Position of Biologics in IBD Circa 2006: Top Down vs. Step Up Therapy

Transcription

1 Position of Biologics in IBD Circa 2006: Top Down vs. Step Up Therapy Stephen B. Hanauer, MD University of Chicago Potential Conflicts: Centocor/Schering, Abbott, UCB, Elan, Berlex, PDL

2 Goals of Treatment

3 Treatment Goals Induce and maintain response/remission Prevent complications Improve quality of life Restore and maintain nutrition Limit surgery

4 Current Therapeutic Pyramids Crohn s Disease Ulcerative Colitis Severe Surgery Infliximab Surgery MTX AZA/6-MP Systemic Steroids Moderate Cyclosporine Infliximab Systemic Corticosteroids Budesonide Antibiotics 5-ASA Mild Aminosalicylates

5 Natural Course of Ulcerative Colitis Progression or Surgery Proctitis Left-Sided Pan-colitis Regression Progression Surgery Based on a multivariate analysis. Langholz E et al.scand J Gastroenterol. 1996;31:

6 Corticosteroids: Short & Long Term Efficacy for UC 1-Month Outcomes* (n=63) Complete Remission 54% (n=34) Partial Remission 30% (n=19) No Response 16% (n=10) 1-Year Outcomes (n=63) Prolonged Response 49% (n=31) Steroid Dependent 22% (n=14) Surgery 29% (n=18) *30 days after initiating corticosteroid therapy Faubion W, et al. Gastroenterology. 2001;121:255.

7 Risk of Surgical Resection in Patients With UC After Starting Corticosteroids* 100 % Cumulative Probability Days *185 patients in Olmsted County, MN diagnosed with UC from 1970 to 1993 Faubion WA Jr, et al. Gastroenterology. 2001;121:255.

8 Long-term Evolution of Disease Behavior in CD Cumulative Probability (%) Inflammatory Penetrating Stricturing Months Patients at risk: N = Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

9 Proportion of CD Patients in Each Treatment State by Year Since CD Diagnosis Probability Progression to surgery Postsurgery remission Surgery Drug refractory Drug dependent Drug responsive Mild Remission Years After Diagnosis Silverstein MD et al. Gastroenterology. 1999;117:49

10 Cumulative Probability of Surgical Intervention in CD 100 ±2 SD 80 Probability (%) Dx Years Events (no.) Munkholm P et al. Gastroenterology. 1993;105:1716.

11 Corticosteroids: Short & 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) Faubion WA Jr., et al. Gastroenterology. 2001;121: *One patient lost to follow-up

12 Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting Corticosteroids Cumulative Probability (%) N= Days Faubion WA Jr et al. Gastroenterology. 2001;121:255.

13 Efficacy of AZA as Crohn s Disease Maintenance Therapy After Steroids in Adults * % Patients Not Failing Trial AZA 2.5 mg/kg per d Placebo 42% p= % Duration of Trial (months) *Remission induced by prednisolone tapered over 12 wk Inclusion: Patients were not steroid dependent Candy S, et al. Gut. 1995;37(4):

14 Methotrexate Maintenance after Steroids in Crohn s Disease Multicenter, randomized, controlled trial 76 steroid-dependent patients In remission following methotrexate 25 mg IM x 16 weeks Randomized to 15 mg IM or placebo x 40 weeks % Remission Feagan B, et al. N Engl J Med % of 45% responders= 30% overall Methotrexate Placebo n=40 65% n=36 39% Weeks since randomization

15 Patients Receiving an Immunomodulator* (%) Increasing Use of Immunomodulators in CD *Azathioprine or methotrexate (n=34) (n=46) (n=102) Cosnes J, et al. Gut. 2005;54: Months After Diagnosis (n=176) (n=207) P<0.0001

16 Do Immunosuppressives Change the Course of Crohn s? No Change in operative rates Cosnes et al (Impact of the increasing use of immunosuppressants in Crohn s disease on the need for intestinal surgery. Gut 2005;54:237 41,

17 Intestinal Resection Rate in CD Remained Stable Over 25 Years Surgery <3 months after diagnosis Surgery >3 months after diagnosis No significant change over time Number of Intestinal Resections/100 Patients Numbers above bars represent number of patients at risk for intestinal resection at beginning of the year. Cosnes J, et al. Gut. 2005;54:

18 Impact of Biologics on Crohn s Disease and Ulcerative Colitis

19 Improvement in Clinical Response With Infliximab* *Patients NOT RESPONDING to Conventional Agents Response (%) Placebo 5 mg/kg 10 mg/kg Treatment group 20 mg/kg Targan SR et al. N Engl J Med. 1997;337:

20 Fistula Healing With Infliximab* *Patients NOT RESPONDING to Conventional Agents Response (%) * 0 Placebo 5 mg/kg 10 mg/kg Treatment group * p < p < Complete response defined as all fistulas closed for 2 consecutive visits (at least 1 month).

21 Accent I: Median Time to Loss of Response Through Week 54 *Patients NOT RESPONDING to Conventional Agents Week 2 Responders 10 mg/kg q 8 wks > 54 weeks 5 mg/kg q 8 wks 38 weeks P = P < Single dose 19 weeks P = Weeks Hanauer S, et al. Lancet. 2002;359:

22 Accent II: Median Time to Loss of Response Through Week 54 *Patients NOT RESPONDING to Conventional Agents Week 14 randomization Responders > 40 weeks 14 weeks Placebo maintenance 5 mg/kg infliximab maintenance Sands B, et al. N Engl J Med. 2004;350:

23 ACCENT I All Patients Median Daily Corticosteroid Dose Through Week 54 Single Dose Infliximab 5 mg/kg q 8 wks (n = 95) Infliximab 10 mg/kg q 8 wks (n = 95) Less than 5mg by wk 14 Rutgeerts P et al. Gastroenterology. 2004;126:402.

24 Proportion of Patients (%) ACT 1 & ACT 2 UC: Clinical Remission at Week 30* *Patients not responding to conventional therapies *p<0.001 p< * * Intent-to-treat Analysis Patients in all groups with baseline medication were continued on stable doses 11 ACT 1 ACT 2 Placebo infusions 5 mg/kg REMICADE (infliximab) 10 mg/kg REMICADE REMICADE US Package Insert. *

25 Clinical Response With Infliximab Retreatment Does not Depend on Baseline Medications All patients (198.9) Corticosteroids Receiving Not receiving (144.1) 6-MP/AZA Receiving Not receiving Aminosalicylates (74.9) (85.7) Receiving Not receiving Antibiotics Receiving Not receiving Placebo Better Infliximab Better Data on file, Centocor, Inc.

26 Management of recent-onset Crohn s disease A controlled randomized trial comparing step-up and topdown therapy Newly diagnosed Crohn s disease (n=129) +AZA MTX +IFX Top-down (n=65) IFX (0/2/6) + AZA IFX + AZA Steroids + (episodic) IFX Steroids Steroids Step-up (n=64) Steroids Hommes D et al. DDW 2005, Late-breaking abstract

27 Management of recent-onset Crohn s disease Top-down n 65 Remission (CDAI 6 mos 75% <150) 12 mos 77% Remission with steroid 6 mos 75% withdrawal 12 mos 77% Steroids added 6 mos 0% 12 mos 0% Immunosuppressant 6 mos 92% 12 mos 94% Endoscopic healing (at 2 years) Repeat infliximab use 75.0% (n=20) 41% Safety 12 mos 86% Hommes D et al. DDW 2005, Late-breaking abstract Step-up 64 73% 76.1% 48%* 64% 25% 12.5% 40% 62.5% 21% (n=14) 73%

28 Infliximab is Most Effective Therapy to Date.So Why not use First Cost? Side effects?

29 COST OF INFLIXIMAB 6MP and Steroids vs Infliximab $2792/Year $28,000/Year 3mo/pred 5mg/kg 75mg/day 6-MP $56,000?Year 10mg/kg

30 Hospitalization Accounts for >50% of Health Care Costs in CD* 1% 2% 3% 2% 4% 8% Inpatient Outpatient MD Office Medications Emergency Room Home Care SNF Other 56% Inpatient 24% *Data from patients with a CD-related medical claim (10/94-09/95) included in a 1994 integrated claims database. Russell D. Cohen, M.D. Feagan BG et al. Am J Gastroenterol. 2000;95:1955.

31 Average Number of Events Per 100 Patients ACCENT I: Hospitalizations and Surgeries Reduced by Time in Remission Hospitalization (p<0.01) Surgeries (p<0.05) 0%-25% 25%-50% 50%-75% 75%-100% (N=272) (N=88) (N=96) (N=117) 23 Percent Time in Remission 3 12 Lichtenstein GR et al. Am J Gastroenterol. 2004;99:91. 2

32 ACCENT I: Impact of Remission in CD Remission associated with Reduced hospitalizations Reduced surgeries Increased employment Normalized quality of life Lichtenstein GR et al. Am J Gastroenterol. 2004;99:91.

33 Influence of Infliximab on Health Care Resources in the UK Audit of 7 UK centres 6 months before and 6 months after initial IFX Moderate-severe CD Hospital admissions Investigations Operations Outpatient visits Indirect costs (employment, etc.) not assessed Jewell DP et al. Gastroenterology 2004;126(4):S1218. Jewell DP et al. Data submitted for publication.

34 Influence of Infliximab on Resources: Results 1093 fewer bed days Fewer investigations (OR 0.39, CI ) OP visits unchanged (standard follow up) Bed days OP vists Invgns 6m pre 6m post Jewell DP et al. Gastroenterology 2004;126(4):S1218. Jewell DP et al. Data submitted for publication.

35 Influence of Infliximab on Resources: Results (Continued) Number of abdominal operations halved 33 fewer EUA s (OR 0.34, CI ) EUA Ops 6m pre 6m post Jewell DP et al. Gastroenterology 2004;126(4):S1218. Jewell DP et al. Data submitted for publication.

36 Anti-TNF Therapy Reduces Costs by Reducing Hospitalizations and Procedures

37 Side Effects

38 TREAT TREAT Registry Crohn s s Therapy Resource, Evaluation and Assessment Tool > 6000 patient CD registry primarily designed to assess long-term safety of infliximab in CD Real world experience 80% community, 20% academic Treatment at the discretion of the patient s physician Pts to be followed at least 5 years Approximately half of the patients have received infliximab, usually in combination with other CD treatments Approximately half have received other CD treatments only Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

39 TREAT Mortality Logistic Regression Data (Multivariate) 39 Current use of infliximab Current use of 6MP/AZA/MTX Current use of corticosteroids Current use of narcotic analgesics Odds Ratio % CI * *p=0.001 Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

40 TREAT Serious Infections Logistic Regression Data (Multivariate) Odds 95% CI Ratio 40 Current use of infliximab Current use of 6MP/AZA/MTX Current use of corticosteroids * * Current use of narcotic analgesics *p< Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

41 TREAT Malignancies Infliximab patients Noninfliximab patients Odds Ratio 95% CI All Cancer* Lymphoma* No difference in Neoplasia *Incidence per 100 patient-years Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

42 Potential Advantages of Inverted Pyramid Early Disease Stabilization (Disease Modifier) Minimize Disease Complications Strictures/Fistulae CD? Progression/Dysplasia UC? Reduction of Post-operative Recurrence? Avoidance of Steroid Toxicity Cosmetic & Metabolic

43 Potential Risks of Reversed Pyramid Prolonged Immune suppression Opportunistic Infections Carcinogenesis Pregnancy outcomes (?)

44 Needs Assessment for Step-up versus Top-down Approaches Controlled Clinical Trials Pre-defined Efficacy outcomes Long-term Safety Quality of Life IMPACT OF IMMUNOMODIFIERS!

45 When to Introduce Biologics? The Tipping Point may be Corticosteroids?

46 Corticosteroids Rapid Improvement but Highest rate of short/long-term side effects Evidence of Disease Resistance Impaired Apoptosis

47 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 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? Arnott ID, et al. Aliment Pharmacol Ther. 2002;16:

48 The art of prophecy is very difficult, especially with respect to the future Mark Twain

49 Traditional Definitions of Clinical Response Response and Remission Magnitude in change of Crohn s Disease Activity Index (CDAI) Change in CDAI >70, 100 Remission Clinical (CDAI <150), endoscopic, or surgical Patients who responded to acute medical interventions Patients who had surgical resection without gross evidence of residual disease Steroid-dependent patients not considered in remission Hanauer SB, et al. Am J Gastroenterol. 2001;96:

50 Current Induction Therapy Based on Severity Severe Surgery Probably too early in most Patients with Mild-Moderate Disease Moderate Mild Immunomodulators Corticosteroids Aminosalicylates Infliximab (Biologic)?

51 Current Induction Therapy Based on Severity Severe Surgery Before Steroids? Possibly to Avoid Steroid AE s/dependence Moderate Mild Immunomodulators Corticosteroids Aminosalicylates Infliximab (Biologic)?

52 Current Induction Therapy Based on Severity Severe Surgery After Steroids Alone? Allows Steroid AE and ATI s Moderate Mild Immunomodulators Corticosteroids Aminosalicylates Infliximab (Biologic)?

53 Current Induction Therapy Based on Severity Severe Surgery After/With Immunomodulator? Concurrent Rx most Effective Long-Term Moderate Mild Immunomodulators Corticosteroids Aminosalicylates Infliximab (Biologic)?

54 Should Biologics be used Earlier in IBD? Anti-TNF is more efficacious than conventional therapies Infliximab is safer than conventional therapies (Corticosteroids) May be more costeffective (over time) than conventional therapies Conventional Therapies Induce/Maintain Remissions in majority of patients Majority of patients do not need cost/toxicity risks of biologics Long-term safety experience in children & pregnancy Potential Requisite for Immunomodulators to Reduce Immunogenicity

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

56 Current and Future Therapeutic Paradigms Current* Bottom-up approach Conservative use of immunomodulators Goals Induce remission Maintain remission Prevent complications Optimize surgical outcomes Future Top-down approach Earlier use of immunomodulators Additional goals Disease modification Mucosal healing Pharmacoeconomics Disease prevention * Hanauer S, Sandborn W. Am J Gastroenterol 2001;96(3):