Treating to Achieve a Target and Disease Monitoring in 2015: State of the Art

Treating to Achieve a Target and Disease Monitoring in 2015: State of the Art David T. Rubin, MD The Joseph B. Kirsner Professor of Medicine Chief, Section of Gastroenterology, Hepatology and Nutrition @IBDMD

Disclosures Consultant: AbbVie, Amgen, Janssen, Pfizer, Prometheus, Takeda, UCB Grant support: AbbVie, Amgen, Janssen, Pfizer, Prometheus, Takeda, UCB

Digestive damage Evolving Treatment Strategies in IBD Traditional: Failure of conventional therapy (optimized? AEs?) Perianal disease Evolving: Based on prognosis (smoking, young age of diagnosis, severe endoscopic lesions) As a result of treat to target Inflammatory activity (CDAI, CDEIS, CRP)

A Proposed Definition of Optimal Use Therapies in IBD the best result obtainable under specific conditions The right time: not too early, not too late The right dose: not too much, not too little The right interval: no breakthrough between infusions The right duration: not too short, not too long? The right efficacy:safety: disease control, no AEs

Evolving Endpoints and Treatment Strategies

Historical Treatment Strategies are Flawed Step-Up Dirty Therapy Disease severity at presentation? Severe Cyclosporine/Tacrolimus Natalizumab Anti-integrin Anti-TNF Anti-TNF (UC)/ Thiopurine/MTX (CD) Moderate Corticosteroids Aminosalicylate (UC)/ Thiopurine/MTX (CD) Mild Aminosalicylate Aminosalicylate Induction Maintenance time

Problems with Existing Treatment Strategies Don t accurately reflect heterogeneity of patient types. Require failure of one step or class before moving onto another. Reactive rather than proactive. Historically symptom-based or complication-based rather than based on objective markers. Imply static treatment levels and do not address changes over time. New therapies tend to be added to the end of the line rather than positioned earlier or more thoughtfully.

How Can We Do This Better? Choosing therapies based on prognosis as well as severity Utilizing validated objective endpoints of disease control Understanding therapy risk in the context of disease risk Adjusting therapies serially until endpoints are achieved Optimizing therapies to match disease severity and inflammatory burden

How Can We Do This Better? Choosing therapies based on prognosis as well as severity Utilizing validated objective endpoints of disease control Understanding therapy risk in the context of disease risk Adjusting therapies serially until endpoints are achieved Optimizing therapies to match disease severity and inflammatory burden

Movement to Objective Measures of Control and Chronic Care Model of IBD: Improved Outcomes Goal Clinical parameters Outcomes Response Improved symptoms Improved QoL Remission No symptoms Normal labs Decreased hospitalization Deep remission Normal endoscopy Mucosal healing Avoidance of surgery Minimal/no disability SUSTAINED DISEASE CONTROL

What is Treat to Target? Example from Rheumatology Shared decision-making between RA patient and doctor Focus on higher risk groups Primary goal: maximize health-related quality of life Control of symptoms Normalization of function and social participation Prevention of progressive structural damage Abrogation of inflammation is the most important mean to achieve goals Treatment to target by measuring disease activity and adjusting therapy accordingly optimizes outcomes in RA Smolen JS et al. Ann Rheum Dis. 2010;69:631.

What Might Be the Target in IBD? Symptoms Growth and Development Laboratory values Mucosal healing How to measure? (SES-CD, UCEIS) What about histology? Surrogate markers

STRIDE: Selecting Therapeutic TaRgets in Inflammatory Bowel Disease Endpoints Methods: 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Results: 12 recommendations for UC and CD. UC TARGET: PRO: resolution of rectal bleeding and diarrhea/altered bowel habit and endoscopic remission: Mayo endoscopic subscore of 0-1. Histological remission is an adjunctive goal. CD TARGET: PRO: resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission: resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal CRP and calprotectin) was considered an adjunctive target. Peyrin-Biroulet, et al. Am J Gastroenterol. 2015, accepted.

Studying Treat to Target in IBD Can it be done? Does it work?

Retrospective Analysis of Patients Having Colonoscopy for UC: Treatment Adjustments to Achieve Targets 1. Treated to target of mucosal healing: Dose adjustments in therapy. 2. Not treated to target of mucosal healing: No change in therapy. Mucosal healing Histologic healing Bouguen G et al. Inflamm Bowel Dis 2014;20(2):231-9.

Prospective REACT Trial: Algorithm based treatment with early combined immunosuppression reduced complications in Crohn s Disease Center-level cluster randomisation to early combined immunosuppression algorithm (ECI) or current best practice (CM) Therapeutic Algorithm for Crohn s Disease 1982 patients recruited from 40 centres Regular clinical review every 4 or 12 weeks Used algorithm to treat to target Primary end-point: Clinical Remission (HBI <5 & no steroids) Khanna R, et al. Presented at DDW, 2014 Abstract 342.

Prospective REACT Trial: Algorithm based treatment with early combined immunosuppression reduced complications in Crohn s Disease Conclusions: There was no difference in clinical remission (primary endpoint). There were significantly reduced rates of surgery and serious complications in the ECI group (secondary endpoints). Hospitalization, Surgery or Serious Disease-Related Complication HR = 0.73 (0.62, 0.86) Khanna R, et al. Presented at DDW, 2014 Abstract 342.

Using Treat to Target to Aid Patient Discussions

Getting Your Patient on Effective Therapy Shared Decision Making Discuss the risk of untreated or ineffectively treated disease Agreement in goals (improved quality of life, avoidance of surgery and hospitalization, etc) Negotiate trial of therapy and plan of followup Perception of risk changes with efficacy Individualize risk Use of objective disease monitoring tools to assess and to communicate disease activity (Treat to Target) Negotiated follow-up (short-term) to reassess disease activity OBJECTIVELY Rubin DT, Krugliak Cleveland N. Am J Gastroenterol. 2015 Apr 7. (In press)

Monitoring: How and When?

The Five Phases of Disease Monitoring Glasziou P et al. BMJ 2005;330:644 8.

In IBD, Many Faces of Monitoring Individualized Approaches Patients, Providers or Both Pre-treatment: what markers correlate with disease activity? Scope? Symptoms/PRO? CRP/fecal calprotectin Initial titration: what markers can be used to address or predict response to therapy? Disease-related and therapy-related CRP/fecal calprotectin Metabolites, serum drug levels Maintenance: what markers can monitor for disease drift or relapse (and distinguish from patient-described flare )? Cessation or de-escalation: how to monitor for relapse or breakthrough after de-escalation

Fecal Calprotectin (µg/g) Evolution of Disease Monitoring Fecal Calprotectin calcium and zinc-binding protein derived from neutrophils and monocytes Patient Reported Outcomes and Monitoring The GI Monitor 1,500 1000 500 0 0 1 2 3 4 Endoscopic Activity (Modified Baron Score) Schoepfer A, et al. Inflamm Bowel Dis. 2013;19(2):332-41. http://www.wellapps.com/ accessed September 29, 2014

Mesalamine Dose Escalation for Clinically Quiescent UC Decreases Fecal Calprotectin (FC) Multicenter open-label RCT in UC patients in remission on 5-ASA <3 g/day (N=119) 58 patients with fecal calprotectin<50 µg/g continued on current therapy 52 patients with fecal calprotectin>50 µg/g randomized to stable or increased dose of MMX mesalamine Results More patients in dose escalation group achieved primary and secondary outcomes than stable-dose mesalamine No serious AEs Continued Remission at Week 6 In clinically quiescent UC, increasing mesalamine may lower fecal calprotectin to levels associated with lower relapse rates 26 patients on alternative 5-ASA switched to MMX mesalamine for 6 weeks and 17/26 proceeded to randomization (3 flares, 4 non-adherent). Osterman M, et al. Presented at DDW; May 6, 2014. Abstract 862.

Clinical Assessment of Disease Control Routine inquiry regarding stability of disease control (stable maintenance between doses) Strict adherence to maintenance regimen Ongoing laboratory assessment of clinical stability Increasing utilization of surrogate markers of inflammatory activity (fecal calprotectin)

Use of Therapeutic Drug Monitoring in IBD Titration Phase Maintenance Phase Stopping/De-escalation Phase

Early Assessment of Drug Levels Correlates with Longer Term Response Crohn s disease: detectable week 14 infliximab trough levels are associated with week 54 efficacy outcomes 1 adalimumab trough levels predict sustained clinical response 2 Ulcerative colitis: higher infliximab concentration at week 8 associated with higher weeks 30 and 54 clinical remission rates 3 rapid clearance of infliximab leads to ATI, non-response 4 1. Singh N et al. Inflamm Bowel Dis. 2014 Oct;20(10):1708-13. 2. Karmiris K et al. Gastroenterology. 2009;137:1628. 3. Adedokun OJ et al. Gastroenterology. 2014 Dec;147(6):1296-1307. 4. Kevans D et al. DDW, 2012.

Trough Levels of Drug Correlate with Clinical Response Higher levels assoc with mucosal healing with infliximab 1, adalimumab 2, certolizumab pegol 3 Associated with response, remission 4 But optimal levels are in a range 5 1. Hanauer SB, Lancet 2001. 2. Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84. 3. Colombel JF et al. Glin Gastroenterol Hepatol 2013. 4. Seow CH et al. Gut 2010;59:49-54. 5. Chiu et al. Inflamm Bowel Dis. 2013.

Probability on infliximab Dose Optimization Increases Probability of Remaining on Infliximab Up to 5 years Retrospective cohort of patients in clinical remission, single physician practice Infliximab dose optimisation to trough concentrations 5 10 µg/ml (n=48) No infliximab dose optimisation (n=78) 100 80 60 p=0.0006 40 20 0 0 Optimised Not optimised 100 200 300 400 500 600 700 Weeks on infliximab Vaughn BP et al. Inflamm Bowel Dis.. 2014;20:1996 2003

Inflammatory burden Therapy Adjustments Over Time The Concept of Disease Burden Induction therapy continues at same dose as maintenance How long? Maintenance therapy decreased/de-escalated Therapy intensity Time Drug Drug

Examples of De-escalation of Therapy Steroid induction steroid-sparing maintenance therapy Steroids withdrawn Therapeutic drug monitoring of infliximab dose reduction? Concomitant IMM + anti-tnf therapy Maintained on combo therapy Possibility of withdrawing IMM (IMM experienced) 1 Possibility of withdrawing anti-tnf (Crohn s disease) 2 5-ASA? MOMENTUM study shows 4.8 g/d 2.4 g/d IF complete response 3 1 Van Assche, et al. Gastroenterol. 2008 Jun;134(7):1861-8. 2 Louis, et al. Gastroenterol. 2012;142(1):63-70. 3 Rubin, D Haens, et al. ACG, Las Vegas, 2012.

Patients (%) Relapse-free survival Optimized Infliximab Levels (3-7 mcg/ml) Associated with Stable Maintenance (TAXIT study) Clinically based (CB) and trough level based (LB) groups 100 p=0.79 1.0 80 62.3 64.3 0.8 60 40 0.6 0.4 LogRank p=0.0038 Breslow p=0.0058 20 0 (N=122) (N=126) CB group LB group Clinical remission 0.2 CB Group LB Group 0 0 8 16 24 32 40 48 56 64 Maintenance phase (weeks) TAXIT: Prospective controlled Trough level Adapted infliximab Treatment Vande Casteele N, et al. Gastroenterol.2015.

CRP (mean, 95% CI/µg/g) Calpro (mean, 95% CI/µg/g) Monitoring of CRP and Fecal Calprotectin Predicts Clinical Relapse in CD Patients after Infliximab Withdrawal: A Sub-Analysis of the STORI Study Lead clinical relapse by 4 mo CRP of 6.1mg/L and calprotectin of 305mcg/g best for prediction of relapse 30 CRP Evolution P<0.001 1200 Calprotectin Evolution P=0.001 25 1000 20 800 15 Non-relapsers Relapsers 600 Non-relapsers Relapsers 10 400 5 200 0 N patients with CRP measurement in relapsers/non-relapsers -14-12 -10-8 -6-4 -2 0 Time before relapse or end of follow-up (months) 3/33 6/36 5/34 12/39 14/44 27/45 31/49 41/50 0 N patients with Calpro measurement in relapsers/non-relapsers -14-12 -10-8 -6-4 -2 0 Time before relapse or end of follow-up (months) 4/35 6/39 6/39 9/41 11/36 27/43 33/43 37/45 De Suray N, et al. Presented at DDW; May 21, 2012. Abstract 864.

Baseline assessment of disease activity by endoscopy paired with surrogate marker A Proposed Algorithm for Treatment of IBD Focused on Target Goal Treatment Escalated Until Goal Met, Patient Refuses, or Run out of Options Choice of initial therapy based on severity and prognosis of patient 3-6 months Re-assessment of disease activity directly or with surrogate marker Disease Monitoring De-escalation? TARGET ACHIEVED? 6-12 months No Yes Discussion with patient treatment options Clinical follow-up that includes assessment of disease stability Clinical follow-up No Is patient willing to proceed with your recommendations? Adjust therapy Yes Treat to Target 3-6 months

Optimizing Therapies for IBD: Therapy-Specific Approaches 5-ASA: maximize dose and delivery Delivery may be impaired in distal colitis Dosing Steroids: don t over treat too long, especially when they aren t working Thiopurines: metabolites can show adherence, shunting profiles allopurinol Anti-TNF: therapeutic drug monitoring immunogenicity, rapid clearance, predict likelihood of response Additional mechanisms to consider: Diversion and bowel rest Calcineurin inhibitors Novel therapies

Future of Patient Disease Monitoring: Home Fecal Calprotectin (FC) Comparison* of Home FC (CalproSmart, n=638) with FC Analyzed in Lab (ELISA, n=894) in IBD Patients (N=221) CalproSmart >600 μg/g 200-600 μg/g <200 μg/g 4.4% inter-assay variability 10.9% intra-assay variability 150 ug/g FC cut-off rho=0.685, P<0.0001 Total test time: 25 minutes *Measured monthly for 6 months. Burisch et al. Presented at DDW; May 19, 2015 Oral Presentation 1024.

Summary: Treating to Achieve Target and Disease Monitoring Movement to objective endpoints of management Precision medicine approaches may include a treat to a target using a systematic assessment and serial adjustments of therapy to achieve validated endpoints Monitoring is key to achieving goals and keeping patients well Monitor for response to therapy, adherence, and disease drift De-escalation is possible