Step up or Step Down for Inflammatory bowel Disease or Have we figured out how to use biologics in IBD yet? What is there left to talk about

Transcription

1 Step up or Step Down for Inflammatory bowel Disease or Have we figured out how to use biologics in IBD yet? Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida What is there left to talk about What do we know? Are UC and Crohn s disease treatment different? Are there any new tools for clinicians? How do I talk to patients about these drugs?

2 Maria T. Abreu, MD IBD management journey Induction of remission Maintenance of remission Maintenance of remission off steroids and / or mucosal healing (histology) Where did the idea of inverting the pyramid in Crohn s disease come from?

3 Comparison of Treatment Strategies in Early Rheumatoid Arthritis BeSt Study 14 Index of bone destruction Change in SIS N=508 Sequential monotherapy Step-up combination therapy with methotrexate Initial combination with prednisone + methotrexate Initial combination with infliximab + methotrexate Time (months) Adapted from Goekoop-Ruiterman YP, et al. Ann Intern Med 2007;146(6): What is the problem? There are probably 2 types of errors in defining the treatment strategy for an IBD patient: Under treating a patient who will develop disabling, complicated or severe disease Over treating a patient with a benign course of the disease

4 Where we are now and where we want to be Diagnosis (usually endoscopy) First visit: IBD panel Genotype Phyllotype Serotype Phenotype Serology (children) CRP/ESR Disease prognosis (clinical parameters) IBD subtype Disease prognosis Treatment based on symptoms +/- endoscopic inflammation Patient-specific treatment plan Integrated target-specific therapy What do we know: Guiding principles Combination therapy is better than monotherapy Early therapy is better than late therapy Well timed surgery is ok in Crohn s disease (esp short segment disease)

5 Biologics in IBD Initial ca2 (infliximab) paper (1995) NEJM 1997 Infliximab approved for Crohn s disease 1998 Adalimumab for Crohn s disease (2002) Certolizumab Pegol for Crohn s disease (2008) Ada for UC (2012) Infliximab for ulcerative colitis (2005) Natalizumab for Crohn s disease (2008) First-line Biologic Agents for the Treatment of CD Infliximab Adalimumab Certolizumab Pegol VL VH No Fc CH 1 PEG IgG 1 Chimeric monoclonal antibody (75% human IgG 1 isotype) Mouse Human PEG, polyethylene glycol. IgG 1 Human recombinant antibody (100% human IgG 1 isotype) PEG Humanized Fab fragment (95% human IgG 1 isotype)

6 Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn s Disease 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 The primary endpoints were remission (CDAI <150) and off steroids at months 6 and 12 D Haens, G. et al. Lancet 371:660; 2008 SONIC Moderate-to-severe CD in patients with no prior exposure to biologic agents or immunomodulators Excluded intermediate TPMT activity Average disease duration 2.3 years AZA 2.5mg/kg IFX 5mg/kg IFX + AZA 1 endpoint: Induction + maintenance of steroid-free remission 2 endpoint: Mucosal healing

7 SONIC Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint Proportion of Patients (%) 100 p< p=0.009 p= /170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel, J.F., et al., N Engl J Med. 362(15): p SONIC 17 Mucosal Healing at Week Proportion of Patients (%) p=0.023 p< p= /109 28/93 47/107 AZA + placebo IFX + placebo IFX+ AZA Colombel, J.F., et al., N Engl J Med. 362(15): p

8 Induction therapy SONIC: steroid-free remission in CD 1 SUCCESS: steroid-free remission in UC 2 60 AZA IFX IFX + AZA * Patients (%) *,** Patients (%) * /170 75/169 96/169 Week /66 17/77 31/78 Week 16 *p<0.05 compared to IFX, **p<0.001 compared to IFX/AZA 1. Colombel JF et al. N Engl J Med. 2010;362: ; 2. Panaccione R et al. Gastroenterology 2011;140(Suppl 1):S-134. *p<0.05 compared to AZA and to IFX Why do immunomodulators alone not look so good? Take longer to work Studies have excluded intermediate metabolizers Weight-based dosing underestimates dose about half the time 1 Morales A et al Inflamm Bowel Dis Apr;13(4):380-5.

9 Should we use thiopurines in a top-down approach? Aka like the Markowitz study in kids Accelerated Step-Care Therapy With Early Azathioprine (AZA) vs. Conventional Step-Care Therapy in Crohn's Disease. a Randomized Study Cosnes J et al. Abstract 943c

10 Design Background In early CD patients at risk for disabling disease, 2 possible treatment strategies may be highly effective: Accelerated step-care (steroids + AZA) Early combined immunosuppression (anti-tnf + AZA) Accelerated step-care strategy (early AZA) has been poorly explored Methods Patients with newly diagnosed CD randomized to receive: Azathioprine 2.5 mg/kg at inclusion (e-aza) Azathioprine on demand according to guidelines Primary end point Proportion of trimesters spent in steroid-free and anti-tnf-free remission during the first 3 years after inclusion Results P=NS 61% 50%

11 Response-guided therapy Mucosal healing + Histologic healing = Deep remission Mucosal healing in IBD: effect of different therapies Crohn s disease UC 5-ASA + 1 Steroids (+) Azathioprine Methotrexate (+) 6? Infliximab Adalimumab Enteral nutrition + 11 (+) indicates mucosal healing was observed in a minority of patients 1. Hanauer S et al. Can J Gastroenterol 2007;21:827 34; 2. Modigliani R et al. Gastroenterology 1990;98:811 18; 3. Truelove SC, Witts LJ. Br Med J 1955:29;2:1041-8; 4. D Haens G et al. Gastroenterology 1997;112: ; 5. López-Palacios N et al. Eur J Intern Med 2011;22:621-5; 6. Kozarek RA et al. Ann Intern Med 1989;110:353e6; 7. Rutgeerts P et al. Gastroenterology 2004;126:402 13; 8. Rutgeerts P et al. N Engl J Med 2005;353: ; 9. Rutgeerts P et al. Gastroenterology 2012;142: ; 10. Sandborn W et al. Gastroenterology 2011;140:S123 4; 11. Fell JM, et al. Aliment Pharmacol Ther 2000;14:281-9.

12 Rutgeerts P et al. Gastroenterology 2010;138(Suppl 1):S-85. Early mucosal healing and long-term remission in CD EXTEND: clinical remission at Week 52 with adalimumab Patients (%) (n=31) p< >5 (n=31) Clinical remission defined as a CDAI score <150 EXTEND subanalysis; primary endpoint was complete mucosal healing at Week 12 (p=0.056); all patients received adalimumab induction therapy from Week 0, before being randomised to placebo or adalimumab maintenance therapy at Week 4 10 SES-CD score at Week 12 Patients with mucosal healing at week 12 (%) The best opportunity to induce mucosal healing is early in Crohn s disease (EXTEND study) <2 years 2 to <5 years 5 years Adalimumab, induction-only (placebo) Adalimumab, every other week 21 4/9 1/14 4/10 7/39 9/43 p=0.029 for adalimumab vs placebo for disease duration <5 years vs. 5years All patients (n=135) received open-label adalimumab 160-/80-mg induction therapy at Weeks 0/2 and 129 patients were randomised at Week 4 to maintenance therapy with adalimumab 40 mg every other week or placebo Sandborn WJ, et al. J Crohn s Colitis 2010; 4:S36 (Abstract P060)

13 When should we assess disease activity? How quickly do our interventions work? CD therapy with azathioprine/6mp Mucosal healing 2 3 months Clinical response 1 6 months Time (Weeks) 1. Present DH et al. N Engl J Med 1980;302:981 7; 2. D Haens G et al. Gastroenterology 1997;112:

14 CD therapy with adalimumab Week 4 Clinical remission 2 Week 1 QoL improvement 2 CRP decrease 2 Clinical response 1 Week 12 Mucosal healing 3 * Time (Weeks) *EXTEND primary endpoint was complete mucosal healing at Week 12 (p=0.056) 1. D Haens GR et al. Gastroenterology 2007;132(Suppl 2):A-502; 2. Hanauer S et al. Gastroenterology 2006;130:323 33; 3. Rutgeerts P et al. Gastroenterology 2012;142: UC therapy with adalimumab Week 8 Mucosal healing 4 Improved CRP, HB and serum proteins 5 Week 4 QoL improvement 2 Clinical remission 3,4 Week 2 2 Clinical response Time (Weeks) 1. Sandborn W et al. Gastroenterology 2012;142:257 65; 2. Reinisch W et al. Am J Gastroenterol 2010;105(Suppl. 1):S441; 3. Reinisch W et al. Gut 2011;60:780 7; 4. Sandborn W et al. Gastroenterology 2012;142:257 65; 5. Reinisch W et al. Am J Gastroenterol 2010;105(Suppl 1):S428

15 New tools for clinicians Pharmacokinetic assessment of anti-tnfs Detectable levels of infliximab at trough are associated with better outcomes Clinical Remission C-reactive Protein Endoscopic Change *P<.001 * *P<.001 *P<.001 * * Undetectable 2.0 ug/ml Undetectable 2.0 ug/ml Undetectable 2.0 ug/ml Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:

16 Clinical outcomes in UC patients treated with infliximab correlate with detectable trough levels P< P< P< Patients developed undetectable levels of infliximab and then developed ATIs Seow C H et al. Gut 2010;59:49-54 Adalimumab levels correlate with CRP CRP significantly lower in ADA 5 µg/ml subjects Median, high ADA = 2.14 mg/l Median, low ADA = mg/l P = 0.002, Mann Whitney U test CRP significantly higher in ATA+ subjects Median, ATA- = 2.10 mg/l Median, ATA+ = mg/l P = 0.008, Mann Whitney U test CRP ADA- ADA+ ATA- ATA+ ATA- ATA+ ATApositive ATApositive ATA- ATA+ 48

17 Crohn s disease patients with higher baseline CRP require more adalimumab Sandborn ACG 2011 Patients develop Abs to biologics when levels nadir Thiopurines and MTX decrease clearance of biologics

18 SONIC: IFX Trough Levels at Week 30* are Higher with Concomitant AZA Median Serum Trough Levels (mg/ml) (N=97) (N=109) * Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis Sandborn, W. et al. NEJM, 2010 Trough Concentration of Infliximab is Higher With Concurrent Methotrexate 6.35 Infliximab plus µg/l 3.75 MTX+IFX IFX alone Feagan B et al. DDW Abs no. 682C.

19 Primary non-response: Risk reduction In patients with high inflammatory burden, consider Infliximab 10mg/kg for first 3 infusions and then de-escalate Adalimumab 160/80 mg dosing may need to go to weekly after load Concurrent immunomodulators Algorithm Based on Therapeutic Anti-TNF Agent Concentrations Sub-therapeutic anti-tnf concentration * Therapeutic anti-tnf concentration increase anti-tnf dose or frequency endoscopy/cte with active disease endoscopy/cte with inactive disease If no response, change to different anti-tnf agent or change mechanism of action change to Rx with different mechanism of action (non anti-tnf agent) investigate for alternate etiology of symptoms Afif W et al. Am J Gastroenteterol. 2010;105:

20 Immunomodulators can be added later if a patient is losing response to the anti-tnf or was never perfect even if they have antibodies Ben-Horin, S. et al. Clin Gastroenterology Hep 2013 What do I want to know when I see a patient? Symptoms Mild (bothered but functions at a normal capacity) Moderate (affects daily life) Severe (close to or needing hospitalization) Severity of Inflammation Superficial ulcerations Deep ulcerations / inflammatory stricture Fibrotic stricture Internal perforating disease (+/- abscess) Perianal perforating Location Limited ileal disease Extensive small bowel involvement Extensive colonic involvement Rectal disease

21 The mildest moderate patient Symptoms Mild (bothered but functions at a normal capacity) Moderate (affects daily life) Severe (close to or needing hospitalization) Severity of Inflammation Superficial ulcerations Deep ulcerations / inflammatory stricture Fibrotic stricture Internal perforating disease (+/- abscess) Perianal perforating Location Limited ileal disease Extensive small bowel involvement Extensive colonic involvement Rectal disease Who needs combination therapy? When can we use sequential monotherapy? Immunomodulators: Thiopurines MTX Anti-TNFs Biologics (immunogenic) Mechanistic synergy Higher levels of biologic Moderate-to-severe disease Extensive SB or colonic disease High inflammatory burden Steroid-refractory disease Severe prognostic markers

22 Who needs combination therapy? When can we use sequential monotherapy? Immunomodulators: Thiopurines MTX Anti-TNFs Biologics (immunogenic) Steroid-dependent disease applies to both CD / UC includes budesonide Mild course/ prognostic markers Low inflammatory burden High risk for complications from combo therapy? Esp old people So what have we learned? Combination therapy better than monotherapy for most patients Imperative not to let biologics nadir to nothing Still role for immunomodulators in steroiddependent disease Assess for inflammation, not just symptoms, when making therapeutic decisions Optimize or start immunomodulators in a patient failing biologics alone Incorporate pharmacokinetic assessment of biologic