Treat to Target in IBD: Which Targets, and Why Does it Matter?

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1 Treat to Target in IBD: Which Targets, and Why Does it Matter? Stephen B. Hanauer, MD Clifford Joseph Barborka Professor of Medicine Northwestern University Feinberg School of Medicine Chicago, IL

2 Disclosures Grants/Research Support: AbbVie, Amgen, Genentech, GlaxoSmithKline, Janssen, Luitpold/American Regent, Novartis, Novo Nordisk, Pfizer, Prometheus, Receptos, Sanofi-Aventis, Takeda, UCB Pharma Consultant/Speaker Bureau: AbbVie, Actavis, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Ferring, Forest Labs, Genentech, Glenmark, GSK, Hospira, Janssen, Luitpold/American Regent, Novartis, Novo Nordisk, Pfizer, Prometheus, Receptos, Salix, Sanofi-Aventis, Seattle-Genetics, Shire, Takeda, UCB Pharma Advisory Board Membership/Drug Safety Monitoring Board: Bristol- Myers Squibb

3 Where Did the Treat-to-target Approach Come From? Originally developed in cardiovascular (CV) disease CV disease is common and associated with considerable morbidity and mortality Trial designs progressed from treatment vs placebo to standard treatment vs intensive treatment Symptom-control strategies evolved into preventative treatment strategies Treating to target improved patient outcomes, by increasing patients chances of surviving a CV event Atar D, et al. Ann Rheum Dis 2010;69:629 30

4 Similarities Between Other Diseases and IBD? Hypertension, type 2 diabetes and rheumatoid arthritis Chronic progressive diseases Failure to treat early and effectively can lead to serious complications and disability Disease management has evolved over time Significant advances in treatment Insights into the importance of early and optimized therapy Focus on a treat to target approach to achieve tight control Pincus T, et al. Arthritis Reumatism 2002;46:851 4

5 Treatment Targets in Management of Chronic, Progressive Diseases Condition Diabetes Hypertension Rheumatoid arthritis Treatment target <7% HbA1c BP: 140/90 mm Hg (135/80 mm Hg for diabetes patients) LDL-cholesterol: 70 mg/dl to decrease incidence of cardiac events Remission Low disease activity

6 Potential Implications of a Treat-to-target Approach Hypertension, type 2 diabetes and rheumatoid arthritis Treatment algorithms are based on treatment targets e.g. achieve absence of disease activity in 3 6 months in RA Frequent monitoring is recommended so that treatment can be optimised e.g. HbA1c monitoring every 3 months in patients with diabetes Modification of the target for high-risk patient groups e.g. lower blood-pressure target of 130/80 mmhg in patients with both hypertension and type 2 diabetes Early disease states are recognised e.g. pre-hypertension, pre-diabetes Diabetes: ADA. Diabetes Care 2011;34(Suppl. 1):S1 98; Hypertension: ESH/ESC Task Force. Eur Heart J 2007;28: ; Rheumatoid arthritis: Smolen JS, et al. Ann Rheum Dis 2010;69:631 7

7 Rheumatoid Arthritis: Tight Disease Control Associated With Higher Remission Rate Patients randomized to intensive management (sustained, tight control of disease activity) or routine care Outcome measures for intensive management vs routine care: Mean fall in DAS: -3.5 vs -1.9 (p<0.0001) Good response: 82% vs 44% of patients (p<0.0001) Remission: 65% vs 16% of patients (p<0.0001) DAS: Disease Activity Score Good response defined as DAS <2.4 and a fall of >1.2 from baseline Remission defined as DAS <1.6 Grigor C, et al. Lancet 2004;364:263 69

8 Rationale Behind Treat to Target in RA Rheumatology and management of RA have reached a new era: Significant advances in treatments Significant advances in validated composite measures Enhanced understanding of optimal treatment strategies Despite this, there is a wide heterogeneity of outcome expectations and treatment strategies in daily clinical practice Clear outcome targets and tight disease control have to be integrated into standard practice

9 Mission of Treat to Target Provide: Clear direction on treatment target(s) and tight control Applicable in daily practice Defining a clinical state where irreversible structural damage and disability is avoided

10 Applying T2T to IBD

11 T2T in IBD? 1 The primary treatment target should be a state of clinical remission Remission defined as absence of signs and symptoms of significant inflammatory disease activity While remission should be target, low disease activity may be acceptable alternative goal, particularly in established disease Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months Use of validated measures of disease activity of utmost importance in routine clinical practice to guide treatment decisions???

12 T2T in IBD? 6 7 Measures of disease activity obtained and documented regularly; e.g. monthly for high/moderate disease activity, less frequently (3-6 months) for patients in sustained low disease activity or remission Structural changes and functional impairment should be considered when making clinical decisions? 8 Desired treatment target should be sustained throughout course of disease? 9 Desired treatment target should be sustained throughout course of disease? 10 Patient has to be appropriately informed about the treatment target and the strategy planned to reach this target

13 Goals of Therapy in IBD Current Induce (clinical) remission Maintain (clinical) remission Prevent complications Therapy Disease Future goals Disease modification Prevent disease progression & complications Neoplasia Strictures / fistulae Surgery Disability Pharmacoeconomics Direct / indirect costs

14 Bowel damage Inflammatory Activity and Progression of Bowel Damage in a Theoretical Patient With CD Surgery Stricture Stricture Fistula/abscess Inflammatory activity (CDAI, CDEIS, CRP) Disease onset Diagnosis Early disease Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.

15 Severity (arbitrary units) Rheumatoid Arthritis Progression Inflammation Disability Radiographs Early RA Intermediate Late Duration of disease (years) ACR Graph: Adapted from Kirwan JR. J Rheumatol 2001;28:881-6 Photo: Copyright American College of Rheumatology

16 Treat-to-target Approach Has Been Adopted in Other Therapy Areas Treatment targets Diabetes <7% HbA1c Rheumatoid arthritis Remission Low disease activity Hypertension BP: 140/90 mmhg (135/80 mmhg for diabetic patients) LDL-cholesterol: 70 mg/dl (to lower incidence of cardiac events) Diabetes: ADA. Diabetes Care 2011;34(Suppl. 1):S1 98; Hypertension: ESH/ESC Task Force. Eur Heart J 2007;28: ; Rheumatoid arthritis: Smolen JS, et al. Ann Rheum Dis 2010;69:631 7

17 Potential Issues with Treating to Target Examples where T2T is harmful Tight glucose control in ICU Confirming value of TARGET vs alternative endpoints Risk/Benefit Pharmacoeconomics Particularly in early disease populations Conflicts of Interest Multi-sponsored (Pharma?) Multi-endorsed (Societies) Is target achievable in majority of patients?

18 Is a Treat-to-target Approach Feasible in IBD? Symptoms QoL Labs CRP Calpro? Mucosal healing Hospitalisations Surgery Biologic (Deep remission) Histologic remission Disease modification

19 What are the Components of Deep Remission? Inflammatory symptoms Laboratory evidence of inflammation CRP, calprotectin, etc. Endoscopic healing Histologic healing (e.g. UC) Stabilization of Imaging (structural damage)

20 What is Disease Modification in IBD? Symptom resolution Stabilized QoL (Quality of Life) and PRO (Patient Reported Outcomes) Reduced disease/therapy complications Structural damage EIMs Neoplasia Reduced disability Improved pharmacoeconomics Direct/indirect costs

21 Treating IBD Beyond Symptoms: Rationale for a Clear Management Strategy Personalized management for IBD will depend on: Disease severity at presentation Clinical and biologic prognostic factors Achievement of clinical and biologic remission Maintenance of clinical and biologic remission Patient adherence Therapeutic monitoring Pharmacoeconomics

22 Cumulative probability (%) Impact of Therapy Will Depend on Degree of Structural Damage and Speed of Progression Penetrating Inflammatory Stricturing Patients at risk: Months N = Cosnes J et al. Inflamm Bowel Dis. 2002; 8:

23 Crohn s Disease Activity Index (CDAI ) Relationship Between Clinical Symptoms & Endoscopic Indices at CD Presentation R=0.13; NS Crohn s Disease Endoscopic Index of Severity (CDEIS) Modigliani R et al. Gastroenterology. 1990; 98:811.

24 Log CRP mg/l Relationship Between CDAI & CRP 100 Low CDAI- High CRP High CDAI-High CRP 10 ULN Low CDAI- Low CRP High CDAI-Low CRP Baseline CDAI Gastroenterology, (4):

25 Mucosal Healing and Time to Colectomy in Infliximab-treated Patients Proportion Without Colectomy or Infliximab Use Endoscopy subscore = 0 Endoscopy subscore = 1 Endoscopy subscore = 2 Endoscopy subscore = Which target? 0.75 p< Time to colectomy or infliximab use (weeks) Colombel JF et al. Gastroenterology. 2011;141:

26 % Patients Comparison of Outcomes for Patients with Deep Remission vs Clinical Remission on QOL No difference between Deep and Clinical Remission DR (N=11) Absence of mucosal ulceration only (N=8) Clinical remission only (N=19) Week-52 IBDQ remission Normal week-52 SF-36 PCS CD-related hospitalisation Colombel, JF. Clin Gastroenterol Hepatol Mar;12(3):414-22

27 WPAI Component Score Week 52 Comparison of Outcomes for Patients with Deep Remission vs Clinical Remission on Work Productivity No difference between Deep and Clinical Remission DR Absence of mucosal ulceration only Clinical remission only TWAI TAI 23 Colombel, JF. Clin Gastroenterol Hepatol Mar;12(3):414-22

28 Summary Current therapeutic strategies for IBD do not modify long-term sequelae Therapies based on symptoms not prognosis Similar to other chronic diseases, treating to prognostic markers can improve long-term outcomes Prospective studies are needed to confirm: Prognostic criteria Relevance of individual (composite) targets Impact on long-term outcomes (benefits/risks) Socioeconomic values of targeted approach

29 Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target IOIBD Working Group

30 Objective To achieve international expert consensus on appropriate evidence-based treatment targets for IBD to be used in treat-to-target strategies in routine clinical practice

31 Methods Systematic literature review and generation of draft recommendations Broad search questions What is the target? How can it be measured? Is the target already used as a target in clinical studies/trials? What are the data supporting the proposed target? 15,681 references in literature search 905 analyzed and used to develop draft recommendations

32 IOIBD Recommendations for Treating to Target UC 1. Resolution of rectal bleeding and normalization of bowel habit should be the target 2. Resolution of symptoms alone is not a sufficient target. CD 1. Resolution of abdominal pain and normalization of bowel habit should be the target 2. Resolution of symptoms alone is not a sufficient target. Objective evidence of inflammation of the bowel is necessary when making clinical decisions.

33 IOIBD Recommendations for Treating to Target Resolution of clinical symptoms and inflammation are goals of treatment that define remission Mucosal healing was recommended as therapeutic goal in clinical practice Associated with better outcomes in both cohort studies and randomized controlled trials

34 IOIBD Recommendations for Treating to Target UC 3. A Mayo Clinic endoscopic subscore of 0 is the optimal target. A Mayo Clinic endoscopic subscore of 1 should be a minimum target. CD 3. Absence of ulceration is the target. While a Mayo Clinic sub-score of 0 is target, there is insufficient evidence to recommend it in all patients Only a Mayo Clinic sub-score of 0-1 can be systematically recommended in clinical practice For CD, the absence of ulceration should be the target

35 IOIBD Recommendations for Treating to Target UC 4. Endoscopic assessment should be performed within 3 to 6 months after the start of therapy for a patient with symptoms. CD 4. Endoscopic or cross-sectional imaging assessment should be performed within 6 to 9 months after the start of therapy.

36 IOIBD Recommendations for Treating to Target UC 5. Histopathology is a sensitive measure of inflammation but is not a target due to lack of evidence of clinical utility. CD 5. Histological remission is not a target. Level of evidence was insufficient to recommend histological healing as target in UC or CD in clinical practice Important to acknowledge role of histopathology in the evaluation of inflammation in patients with UC

37 IOIBD Recommendations for Treating to Target UC 6. Cross-sectional imaging is not a target in UC. CD 6. When endoscopy cannot adequately evaluate inflammation, resolution of inflammation as assessed by cross-sectional imaging is a target. Endoscopy is more mature instrument for defining mucosal healing Defining normalization of inflammation using imaging is less well established Cross-sectional imaging is not a universal target, although role in patients with CD not adequately assessed by colonoscopy

38 IOIBD Recommendations for Treating to Target UC 7. Available biomarkers including CRP and calprotectin are not targets. 8. CRP & calprotectin are adjunctive measures of inflammation for monitoring Failure of CRP or calprotectin normalization should prompt further endoscopic evaluation, irrespective of symptoms. CD 7. Available biomarkers including CRP and calprotectin are not targets. 8. CRP and fecal calprotectin are adjunctive measures of inflammation for monitoring Failure of CRP or calprotectin normalization should prompt further endoscopic or radiologic evaluation, irrespective of symptoms.

39 IOIBD Recommendations for Treating to Target Biomarkers are not a target because insufficient evidence to recommend treatment optimization by taking into account biomarkers alone Biomarkers may reflect residual intestinal inflammation, but endoscopy and/or MRI should be performed before optimizing medical treatment Biomarkers facilitate monitoring of a patient rather than being a target for treatment

40 IOIBD Recommendations for Treating to Target UC 9. Primary patient-reported outcome (PRO)-Resolution of rectal bleeding and normalization of bowel habit 10. In addition to resolution of rectal bleeding and altered bowel habit Patient s individual goals should also be addressed CD 9. Primary PRO-Resolution of abdominal pain and normalization of bowel habit 10. In addition to resolution of abdominal pain and altered bowel habit Patient s individual goals should also be addressed.

41 IOIBD Recommendations for Treating to Target UC 11. Frequency of outcome assessment should be tailored to patient s symptoms, with minimum frequency of every 3 months until resolution. Frequency of outcome assessment after symptom resolution should be at least every 6-12 months. CD 11. Frequency of outcome assessment should be tailored to the patient s symptoms, with minimum frequency of every 3 months until resolution. Frequency of outcome assessment after symptom resolution should be at least every 6-12 months.

42 IOIBD Recommendations for Treating to Target PROs are extensive and varied Ultimate PRO is normalization of quality of life achieved through resolution of symptoms and inflammation Acknowledging great variability in symptoms, particularly in CD, other individual symptoms affecting quality of life must be addressed The goals of treatment should be tailored to the individual patient, and agreed to by them

43 IOIBD Recommendations for Treating to Target: Composite Endpoints UC 12. Clinical/PRO remission defined as resolution of rectal bleeding and diarrhea/altered bowel habit, assessed at a minimum of 3 months during active disease and Endoscopic remission defined as resolution of friability and ulceration at sigmoidoscopy or colonoscopy, assessed at 3 month intervals during active phase. CD 12. Clinical/PRO remission defined as resolution of abdominal pain and diarrhea/altered bowel habit, assessed at a minimum of 3 months during active disease and Resolution of ulceration at ileocolonoscopy, or resolution of inflammation on cross sectional imaging assessed at 6 9 month intervals during active phase.