LOSS OF RESPONSE TO INFLIXIMAB ANTIBODIES TO INFLIXIMAB (+) (-) NO INFLIXIMAB (-) INFLIXIMAB PRESENT ALTERNATIVE ANTI-TNF REDUCE INFUSION INTERVAL\INCREASE DOSE (10mg/kg) NATALIZUMAB

NATALIZUMAB Humanized monoclonal igg 4 antibody against α4-integrins Disrupts adhesive interactions necessary for recruitment/migrations of α4-integrins-expressing leukocytes across vascular endothelium into gut mucosa Interrupts inflammatory cascade and ameliorates chronic inflammation

ENCORE Natalizumab Induction Efficacy Response at Both Weeks 8 and 12 by TNF Exposure PLACEBO NATALIZUMAB 50 48 p<0.05 45 40 35 32 38 38 Percent 30 25 20 15 21 14 10 5 0 ITT n=509 PriorTNF Exp n=242 PriorTNF Fail n=172 Prior TNF Exp = patients with previous exposure to anti-tnfa therapy Prior TNF Fail = patients who failed previous anti-tnfa therapy Targan SR et al. Gastroenterology. 2007;132:1672-1683. Data on file. Elan Pharmaceuticals, Inc.

ENACT-2 Natalizumab Steroid Sparing Remission at 6 & 12 Months Without Concomitant Steroids PLACEBO NATALIZUMAB 40 39 36 p<0.05 35 30 25 Percent 25 20 15 15 10 5 8 5 0 ITT PriorTNF Exp PriorTNF Fail Prior TNF Exp = patients with previous exposure to anti-tnfa therapy Prior TNF Fail = patients who failed previous anti-tnfa therapy Sandborn WJ et al. N Engl J Med. 2005;353:1912-1925. Data on file. Elan Pharmaceuticals, Inc.

CONCLUSIONS Natalizumab induces and maintains response and remission through in patients with prior anti-tnf exposure Nearly 40% of patients with prior exposure to anti- TNF therapy are in: Response at both Weeks 8 and 12 with induction therapy Continuous remission for >1 year Remission without the need for steroids at 6 and 12 months

SERIOUS INFECTIONS AND ANTI-TNF THERAPIES THE PROBLEM WITH CONFOUNDING FACTORS TREAT registry data as of August 2005 (n=6,273 with 15,000 patient-years'follow-up) Current use of infliximab* (1.29 serious infections /100 pt-yrs) 1.40 0.95-20.7 Current use of corticosteroids 2.01 1.40-2.90 Current use of narcotic analgesics 2.72 1.87-3.96 *Serious infections were determined within 3 months of an infliximab infusion +p<0.0001 Lichtenstein et al, Gastroenterology 2006; 4: 621-30

ANTI-TNF-A RISKS Immunogenicity (all biologiest) Infliximab specific - Infusion reactions Class effect Drug-induced lupus Injection site reactions (adalimumab, certolizumab pegol) Non-Hodgkin's lymphoma (including hepatosplenic T-cell lymphoma in children on infliximab + azathioprine) Serious infections (-3%) Opportunistic infections (including tuberculosis, histoplasmosis, coccidiomycosis) Demyelination

OPPORTUNISTIC INFECTIONS AND ANTI-TNF THERAPIES Case-control study of 100 patients (1998-2003) Any medication (5-ASA, AZA/6-MP, steroids, MTX, infliximab) 3.50 (1.98-6.08) <0.0001 5-ASA 0.98 (0.61-1.56) 0.94 Corticosteroids 3.35 (1.82-6.16) <0.0001 AZA/6-MP 3.07 (1.72-5.48) 0.0001 MTX 4.00 (0.36-4.11) 0.26 Infliximab 4.43 (1.15-17.09) 0.03 One medication 2.65 (1.45-4.82) 0.0014 Toruneretal, Gastroenterology 2006; 130(Suppl2): A-71

EXCESS RISK OF LYMPHOPROLIFERATIVE DISORDERS (LPD) IN INFLAMMATORY BOWEL DISEASES (IBD): INTERIM RESULTS OF THE CESAME COHORT (CONT.) Results (Cont): * 1 case of Hodgkins Dx & 16 cases of non-hodgkin's LPD * Compared with general population SIR* of LPD = 1.86 (CI 95% 1.08-2.97) p = 0.03 SIR Hodgkins Dx = 0.7 (CI 95% 0.01-3.92) p = 0.82 SIR non-hodgkin's LPD = 2.07 (CI 95% 1.2-3.3) p = 0.01 Among the 16 cases of non-hodgkin's LPD 11 could be tested for EBV 7/11 (64%) were EBV associated Conclusion: * Interim results suggest an overall increased risk of LPD in IBD. * The excess risk appears to be related to IT, since 75% of incident LPD occurred in pts receiving AZA. Fatal in almost half of the cases Frequently associated with EBV infection *SIR=Standard Incidence Ratio, AKA relative risk Beaugeriel L et al, DDW 2008, San Diego CA, Oral Presentation 818

RISK OF LYMPHOMA ASSOCIATED WITH ANTI-TNF AGENTS FOR THE TREATMENT OF CROHN'S DISEASE: A META-ANALYSIS (CONT.) Results: 26 studies involving 8,843 pts (18,296 pt-yrs) included 10 case of NHL, or a rate of 5.5 per 10,000 pt-yrs for anti-tnf treated pts Compared to the expected rate of NHL in SEER, the IRR was 2.88 (95% C11.19-6.50) Compared to the rate of NHL in CD pts treated with immunomodulators alone the IRR was 1.50 (95% CI 0.43-6.57) Conclusion: Compared with the general population or to CD pts treated with immunomodulators alone, the data demonstrate an increased risk of NHL in pts treated with anti-tnf agents. Though the absolute risk is low, tx decisions can be made Siegel C et al, DDW 2008, San Diego CA, Oral Presentation 970

RISK OF HEPATOSPLENIC T CELL LYMPHOMA Occurs in patients who have received either Azathioprine alone 6 (?8) case every reported Occurs in patients with Azathioprine plus biologic therapy Has been reported with Infliximab and Infliximab initially then adalimumab Requires at least 3 years of Azathioprine use Siegel C et al, DDW 2008, San Diego CA, Oral Presentation 970

CONCLUSION NOT: Should we EVER use biologic agents Appropriate Question -When should we use biologic agents Suggestion: After Steroids: Use AZA / 6-MP first for 3 to 6 months If not beneficial move to biologic agents +/- AZA / 6-MP No documented deleterious events with this approach May never need biologic therapy Remember: Remission 42% in Candy Wright study at 15 mos Approximately 80% remission in Markowitz (early treatment: new onset) Natural History of Disease Poor Prognosis with CD and UC: After steroids usually need a maintenance medication

CONCLUSION Efficacy of Agents for Mucosal Healing CROHN`S DISEASE Steroids Efficacy?? AZA: SONIC Trial Only one year. Biologic Therapy young patients with extensive disease deep ulceration on endoscopy severe systemic symptoms rectal involvement fistulazed disease extraintestinal manifestation smokers

CONCLUSION Clinical Efficacy No good data to support that AZA does not change rate of surgery Risk Lymphoma rates are low with biologics and AZA/6-MP Cost Cost effective but costly Individual dosing with increasing the dose and/or shortening the intervals First cut is the deepest Possible changing the mechanism of disease KS+AZA KS+IFX IFX+AZA

COMPARASION OF GOAL Current Future Symptom control (induce and maintain remission) Improve quality of life Minimize drug toxicity Minimize disease complications Optimize surgical outcomes Mucosal healing Disease modification Predictive Biomarkers Molecular/Genetic markers predicting course &therapeutic response Find the cause... Eliminate or tolerize to Environmental factors

NEW THERAPEUTIC GOALS Modification of the long-term course of IBD Asymptomatic and complete and persistent mucosal healing - Patients who achieve clinical remission with traditional therapies exhibit persistent subtle mucosal inflammation Increased risk of recurrent relapse Increased risk of neoplasia in Ulcerative colitis - Mucosal healing may change the long-term course of disease (disease modification) Avoid complications - Strictures/fistulae? Improved quality of life? Decreased hospitalization? Avoidance of surgery? Amott ID, et al. Aliment Pharmacol Ther. 2002:16:857-867

CAN THERAPY ALTER THE NATURAL HISTORY OF IBD? Disease complications Induce and maintan gastrointestinal healing Prevent need for steroids Natural course Prevent strictures and penetrating complications Prevent extra-intestinal complications Decrease hospitalization/surgery Decrease long-term cost of care Years

INFLAMMATORY DISEASE IS MORE FREQUENT IN EARLY CROHN S 100 90 BIOLOGICAL 80 THERAPY IS 70 PENETRATING 60 CHANGING THE COURSE OF 50 40 30 CROHN S DISEASE STRICTURING 20 Cumulative Probability (%) 10 INFLAMMATORY 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk: N = 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis. 2002;8:244