Optimization of therapies for IBD:

Optimization of therapies for IBD:
How to fine tune management David T. Rubin, MD The Joseph B. Kirsner Professor of Medicine Chief, Section of Gastroenterology, Hepatology and Nutrition @IBDMD

Why Do We Need This? Acknowledged heterogeneity of IBD Large primary non-response Large secondary loss of response Disease changes over time Patient changes over time!

One Size Does Not Fit All

Where do we want to be? Optimal Use of Therapy for IBD

The right time not too early, not too late earlier is better but understanding of prognosis is necessary

The right time not too early, not too late earlier is better but understanding of prognosis is necessary The right dose not too little not too much (?)

The right time not too early, not too late earlier is better but understanding of prognosis is necessary The right dose not too little not too much (?) The right interval no breakthrough between doses

The right time not too early, not too late earlier is better but understanding of prognosis is necessary The right dose not too little not too much (?) The right interval no breakthrough between doses The right duration not too short not too long (?)

The right time not too early, not too late earlier is better but understanding of prognosis is necessary The right dose not too little not too much (?) The right interval no breakthrough between doses The right duration not too short not too long (?) The right efficacy: safety disease control, no AEs

The right time not too early, not too late earlier is better but understanding of prognosis is necessary The right dose not too little not too much (?) The right interval no breakthrough between doses The right duration not too short not too long (?) The right efficacy: safety disease control, no AEs The right cost!

Why aren’t we there yet? Existing classification system isn’t specific enough to direct therapy Goals for management are wrong Therapies don’t work! There is a disconnect between patient and health-care provider

Why aren’t we there yet? Variations in phenotypes Changing patterns over time Existing classification system isn’t specific enough to direct therapy Goals for management are wrong Therapies don’t work! There is a disconnect between patient and health-care provider

Why aren’t we there yet? Variations in phenotypes Changing patterns over time Existing classification system isn’t specific enough to direct therapy Goals for management are wrong Therapies don’t work! There is a disconnect between patient and health-care provider Subjective, symptom-based Crisis management and not chronic care!

Why aren’t we there yet? Variations in phenotypes Changing patterns over time Existing classification system isn’t specific enough to direct therapy Goals for management are wrong Therapies don’t work! There is a disconnect between patient and health-care provider Subjective, symptom-based Crisis management and not chronic care! Inter-patient variation Mechanisms don’t work Wrong dosing, misunderstanding of pK issues Lack of patient adherence

Why aren’t we there yet? Variations in phenotypes Changing patterns over time Existing classification system isn’t specific enough to direct therapy Goals for management are wrong Therapies don’t work! There is a disconnect between patient and health-care provider Subjective, symptom-based Crisis management and not chronic care! Inter-patient variation Mechanisms don’t work Wrong dosing, misunderstanding of pK issues Lack of patient adherence Lack of communication Misunderstanding Different expectations

We Have Made Great Progress in Phenotyping and in Therapeutics…
We Have Made Great Progress in Phenotyping and in Therapeutics…. But Not Enough!

Clinical Observations
We Have Made Great Progress in Phenotyping and in Therapeutics…. But Not Enough! Clinical Observations Regional enteritis Ulcerative colitis Treatments Empiric Evidence-based Targeted Cures

We Have Made Great Progress in Phenotyping and in Therapeutics…. But Not Enough! Clinical Observations Regional enteritis Ulcerative colitis Treatments Empiric Evidence-based Targeted Cures Phenotypes Location Behavior Age of onset Prognostic indicators Genetics Observations among affected families Co-disease associations Linkage analysis GWAS Functional genomics, etc. Immunologic Serotypes Immunotypes Environment Diet Epiphenomenon Microbiome

We Have Made Great Progress in Phenotyping and in Therapeutics…. But Not Enough! Clinical Observations Regional enteritis Ulcerative colitis Treatments Empiric Evidence-based Targeted Cures Phenotypes Location Behavior Age of onset Prognostic indicators Genetics Observations among affected families Co-disease associations Linkage analysis GWAS Functional genomics, etc. Immunologic Serotypes Immunotypes Environment Diet Epiphenomenon Microbiome Desperation Anecdotal Theoretical Poor outcomes Evidence-based Small trials Symptom-based outcomes Short-term Adoption from other diseases Step-up care Disease-modifying Top-down care? Longer-term studies Objective endpoints Chronic care model Quality of life Treat to target Objective measures Serial assessment and adjustments Improved outcomes?

We Have Made Great Progress in Phenotyping and in Therapeutics…. But Not Enough! Clinical Observations Regional enteritis Ulcerative colitis Treatments Empiric Evidence-based Targeted Cures Identifying Subtypes of Disease that Define Treatment Options Effective, Sustainable, Safe Therapies Cures for Some Patients

Factors Influencing Disease Control
Adapted from Rutgeerts P, et al. Dig Dis 2012;30:396–399.

Patient Factors Disease Factors Therapy Factors Adapted from Rutgeerts P, et al. Dig Dis 2012;30:396–399.

Patient Factors Disease Factors Therapy Factors Lag time before dx Phenotype Genotype Microbiome Immunology CRP Adapted from Rutgeerts P, et al. Dig Dis 2012;30:396–399.

Patient Factors Disease Factors Therapy Factors Lag time before dx Phenotype Genotype Microbiome Immunology CRP Resections Prior failed therapy Steroids Dose-Response Half-life Delivery Adapted from Rutgeerts P, et al. Dig Dis 2012;30:396–399.

BMI Gender Nutritional status Pharmacogenomics Adherence Smoking Disease Control Patient Factors Disease Factors Therapy Factors Lag time before dx Phenotype Genotype Microbiome Immunology CRP Resections Prior failed therapy Steroids Dose-Response Half-life Delivery Adapted from Rutgeerts P, et al. Dig Dis 2012;30:396–399.

Treatments are Aimed at Observations and Theories (the Not Cause of the Disease)
1Turnbaugh, et al. Sci Transl Med November 11; 1(6): 6ra14.

Immune modification Steroids Thiopurines/methotrexate Anti-TNFα biologicals Inhibition of other cytokines Leukocyte trafficking inhibitors 1Turnbaugh, et al. Sci Transl Med November 11; 1(6): 6ra14.

Immune modification Steroids Thiopurines/methotrexate Anti-TNFα biologicals Inhibition of other cytokines Leukocyte trafficking inhibitors Microbiota manipulation Antibiotics Prebiotics Probiotics Fecal transplantation Bacterial derived proteins Diet?1 1Turnbaugh, et al. Sci Transl Med November 11; 1(6): 6ra14.

Surgery Immune modification
Treatments are Aimed at Observations and Theories (the Not Cause of the Disease) Immune modification Steroids Thiopurines/methotrexate Anti-TNFα biologicals Inhibition of other cytokines Leukocyte trafficking inhibitors Microbiota manipulation Antibiotics Prebiotics Probiotics Fecal transplantation Bacterial derived proteins Diet?1 Surgery Resection of fibrostenosis Resection in fulminant disease 1Turnbaugh, et al. Sci Transl Med November 11; 1(6): 6ra14.

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

Clinical Predictors of Disabling Crohn’s Disease
Referred cohort of 1128 CD patients 3 factors independently predictive of a disabling CD course within 5-years Initial requirement for steroids: OR: 3.1 [95% CI: 2.2 – 4.4] Age at diagnosis below 40 years: OR: 2.1 [95% CI: 1.3 – 3.6] Perianal disease at diagnosis: OR: 1.8 [95% CI: 1.2 – 2.8] Beaugerie L et al. Gastroenterology 2006;130:650-6.

Predictors of Poor Response or Colectomy
Low serum albumin ESR >30 mm/h Bandemia Prolonged flare Active infection Hospitalization setting Severe endoscopic lesions Disease duration Stool frequency Percentage of bloody stools Body temperature >37.5 Heart rate >90 bpm Increased CRP Toxic megacolon Low hemoglobin <10.5 g/dL CRP=C-reactive protein. Lindgren SC, et al. Eur J Gastroenterol Hepatol. 1998;10: Gonzalez-Lama Y, et al. Hepatogastroenterology. 2008;55: Suzuki Y, et al. Dig Dis Sci. 2006;51: Cacheux W, et al. Am J Gastroenterol. 2008;103: Ananthakrishnan AN, et al. Am J Gastroenterol. 2008;103:

Factors contributing to primary non-response or loss of response to TNF inhibitors
No inflammation (IBS) Wrong endpoint Structural damage, i.e. stricture Bile-salt diarrhea, bacterial overgrowth, B12 deficient Celiac disease Mechanism of inflammation not TNF dependent Normal CRP1 pANCA positive?2,3 Polymorphism in IgG Fc receptor IIIa4 Smoking5 Pharmacokinetic issues 1. Louis, E et al Scandinavian Journal of Gastroenterology. 37:818. 2. Taylor, K. D., et al Gastroenterology 120:1347. 3. Esters, Net al American Journal of Gastroenterology. 97:1458. 4. Louis, E., et al Aliment Pharmacol Ther 19:511. 5. Parsi, M. A.,et al. Gastroenterology 123:707.

Factors Affecting the Pharmacokinetics of Monoclonal Antibodies
Impact on Pharmacokinetics Presence of ADAs Decreases serum mAbs Threefold-increased clearance Worse clinical outcomes Concomitant use of IS Reduces formation Increases serum mAbs Decreases mAb clearance Better clinical outcomes High baseline TNF-α May decrease mAbs by increasing clearance Low albumin Increases clearance High baseline CRP Body size High BMI may increase clearance Gender Males have higher clearance Ordas I et al. Clin Pharmacol Ther. 2012;91:635.

Factors Affecting the Pharmacokinetics of Monoclonal Antibodies
Drug Levels (Exposure) Impact on Pharmacokinetics Presence of ADAs Decreases serum mAbs Threefold-increased clearance Worse clinical outcomes Concomitant use of IS Reduces formation Increases serum mAbs Decreases mAb clearance Better clinical outcomes High baseline TNF-α May decrease mAbs by increasing clearance Low albumin Increases clearance High baseline CRP Body size High BMI may increase clearance Gender Males have higher clearance Ordas I et al. Clin Pharmacol Ther. 2012;91:635.

Fecal Loss of Infliximab (IFX) is a Cause of Lack of Response in Severe Colitis
11 pts with colitis (8 UC, 3 CD) Compared to responders, non-responders to IFX had: Higher fecal IFX concentration at day 1 (P=0.02) Lower serum IFX concentration at day 14 (P=0.03) Brandse JF, et al. Presented at DDW, May 18, Abstract 157.

Optimizing Therapies for IBD
EDUCATE your patient on what the goals of management are! Choose initial therapy based on severity, prognosis, and additional factors Don’t underdose! Have a plan for follow-up (set a time limit)

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

Choose Your Outcome Measure: “Treating to a Target”
Symptoms Growth and Development Laboratory values Mucosal healing Threshold? Valid indices (SES-CD, UCEIS) (histologic?) Surrogate markers

A Proposed Algorithm for Treatment of IBD Focused on Target Goal
Baseline assessment of disease activity by endoscopy paired with surrogate marker Treatment Escalated Until Goal Met, Patient Refuses, or Run out of Options

Baseline assessment of disease activity by endoscopy paired with surrogate marker Treatment Escalated Until Goal Met, Patient Refuses, or Run out of Options Choice of initial therapy based on severity and prognosis of patient

Baseline assessment of disease activity by endoscopy paired with surrogate marker Treatment Escalated Until Goal Met, Patient Refuses, or Run out of Options 3-6 months Choice of initial therapy based on severity and prognosis of patient Re-assessment of disease activity directly or with surrogate marker

Baseline assessment of disease activity by endoscopy paired with surrogate marker Treatment Escalated Until Goal Met, Patient Refuses, or Run out of Options 3-6 months Choice of initial therapy based on severity and prognosis of patient Re-assessment of disease activity directly or with surrogate marker TARGET ACHIEVED? Yes No

Baseline assessment of disease activity by endoscopy paired with surrogate marker Treatment Escalated Until Goal Met, Patient Refuses, or Run out of Options 3-6 months Choice of initial therapy based on severity and prognosis of patient Re-assessment of disease activity directly or with surrogate marker Clinical follow-up that includes assessment of disease stability 6-12 months TARGET ACHIEVED? Yes No

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

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

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

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

Can Treat to Target Actually be Done in IBD? (sometimes)
Retrospective analysis of patients undergoing colonoscopy for UC: Treated to target of mucosal healing: Dose adjustments in therapy. 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.

Therapy Adjustments Over Time The Concept of Disease Burden
Inflammatory burden Therapy intensity Time

Induction therapy continues at same dose as maintenance Inflammatory burden Therapy intensity Time

Induction therapy continues at same dose as maintenance Inflammatory burden Therapy intensity Time Drug

Induction therapy continues at same dose as maintenance Inflammatory burden Therapy intensity Maintenance therapy decreased/de-escalated Time Drug

Induction therapy continues at same dose as maintenance Inflammatory burden Therapy intensity Maintenance therapy decreased/de-escalated Time Drug Drug

Induction therapy continues at same dose as maintenance Inflammatory burden Therapy intensity Maintenance therapy decreased/de-escalated How long? Time Drug Drug

Examples of De-escalation of Therapy
Steroid induction  steroid-sparing maintenance therapy Steroids withdrawn 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 response3 1Van Assche, et al. Gastroenterol Jun;134(7): 2Louis, et al. Gastroenterol. 2012;142(1):63-70. 3Rubin, D’Haens, et al. ACG, Las Vegas, 2012.

The Importance of Monitoring in Stable Disease or When De-escalating Therapy
Monitoring is periodic measurement that guides the management of a chronic or recurrent condition. It can be done by clinicians, patients, or both. Different phases of monitoring are based on where in the treatment algorithm you are. Once a target is reached monitoring for disease drift or early relapse should occur. Glasziou P et al. BMJ 2005;330:644–8.

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 Calpro (mean, 95% CI/µg/g) -14 Time before relapse or end of follow-up (months) -6 1200 400 800 1000 200 600 N patients with Calpro measurement in relapsers/non-relapsers -12 -10 -8 -4 -2 4/35 6/39 9/41 11/36 27/43 33/43 37/45 P=0.001 Non-relapsers Relapsers Calprotectin Evolution CRP (mean, 95% CI/µg/g) -14 Time before relapse or end of follow-up (months) -6 30 10 20 25 5 15 N patients with CRP measurement in relapsers/non-relapsers -12 -10 -8 -4 -2 3/33 6/36 5/34 12/39 14/44 27/45 31/49 41/50 P<0.001 Non-relapsers Relapsers CRP Evolution De Suray N, et al. Presented at DDW; May 21, Abstract 864.

Patterns of Fecal Calprotectin in CD Patients After Surgery
Sorrentino, et al. Dig Dis Sci. 2012;57:1341.

600 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 No Recurrence FC (mg/kg) Sorrentino, et al. Dig Dis Sci. 2012;57:1341.

Endoscopy/beginning of treatment 600 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 No Recurrence FC (mg/kg) Sorrentino, et al. Dig Dis Sci. 2012;57:1341.

Endoscopy/beginning of treatment 600 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 No Recurrence FC (mg/kg) 400 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Recurrence – No response to treatment FC (mg/kg) 600 3000 800 Sorrentino, et al. Dig Dis Sci. 2012;57:1341.

Endoscopy/beginning of treatment 600 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 No Recurrence FC (mg/kg) 400 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Recurrence – No response to treatment FC (mg/kg) 600 3000 800 600 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Recurrence – Response to infliximab FC (mg/kg) Months Surgery Endoscopy/beginning of treatment Sorrentino, et al. Dig Dis Sci. 2012;57:1341.

Therapeutic Drug Monitoring (not just for anti-TNF therapies!)
Assessment of loss of response1 Prediction of stable response Week 14 levels predict week 52 response2 Pre-emptive dose adjustment Adjustment of levels within a “therapeutic window” enable prevention of clinical relapse3,4 Dose reduction to avoid toxicity5 1Afif, et al. Am J Gastroenterol ;105(5): 2Dubinsky. Presented at AIBD 2012. 3Vande Casteele, et al. Presented at DDW 2012. 4Vaughn, et al. Presented at DDW 2014. 5Dubinsky. Curr Gastroenterol Rep. 2003;5(6):

The Future of Drug Selection and Dosing

Future Approaches Measurement of biologic targets in order to choose therapy Additional biomarkers of response More sophisticated use of combination therapy and de-escalation strategies Pharmacogenomics Standardized disease activity methods (at home?)

Genomic Prescribing System (GPS)
from Ratain CPT 2007

Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
Arijs I, et al. Gut 2009;58: doi:10.

From Siegel and Dubinsky, 2014.

Summary – Optimization of therapies for IBD: How to fine tune management
One size does not fit all Use clinical markers of disease severity to guide initial therapy Treat to a target using a systematic assessment and approach Consider disease intensity and disease burden over time Monitor for disease drift

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