Il ruolo degli anticorpi anti farmaco nella pratica clinica Daniela Pugliese, MD IBD Unit Complesso Integrato Columbus Gemelli Hospital Catholic University Foundation, Rome - Italy
Therapeutic Drug monitoring Drug Dose Effect drug is absorbed, distributed, metabolized and eliminated by the body PK Blood concentration PK-PD What the drug does to the body Therapeutic Drug Monitoring Measuring of drug concentration in blood to help individual dose adjustment Concept of optimal therapeutic window
Pharmacokinetic profile of IV or SC administered TNF agent according to a theoretical maintenance dosing regimen Peak level Intermediate level Trough level Trough level «trough level» for therapeutic drug monitoring 3 Adapted from Vande Casteele N et al. J Clin Pharmacol 2015
Factors affecting the PK of mabs Impact on PK Presence of anti-drug antibodies (ADAs) Concomitant IS High baseline TNF Low albumin High baseline CRP Body size Gender Decrease serum mabs Threefold increase clearance Worse clinical outcome Reduces ADA formation Increases serum mabs Decreases mabs clearance Better clinical outcome Increase mabs clearance Increase mabs clearance Worse clinical outcome Increase mabs clearance High BMI increases clerance Males have higher clearance Ordas I, CPT 2012
Infliximab trough levels correlate with outcomes CD UC 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% P< 0.001 P<0.001 P<0.001 15% 69% Remission 28% Undetectable 76% Endoscopic improvement Detectable 55% 7% Colectomy Higher trough serum IFX concentrations associated with better outcomes Maser E, et al. CGH 2006; Seow CH, et al. Gut 2010
Median serum infliximab TL in patients with and without sustained response to scheduled maintenance infliximab (ACCENT I) Cornillie F, et al. Gut 2014
Adalimumab trough levels correlate with clinical response ADA TL: 2.1 [0.8 4.1] vs 6.1 [3.2 11.5] g/ml; P.02; Higher trough serum ADA concentrations associated with better outcomes Karmiris K, et al. Gastroenterology 2009
Antibodies to adalimumab are associated with future inflammation in CD patients receiving maintenance therapy (post-hoc analysis of the Karmiris trial) Baert F, et al Gut 2015 p<0.001)
Higher Adalimumab drug levels associated with more UC clinical remission at week 8 (ULTRA 2) Drug level quartiles &clinical remission at Week 8 Linear model fit for drug levels clinical remission at Week 8 Patients in remission (%) 50 40 30 20 10 8.6% 17.2% 19.0% 25.9% Probability (%) of remission per Mayo Score 50 40 30 20 10 p <0.001 0 n=58 n=58 n=58 n=58 5 >5 to 8 >8 to 11.7 >11.7 Adalimumab trough concentration quartiles (µg/ml) 0 0 4 8 12 16 Adalimumab concentration (µg/ml) Wolf D, et al. Aliment Pharmacol Ther 2014
Correlation of anti-tnf drug levels with control of inflammation p<0.0001 p<0.0001 p<0.0001 100 90 (P<0.001) 10.0 Mucosal healing (%) 80 70 60 50 40 30 20 Infliximab concentration at Week 54 (μg/ml) 1.0 0.1 10 0 <1.9 1.9 4.9 4.9 6.0 >6.0 Adalimumab trough level (µg/ml) 0 n= 53 105 49 109 75 83 No Yes No Yes No Yes Clinical response Mucosal healing Clinical remission ACT 1 Roblin X, et al. Clin Gastroenterol Hepatol 2014 Adedokum OJ, et al. Gastroenterology 2014
Drug Level Versus Clinically Based Dosing of IFX Maintenance Therapy in IBD (TAXIT) Primary endpoint: Clinical (HBI/PMS) and biologic (CRP<5 mg/l) remission at 1 year N=226 p=0.07 n = 111 n=115 Undetectable TL more frequent in CB than in LB (RR 3.7; 95% CI 1.7-8.0; p<0.001) Higher frequency of ATI in CB vs. LB (RR 3.3; 95% CI 1.4-7.7; p<0.01) Vande Casteele et al, Gastroenterology 2015
Drug-Concentration Versus Symptom-Driven Dose Adaptation of Infliximab in Patients with Active CD: a Prospective, Randomized, Multicenter Trial (Tailorix) A prospective randomized, double-blinded, multicenter (27 centers) controlled trial in 122 biologic naïve adult patients with active CD At Week 14, after induction with 3 infusions of IFX 5 mg/kg + AZA, patients were randomized to 1 of 3 different maintenance strategies: 1. dose intensification of IFX in (maximally 2) steps of 2,5 mg/kg based on clinical symptoms, biomarker analysis and serum IFX concentrations drawn before the previous infusion (Group 1) 2. dose intensification of IFX from 5 to 10 mg/kg based on the same criteria (Group 2) 3. IFX dose increase to 10 mg/kg based on clinical symptoms alone (Group 3) In this prospective randomized exploratory trial in patients with active CD, proactive trough-level based dose intensification was not superior to dose intensification based on symptoms alone. D Haens G et al, ECCO 2016, OP029
Loss of response to anti-tnf alpha Infliximab 13% per patient-year of FU (annual risk) 12-month Loss of response in case series and in RCTs ranges between 23% and 46% Adalimumab 20% per patient-year of FU (annual risk) Ben-Horin S, et al. APT 2011 Gisbert JP, et al. AJG 2009; Billioud V, et al. AJG 2011
Why do treatment failures occur?
Scheduled IFX therapy Loss of response: ATI & IFX trough levels Responding patients Complete loss of response ATI positive ATI negative P Detectable IFX in sera 14 (33%) 57 (85%) <0.001 Mean IFX level (ug/ml) 3.3±4.6 11.8±12 <0.001 Ben-Horin S et al, Gut 2011
Managing loss of response Dose intensification Dose escalation results in ~60% response rates of regained response to anti-tnf intensification regimen Ben-Horin S, et al. APT 2011
Levels of adalimumab drug and anti-drug antibodies: association with outcome of interventions after loss of response to adalimumab Clinical remission (%) 100 80 60 40 20 p<0.01 n=82 High drug and Low Ab Low drug and Low Ab Low drug and high Ab 0 After dose increase After switch to IFX Low drug and Low Ab more remission with dose-increase Low drug and high Ab more remission with switch to IFX Roblin X, et al Am J Gastroenterol 2014
Levels of drug/anti-drug antibodies and outcome of interventions after loss of response to anti-tnfs Low drug and high titer anti-drug Ab Low drug and low titer anti-drug Ab Maintained re-gained response (%) 100 80 60 40 20 0 Dose intensification Switch anti-tnf p=0.03 (Log rank test) 100 80 60 40 20 0 Dose intensification Switch anti-tnf p=0.02 (Log rank test) 0 6 12 18 24 Months since intervention 0 6 12 18 24 Months since intervention Yanai H, et al. Clin Gastroenterol Hepatol 2015 High-titer anti-drug Ab: >4 µg/ml anti-adalimumab Ab >9 µg/ml anti-infliximab Ab
Individualised therapy vs dose intensification in patients with CD who lose response to anti-tnf Randomised, single-blind, multicentre Danish study in CD (n=69) Patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) or interventions based on serum IFX and IFX antibody levels 10 Intention-to-treat Per protocol -50% -25% 0% 25% 50% True difference Cost per patient, mean 8 6 4 2 *p<0.001 * * IFX intensification Algorithm IFX intensification better Algorithm better 0 0 4 8 12 Study week Co-primary clinical endpoint in intention-to-treat and per protocol populations. Dashed lines illustrate the predefined non-inferiority margin Co-primary economic endpoint in per protocol populations. Data are average treatment per patient Steenholdt C, et al. Gut 2013
Loss of response to anti-tnf alpha and therapeutic drug monitoring Maintenance on anti-tnf No sign of LoR: Sign of LoR: same maintenance dose perform trough levels and ADA* Trough levels detectable (high/therapeutic): disease assessment Trough levels undetectable/low: If inflammation: Stop and switch out of class If healing: Search other cause for symptoms (e.g. stenosis, bacterial overgrowth, IBS) No or low ADA*: optimize (decrease interval, increase dose, consider adding IM) High ADA*: Switch within class *ADA: Anti-drug antibodies
Relapse Rate After Discontinuing anti-tnf in longterm deep remission is lower when nil drug levels Undetectable drug Measurable drug levels 48 patients stopped IFX (n=35) or adalimumab (n=13) in deep endoscopic remission P<0.001 (Log rank test) Months since anti TNF cessation - Ben-Horin S, et al. APT 2015
Long-Term Outcome of Patients With CD Who Discontinued anti-tnf Therapy Upon Clinical Remission MH TL 52% of patients remained in Sustained Clinical Remission after a median FU of 9.7 years (IQR 8-11.5) Papamichael K, et al. CGH 2015
Conclusions Drug levels of anti-tnfs are associated with outcome in IBD (exposure-response relationship) Antibody status is not clearly associated with outcome, but is important in understanding reasons for LoR to anti-tnf and could guide therapeutic decisions For LoR to anti-tnf, clinical interventions based on TDM of TL and ADA result in lower treatment costs Undetectable TL in patients with stable long-term remission may identify a subset of patients whose clinical remission is no longer dependent on anti-tnf treatment