CAG Symposium: IBD Managing Biologics Optimizing Response Waqqas Afif, MD, M. Sc., FRCPC, Assistant Professor, Department of Medicine Division of Gastroenterology McGill University Health Center
CanMEDS Roles Covered X X X Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional values in their provision of high-quality and safe patient-centered care. Medical Expert is the central physician Role in the CanMEDS Framework and defines the physician s clinical scope of practice.) Communicator (as Communicators, physicians form relationships with patients and their families that facilitate the gathering and sharing of essential information for effective health care.) Collaborator (as Collaborators, physicians work effectively with other health care professionals to provide safe, high-quality, patient-centred care.) Leader (as Leaders, physicians engage with others to contribute to a vision of a high-quality health care system and take responsibility for the delivery of excellent patient care through their activities as clinicians, administrators, scholars, or teachers.) Health Advocate (as Health Advocates, physicians contribute their expertise and influence as they work with communities or patient populations to improve health. They work with those they serve to determine and understand needs, speak on behalf of others when required, and support the mobilization of resources to effect change.) X X Scholar (as Scholars, physicians demonstrate a lifelong commitment to excellence in practice through continuous learning and by teaching others, evaluating evidence, and contributing to scholarship.) Professional (as Professionals, physicians are committed to the health and well-being of individual patients and society through ethical practice, high personal standards of behaviour, accountability to the profession and society, physician-led regulation, and maintenance of personal health.)
Dr. Waqqas Afif Financial Interest Disclosure (over the past 24 months) Commercial Interest Janssen/Abbvie Takeda/Pfizer/Merck/Shi re/ferring Prometheus/Theradiag/ Buhlmann Relationship Advisory board/consultant/investigator Advisory board Investigator
earning Objectives t the end of this session, participants will be able to: Compare the risks and benefits of combination therapy versus monotherapy in the treatment of patients with IBD Assess the utility of premedication in the treatment of patients with IBD on biologic therapy Manage the treatment of patients with IBD on biologic therapy using therapeutic drug monitoring
Combination Therapy in IBD A very long history
REACT Trial: Algorithm based Treatment with Early Combined Immunosuppression Reduced Complications in CD nter level cluster randomisation to ly combined immunosuppression orithm or current best practice patients recruited from 40 centers 1982) egular clinical review at 4 weeks and hen Q12 weeks sed algorithm to treat to target ollowed for 24 months mary endpoint: clinical remission I <5 & no steroids) at 12 months Therapeutic Algorithm for CD Khanna R, et al., La
CT Trial: Algorithm based Treatment with Early Combin Immunosuppression (ECI) Reduced Complications in CD imary endpoint mptomatic remission) s not met BUT Hospitalization, Surgery or Serious Disease Re Complications Khanna R, et al., La
100 SONIC: Mucosal Healing at Week 26 Median disease duration 2.4 years P<.001 Proportion of Patients (%) 80 60 40 20 16.5 P=.02 30.1 P=.06 43.9 0 18/109 28/93 47/107 AZA+PBO IFX+PBO IFX+AZA Sandborn WJ et al. N
SONIC Study: Serum Infliximab Trough Levels at Week 30 Serum IFX Concentration (ug/ml) 10 4.1 3.1 1 2.1 1.1 Median IFX Concentration P<0.001 3.5 1.6 19/32 13/23 N=97 N=109 0.1 0.1 IFX IFX+AZA Colombel JF et al, N Engl J Med 2010;362
DIAMOND bination therapy vs monotherapy with ADAL: Primary Endpoint at week 100 NS NS Remission rate (%) 80 60 40 71.8 72.6 68.1 79.5 20 0 n=85 n=91 n=84 n=78 ITT (NRI) ADA ADA + AZ Per protocol Matsumoto T, et al.. J Crohns Colitis 2016. Epub ahead
DIAMOND bination therapy vs monotherapy with ADAL: Primary Endpoint at wee 15 ADA Trough Level (µg/ml) p=0.084 p=0.078 10 13.2 6.5±3.9 7.6±3.6 5 0 ositive Rate of AAA (%) 6.5 7.6 4.0 n=76 n=75 n=76 n=75 AAA ADA TL ADA ADA + AZA Matsumoto T, et al.. J Crohns Colitis 2016. Epub ahea
Meta analysis: Anti TNF mono or combination therapy: Induction of clinical response (between week 4 to 14) and concomitant IMM use limumab tolizumab OR: 0.88 (0.60 1. OR: 1.01 (0.66 1. ximab OR: 2.02 (1.09 3. 0.1 1 10 Favours anti TNF mono Favours anti TNF combo stematic review of 11 RCTs in patients with luminal and/or fistulising CD who received anti TNF erapy with/without concomitant IM therapy; combination therapy was not associated with rious adverse events compared to monotherapy across all anti TNF therapies Jones J, et al. Clin Gastroenterol Hepatol 2015;13
COMMIT: MTX plus IFX in CD 00 80 60 40 20 0 76.2 77.8 55.6 57.1 Week 14 Week 50 MTX+IFX Placebo + IFX Patients with treatment success (%) Proportion of patients with treatment 100 80 60 40 20 0 p=0.63 0 4 8 12162024283236404448 Weeks since randomization MTX Placeb Feagan et al. Gastroenterology. 2014;146(3
COMMIT: MTX for the Prevention of ADA ds: 126 MTX naïve CD pts (63 w/ IFX) ATI and Trough levels (TL) were measured ATI +* (%) detectable TL (%)# TL (mg/ml)** 50% 8.0 6.35 40% 3.75 6.0 30% 25.9% 20.4% 4.0 20% 14.0% 10% 4.0% 2.0 0% 0.0 IFX IFX + MTX 0.01 **P=0.08 #P=0.13 IFX Kinetic Measurements 80% 70% 60% 50% 40% 30% 20% 10% 0% Detectable TL + treatment success** 52% IFX 72% IFX + MT Feagan et al. Gastroenterology. 2014;146(3
2016 ECCO Guidelines: CD and UC ropean Crohn s and Colitis Organisation. Anti TNF therapy. http://www.e guide.ecco ibd.eu/algorithm/anti t
Safety: Combination Therapy
ACT: Safety of Early Combined Immunosuppressio No increased risk of infections tes of Complications / SAEs Conventional Management (n=898) Early Combined Immunosuppression (n=1084) orsening Disease 92 (32%) 97 (36%) sease Related Complications 134 (47%) 113 (42%) tra Intestinal Manifestations 50 (17%) 47 (17%) ocedural Complication 2 (0.7%) 2 (0.7%) edication Related 10 (3.5%) 10 (3.7%) Khanna R, et al., La
CESAME: Risk of Lymphoma with Thiopurines Beaugerie et al. Lancet
CESAME: Risk of NMSC with Thiopurines Peyrin Biroulet et al. Gastroenterology 2011;141:1
NMSC: Risk with combination therapy likely attributable to immunomodulators f NMSC with ADA monotherapy or combination therapy compared to the general popu ients treated with adalimumab combination therapy (either with any IMM or with thiopurine) nificant 5 fold increased risk of NMSC when compared to the general population. Osterman et al., Gastroenterology 2014;146(4
Malignancies excluding NMSC: Risk with combination therapy likely attributable to immunomodulators f malignancies excluding NMSC with ADA monotherapy or combination therapy compa eneral population ients treated with adalimumab combination therapy (either with any IMM or with thiopurine) nificant 3 fold increased risk of malignancies other than NMSC when compared to the ge ulation. Osterman et al., Gastroenterology 2014;146(4)
Do we need to continue immunosuppression long term?
Meta analysis: Decreased antibody formation with IS Rx comitant IS reduced detectable ADA by 37% (RR=0.63; CI=0.42 to 0.67) Garces et al. Ann Rheum
Meta analysis: Maintenance anti TNF mono or combination therapy Jones J, et al. Clin Gastroenterol Hepatol 2015;13
ZA Dose Reduction in Patients on Combination Therapy Pharmacokinetics 50 45 40 35 30 25 20 15 10 5 0 Unfavourable evolution of IFX pharmacokinetics at Week 52 p=0.087 p=0.022 p=0.039 Cohort A n=28 Cohort B n=27 Cohort C n=26 IFX and IFX and IFX and AZA unchanged halved AZA stop AZA TRI < 1 Undetectable TRI with ATI + Del Tedesco E, et al,
Withdrawal of immunosuppression Primary Endpoint: No need for early rescue IFX 1.0 Cumulative survival 0.8 0.6 0.4 0.2 Continued Log Rank (Cox): 0735; Breslow: 0.906 Discontinued 0.0 0 20 40 60 80 100 Time (Weeks) Van Assche G, et al. Gastroenterology. 2008 Jun;134
X trough levels at the time of withdrawal predicts loss of response 223 CD on IFX maintenance rial serum samples for TLs Drobne D et al., Gastroenterology 2011; 140(5) (Suppl) S-62. (oral pres
Optimizing Therapy: Combination Therapy Consider combination therapy during induction Increased risk of malignancy with thiopurines After 6 12 months, consider ½ dose thiopurine versus low dose MTX Consider withdrawal in patients with a durable response and adequate drug concentrations
Optimizing Therapy Premedication
Premedication with IV corticosteroids in episodic therapy Decreased antibody formation with regular dosing Farrell RJ, Alsahli M, Jeen YT et al. Gastroenterology 2003; 124
medication: No decrease in infusion reactions Pediatric IBD study of 243 pts (Jacobson et al.): No decreased risk of infusion reactions with pre medications Non significant trend towards less repeat infusion reactions with pre medicat Lecluse et al., The British Journal of Dermatology. 2008;159(3):527 536. Jacobstein DA, Markowitz JE, Kirschner BS et al.. Inflamm Bowel Dis 2005;
Optimizing Therapy Post induction
Post Induction TDM ROC analysis of TLI at week 14 showed that a TLI<2.2 gave 94% specificity and 79% sensitivity for ATI forma An IFX trough level at week 14 <2.2 μg/ml predicted I discontinuation due to persistent loss of response (LO hypersensitivity reactions with 74% specificity and 82 sensitivity (likelihood ratio 3.1; P=0.0026). Vande Casteele et al. :
Post Induction TDM diatric IBD prospective cohort ypothesis: Trough levels at week 14 predict IFX durability sults Trough level at week 14 >3mcg/mL >4mcg/mL >7mcg/mL PPV for week 54 clinical remission without IFX intensification 64% 76% 100% fliximab trough level <3μg/ml: 4 fold increased risk of developing ADA Singh, N., et al.. Inflamm Bowel Dis, 2014. 20(10): p
Post Induction TDM Papamichael et al.,
Association Between Low VDZ TLs During Induction Predicts Need for Optimization Within 6 months E Mentoring in IBD Vol10:Iss04: Feb 21, 2017 ctive study of 27 CD and 7 UC pts starting VDZ, low TL s at week 6 (<19 μg/ml) are associated wit ditional doses (given at week 10 and then every 4 weeks) ients receiving these additional doses achieved a clinical response 4 weeks later Williet et al. Clin Gastroenterol Hepatol 2016 Nov 24. (16
Optimizing Therapy Maintenance Treatment
ective Controlled Trial of Trough Level Adapted Infliximab Treatment (TA CB Group IFX dosing based on clinical symptoms & CRP ntenance > Stable response Dosing based on IFX TL (3 7 µg/ml) IFX TL within optimal interval Randomized 1:1 LB Group IFX dosing based on IFX TL (3 7 µg/ml) Optimization phase Maintenance phase (n weeks) (52 weeks) eening Randomization Primary en y end point = rate of clinical (Harvey Bradshaw or Partial Mayo score) and biological (C reactive protein 5 mg/l) remission year after randomization in each group nically Based Group; LB Group= Level Based Group Vande Casteele N, et al. Gastroenterology 2015;14
TAXIT Results: Maintenance Phase Primary end point CB Group (N = 122) LB Group (N = 126) 100 P = 0.79 Patients (%) 80 60 40 20 62.3 64.3 0 Clinical Remission* *Harvey-Bradshaw index score 4 (CD) or Partial MAYO score 2 (UC) and C-reactive protein level 5 mg/l. Primary end point could not be calculated for 3 Patients (1 CD from CB and 1 UC and 1 CD from LB group). Vande Casteele N, et al. Gastroenterology 2015;14
TAXIT Results: Maintenance Phase Secondary end point (loss of response and need for an intervention).0.8.6.4.2.0 CB Group LB Group LogRank P=0.0038 Breslow P=0.0058 0 8 16 24 32 40 48 56 64 Maintenance Phase (W eeks) 17.3% of CB Group of LB Group needed therapy by the end maintenance ph 127 126 122 122 119 116 65 1 120 118 116 109 105 100 57 1 Vande Casteele N, et al. Gastroenterology 2015;14
TAILORIX: Proactive TDM in Maintenance sults: active trough level based dose ensification was not superior to dose ensification based on symptoms alone. % 100 80 Primary endpoint P=NS se increase of 2.5mg/kg as effective as g/kg 60 40 20 47 P=NS 38 40 tailed pharmacokinetic, munogenicity, and biomarker analysis nding 0 TDM 1 TDM 2 Usual Care *Steroid-free clinical remission from weeks 22-54 & absence of ulceratio ECCO 2016. OP029 G. D Haens et a
boptimal IFX concentrations of the TDM group dditional outcomes Percent of patients TDM1 TDM2 Usual care IFX dose escalation 51 65 40 Sustained IFX > 3 µg/ml weeks 14 52 47 46 60 CD Endoscopic Index of Severity < 3 49 51 45 Absence of ulcers Week 12 Week 54 36 36 16 43 40 48 ECCO 2016. OP029 G. D Haens et a
Optimizing Therapy Loss of Response
Progressive LOR to Anti TNF Therapy in CD ary non responder rate ; 20% 1. Chaparro M et al. IBD doi:10.2001/ 2. Chaparro M et al. Clin Gastro 2011;1
Variables Affecting TNF α Inhibitor Levels Immunomodulator Usage Antibody formation Drug concentration Drug clearance Anti drug antibodies Drug concentration Drug clearance Male Gender Drug clearance ow serum albumin (marker for protein losing colopathy?) Drug clearance TNF α inhibitor levels High baseline C Drug clearance High BMI Drug clearance High baseline TNF concentration Drug clearance Ordás I, et al. Clin Gastroenterol Hepatol. 2012 Oct;10(
Managing loss of response: dose intensification Dose escalation results in ~60 70% short term response 100 ADA (CHARM) IFX Madrid IFX (London) IFX (Pittsburgh) IFX (PIBDCRG) IFX (REACH) IFX (ACCENT I) CZP (PRECISE II)* CZP (WELCOME)* 80 60 40 20 % regained response ADA (New-York) ADA (Rotterdam) 0 Ben Horin S, Aliment Pharmacol
drug (and anti drug antibodies) concentrations gu which intervention is best for loss of response?
els of drug/anti drug antibodies and outcome of interventions after loss response to infliximab or adalimumab Low drug and high titer anti-drug Ab Low drug and low titer anti-drug Ab 0 0 Dose intensification Switch anti-tnf 100 80 Dose intensification Switch anti-tnf 0 60 0 40 0 p=0.03 (Log rank test) 20 p=0.02 (Log rank te 0 0 0 6 12 18 24 Months since intervention 0 6 12 18 2 Months since intervention High-titer anti-drug Ab: >4 µg/ml anti-adalimumab Ab >9 µg/ml anti-infliximab Ab Yanai H, Clin Gastroenterol Hep
Disappearance of Anti Drug Antibodies to IFX and ADA Following Immunosuppressant in IBD Rate of Antibody- Positivity Antibody-positive if levels were 12 AE/ml Intervention after antibody formation (n = 159) Anti-TNF switched/terminated (n = 118/159) Rate of Success Following Intervention (reduction of antibodies and/or inc. drug levels) 26 27 86% 70% 100% 98/376 61/226 36% n = 7 n = 10 n = 22 n = 2 Antibodies to IFX Antibodies to ADA + MTX + AZA optimize optim ctional study of 602 IBD pts receiving atnf therapy body levels measured with ELISA and RIA, respectively (Sanquin) Strik et al. ECCO 2016
e titer of measurable antibodies predicts response to dose escalation versus switch
Anti TNF concentrations
Drug concentration is adequate and IBD inflammation: switch out of class is better than anti TNF optimization (anti-tnf optimization = dose-increase or switch in-class) 00 80 Out-of-class 60 40 p=0.006 (Log rank test) Adequate: IFX >3.8 µg/ml ADL >4.5 µg/ml 20 Anti-TNF optimisation 0 0 6 12 18 24 Months since intervention Yanai H, Clin Gastroenterol Hep
roved outcomes using TDM Fraction of Patients (%) 100 80 60 Response: Subtherapeutic IFX 86 40 33 20 0 p <0.016 n = 29 n = 6 Increase IFX Change Anti-TNF Fraction of Patients (%) 100 80 60 40 20 0 Result: Detectable ATI p <0.004 17 92 n = 17 n = 12 Increase IFX Change Anti- gle centre, retrospective study, n = 155 pts with TDM test s ELISA assay Afif et al. Am J Gastroenterol 2010;105:
Dose Optimization Using TDM is More Effective Than Dose imization Based on Clinical Assessment Alone Clinical Outcomes Post Dose Adjustment Trough Lev 69 66 57 * P < 0.05 * * 47 2 1.5 1 0.5 0.3 TDM-based (n=88) Clinically-based (n=130) 0.7 * P < 0.05 * 0.5 1.0 * Median IFX TL (ug/ml) 10 P < 0.05 Clinical response Endoscopic remission 0 Hospital admissions 1 TDM BD pts IFX dose optimization following secondary LOR (2008 2014) based optimization led to higher rates of clinical response, endoscopic remission, italization and flares (all p < 0.05) improvement in symptoms + biomarkers markers and/or endoscopic response; Remission: Mayo subscore 1 or SES CD < 3 or Rutgeert s score i1, Assay: Prometheus HMSA Kelly et al. DDW 2015, Abstra Flares Clin
TDM Results and Algorithm
rify that the patient is taking the drug! p to 15% 29% of adalimumab/infliximab-treated patients are no adherent to their injections (Missed at least one injection/infusion during the last 3 months) Billioud V, et al. Inflamm Bowel Dis 2011;1 Lopez A, et al. Inflamm Bowel Dis 2013;19
Dynacare A 8 ug/ml = 1 Heron and Afif, GCNA, 2017 (ahea
Optimizing therapy for differing phenotypes Perianal fistulising disease 117 Crohn s patients with perianal fistulising disease Higher concentration for fistula healing vs active fistulas. Median infliximab trough level 18.5μg/mL versus 6.5μg/mL, P<0.0001 Incremental improvement in perianal fistula healing Trough level (ug/ml) 2.9 10.1 20.2 Fistula healing rate % 65 79 86 Yarur, A., et al., 514. Gastroenterology, 2016. 150(4, S1): p. S
Optimizing treatment using TDM in IBD Secondary loss of response/partial response: yes Post induction prior to maintenance therapy likely Maintenance therapy in patients in remission no Withdrawal of immunosuppression in combination therapy yes Dose de escalation After drug holiday Use for UST and VDZ yes yes likely Heron and Afif, GCNA, 2017 (ahead of
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