Top Down vs. Step Up Therapy Biologics in IBD: Treatment Algorithms Stephen B. Hanauer, M.D. University of Chicago
Treatment Goals c.2008 Induce and maintain response/remission Prevent complications Disease Related Therapy Related Improve quality of life Limit surgery? Cosnes et al. Inflamm Bowel Dis 2002; 8: 244
Current Therapeutic Pyramids Crohn s Disease Ulcerative Colitis Severe Surgery Infliximab MTX AZA/6-MP Systemic Steroids Budesonide Antibiotics 5-ASA Concept Obfuscates Induction/Maintenance Strategies Moderate Mild Surgery Cyclosporine Systemic Corticosteroids Infliximab Aminosalicylates
Conventional approach to Induction Therapy: step-up Natalizumab Anti TNF-α Disease severity Aminosalicylates Non-systemic corticosteroids Systemic corticosteroids Time Clinical approach to use mildest form of drug therapy to treat patients first Move to next step in non-responders
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
IBDs are chronic, life-long long We cannot just look at the short-term induction therapy
Long-Term Therapy for IBD is Sequential Induction Maintenance
Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression Cumulative Probability (%) 100 80 60 40 20 High Potential Low Potential Penetrating Stricturing Inflammatory 0 0 12 24 36 48 60 72 84 96108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk: n= 2002 552 229 95 37 Cosnes et al. Inflamm Bowel Dis 2002; 8: 244
Efficacy of AZA as Crohn s Disease Maintenance Therapy After Steroids in Adults * % Patients Not Failing Trial 100 80 60 40 20 0 AZA 2.5 mg/kg per d Placebo 42% p=0.001 7% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Duration of Trial (months) Candy S, et al. Gut. 1995;37(4):674-678. *Remission induced by prednisolone tapered over 12 wk Inclusion: Patients were not steroid dependent
Efficacy of 6-MP 6 as Crohn s s Disease Maintenance Therapy After Steroids in Steroid-naïve Children % of Patients in Remission N=55 100 90 80 70 60 50 40 30 6-MP 91% Control P<.007 53% 0 50 100 150 200 250 300 350 400 450 500 550 600 Days Since Remission Induction Markowitz J et al. Gastroenterology. 2000;119:895. At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission.
TNF:Fusion Fusion protein, antibodies and PEGylated Fab' fragment Three classes of anti-tnf:fusion protein, Etanercept Receptor Infliximab Fab Adalimumab Fab Certolizumab pegol IgG1 Fc IgG1 Fc PEG Human recombinant receptor/fc fusion protein Chimeric Monoclonal antibody Human PEGylated humanized Fab fragment 2 20 kda PEG Coutesy of Stephen B. Hanauer, M.D.
Clinical Trials with Anti-TNF Biologics in Refractory Crohn s s disease Drug Targan/Infliximab Classic I/Adalimumab Placebo ACCENT I/Infliximab CHARM/Adalimumab PRECiSE 2/Certolizumab Drug Responder Drug Placebo Maintenance Drug Response Maintenance CLASSIC II/Adalimumab PRECiSE1/Certolizumab Placebo
Patients (%) Comparing ACCENT I, CHARM, and PRECiSE 2 Results 100 80 60 40 20 0 60 Week 4 Response Patients (%) 80 60 40 20 0 CHARM** (adalimumab) 40 Week 26 Remission 58.5 Week 2 Response ACCENT I* (infliximab) 80 60 40 20 0 64.1 Week 6 Response PRECiSE 2 (certolizumab pegol) 47.9 Week 26 Remission *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. 24 Overall Remission Week 26 39.0 Week 30 Remission Patients (%) 22.8 Overall Remission Week 30 30.7 Overall Remission Week 26
Impact of Disease Duration
Clinical Remission at Weeks 26 by Disease Duration in adalimumab CHARM study Placebo All Adalimumab % of patients 70 60 50 40 30 20 10 0 59* 40 41** 25 17 14 N=23 N=39 N=36 N=57 N=111 N=233 <2 years 2 to <5 years 5 years *p=0.002, **p<0.001, p=0.014, p=0.001 all vs placebo Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147
Week 26 Remission with certolizumab by Duration Of Crohn s s Disease In PRECiSE 2 100% 80% 68% Certolizumab Remission Placebo Remission 60% 40% 55% 37% 36% 47% 29% 44% 24% 20% 0% < 1 Year 1-2 Years 2-5 Years > 5 Years
Impact of Concomitant Immunomodulators
Comparable clinical outcomes with or without immunomodulators ACCENT I: Comparable clinical outcomes 100 With concomitant IMM Without concomitant IMM Patients (%) 63 53 50 52 41 39 37 32 0 Week 30 Week 54 Week 30 Week 54 Response Remission Lichtenstein et al, Gastroenterology 2007; 132: A-146 (No. 982)
CHARM: Effect of concomitant adalimumab and immunosuppressive therapy on remission at week 26 and 56 Patients in remission (%) 100 0 50 37 39 33 12 13 131 136 121 39 36 36 With IMM Without IMM Placebo Adalimumab 40 mg EOW, sc Adalimumab 40 mg q-weekly, sc Week 56 Remission defined as CDAI <150 Colombel et al, Gastroenterology 2007; 132: 52
Continuous vs interrupted use of immunomodulators in the long-term efficacy of infliximab (IFX): The IMID Trial No need for early rescue IFX: primary endpoint Cumulative survival 1.0 0.8 Log Rank (Cox): 0735; Breslow: 0.906 Median IFX levels, Week 8 to Week 104 combined IFX trough levels (μg) 100 p<0.005 0.6 0.4 0.2 Continued Discontinued 10 1 0.0 0 20 40 60 80 100 Time (weeks) 0 Continued Discontinued 80 patients randomized to continue ( + CON, n=40) or to interrupt ( ++ DIS, n=40) immunomodulators (azathioprine or methotrexate) 6 months after the start of infliximab (5 mg/kg IV) Van Asche et al, Gastroenterology 2007; 132: A-103 (No. 734)
Recent Anti-TNF Biologic Trials Steroids Steroids IS Step-up/Top-down (Steroid-naïve) Infliximab + IS COMMITT (Steroid-induced, IS naive) SONIC (Steroid-refractory, IS naïve) Infliximab Infliximab + MTX Infliximab Infliximab + AZA AZA
Early Aggressive Biologic Therapy vs Conventional Management of Crohn s s Disease Newly diagnosed, antimetabolite, anti-tnf, or steroid-naïve CD patients (n=133) Steroids Steroids + AZA MTX + IFX Early aggressive (n=67) IFX (0,2,6 weeks) + AZA + (episodic) IFX Steroids Conventional therapy (n=66) D Haens et al. Lancet 2008;371:660
Step-Up vs. Top-Down: Results % of Patients % of Patients CDAI < 150 & No Steroids 80 60 40 20 0 Steroid Use 40 30 20 10 0 P = 0.03 P = 0.19 60 41 61 50 6 Months 12 Months P < 0.001 P < 0.001 0 31 0 6 Months 12 Months D'Haens G, et al. Lancet 2008;371:660-667 17 Percent of Patients 35 30 25 20 15 10 5 0 Treatment Success* From Week 14 Through 2 Years 29 P < 0.001 Top Down Step Up *Remission (CDAI < 150), discontinuation of steroids and infliximab, and no resection. 5
Step Up vs. Top Down: Complete Endoscopic Remission at 2 Years 100 ** 73 **p=0.003 Patients (%) 30 0 (n=26) Early aggressive (n=23) Conventional therapy D Haens et al. Lancet 2008;371:660
COMMITT: MTX plus IFX in CD (1) Patients with active CD on corticosteroids 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
COMMITT: MTX plus IFX in CD (2) Patients in Remission off Steroids (%) 100 80 60 40 20 0 p=0.83 76.2 77.8 p=0.63 55.6 57.1 Week 14 Week 50 MTX + IFX PBO + IFX No difference in ITT analysis, duration of disease <2 years, by CDAI score No difference in infectious AEs (58.7% MTX vs 61.9% PBO) Feagan B, et al. DDW 2008: #682C
SONIC Induction + maintenance of steroid-free remission, mucosal healing, IFX monotherapy vs IFX+AZA combination vs AZA monotherapy in moderate-to-severe CD in patients with no prior exposure to biologic agents and immunosuppressants Cosnes et al. Inflamm Bowel Dis 2002; 8: 244
Clinical remission without corticosteroids at week 26 Primary endpoint 100 Proportion of Patients (%) 80 60 40 20 31 p=0.009 p<0.001 44 p=0.022 57 0 52/170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Sandborn et al., ACG 2008 annual meeting, abstract #29
Mucosal healing at week 26 Secondary endpoint 100 Proportion of Patients (%) 80 60 40 20 17 p=0.023 p<0.001 30 p=0.055 44 0 18/109 28/93 47/107 AZA + placebo IFX + placebo IFX+ AZA Sandborn et al., ACG 2008 annual meeting, abstract #29
COMMITT vs. SONIC COMMITT SONIC Steroid-induced patients IS Naïve Steroid-Induced Forced steroid-taper by week 14 40% Steroid-dependent (refractory CDAI>250) IS Naïve Ad lib steroids to week 14 ( ) then taper Cosnes et al. Inflamm Bowel Dis 2002; 8: 244
Yin & Yang of Concomitant Immunomodulators All biologics are immunogenic Antibodies (at least to infliximab) Associated with acute/delayed infusion reactions Shorter duration of response (with episodic therapy) Immunomodulators reduce immunogenicity across all trials Yet No difference in short- or long-term responses to induction + maintenance therapy in refractory CD ACCENT,CHARM, PREcISE No benefit with steroidinduction (COMMIT) Positive Benefit in steroiddependent (SONIC) Increase long-term toxicity Serious infections Risk of neoplasia
Anti-TNF-α Risks Immunogenicity (all biologics) 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
When to Introduce Biologics? The Tipping Point may be Corticosteroids?
Challenges of Induction Maintenance 2009: Consider the Population Steroid-Naïve Steroid-Induction Thiopurine/MTX Maintenance (Markowitz) Anti-TNF Induction Thiopurine/MTX Maintenance (Step-up/Top-Down)
Challenges of Induction Maintenance 2009: Consider the Population Steroid-Dependent Thiopurine/MTX Maintenance (Candy, Markowitz, Feagan) Failure Biologic (ACCENT,CHARM,PREcISE)
Challenges of Induction Maintenance 2009: Consider the Population Steroid-Refractory Immunosuppressive naïve Steroid-Refractory Despite Immunosuppressive Anti-TNF + AZA induction & Maintenance (SONIC) Anti-TNF induction & Maintenance Stop Immunosuppressive Fail Assess Inflammation, Immunogenicity Switch Anti-TNF or Natlizumab
Current and Future Therapeutic Paradigms Current Bottom-up approach Conservative use of immunomodulators Goals Induce remission Maintain remission Prevent complications Optimize surgical outcomes Future Early aggressive approach Earlier use of immunomodulators Additional goals Disease modification Mucosal healing Pharmacoeconomics Disease prevention!