Dashboard-Driven Accelerated Infliximab Induction Dosing Increases Infliximab Durability and Reduces Immunogenicity

Background and Aims Accelerated infliximab (IFX) induction is often based on clinical parameters as opposed to pharmacokinetics (PK). We aimed to investigate the impact of dashboard-guided optimized induction dosing on IFX durability and immunogenicity in a real-world inflammatory bowel disease (IBD) setting. Methods Pediatric and adult IBD patients were enrolled in a prospective single arm intervention trial. Cumulative data from each infusion (INF), weight, albumin, C-reactive protein, IFX dose, IFX trough level, and antidrug antibody presence were used to inform subsequent INF dosing. Forecasts driven by adaptive Bayesian modeling were generated to maintain trough levels for the third (INF3) and fourth (INF4) infusions of 17 μg/mL and 10 μg/mL, respectively. The primary outcome was proportion of patients prescribed accelerated dosing (AD) intervals by INF3 (<22 days) or INF4 (<49 days). Secondary outcomes included week 52 clinical and PK outcomes. Multivariate analyses and Kaplan-Meier curves compared outcomes based on adherence to dashboard forecasts. Results Of the 180 per-protocol population, AD was forecast for 41% (INF3) and 69% (INF4) of patients with median intervals of 17 (INF3) and 39 (INF4) days. Baseline age >18 years, albumin >3.5 g/L, and 10-mg/kg dose were independently associated with lower rates of AD by INF4. Nonadherence with the INF4 forecast (n = 39) was an independent predictor of antidrug antibody (P < .0001) and IFX discontinuation (P = .0006). A total of 119 of 123 patients on IFX at week 52 were in steroid-free remission. Conclusions The application of a PK dashboard during induction can optimize dosing early to improve IFX durability and immunogenicity.

Gastroenterologists Adherence to Tumor Necrosis Factor Antagonist Combination Therapy in Inflammatory Bowel Disease

Introduction: Tumor necrosis factor antagonists (anti-TNF) therapies are used for the management of moderate to severe inflammatory bowel disease (IBD). Anti-TNF combination therapy, with immunomodulators, has been shown to reduce immunogenicity, especially for infliximab, improve treatment success rate and patient outcomes. We evaluated factors associated with gastroenterologists adherence to anti-TNF combination therapy.Methods: A retrospective cohort study was performed to evaluate the adherence of gastroenterologists (n = 14), at an inflammatory bowel disease center, to anti-TNF combination therapy. Records of patients who received Infliximab (n = 137) or adalimumab (n = 152) were obtained and their ordering physicians' data was analyzed. Gastroenterologists were divided into six groups according to their age and interest in IBD. The baseline characteristics of their patients were also obtained.Results: The proportion of patients on combination therapy in the young gastroenterologists group was higher than those in the senior gastroenterologists group for both infliximab (83.2 vs. 55.6%, respectively, P < 0.001) and adalimumab (59 vs. 30.8%, respectively, P < 0.001). Gastroenterologists with interest in inflammatory bowel disease (IBD interest group) had also more proportion of patients on adalimumab combination therapy compared to gastroenterologists with no interest in IBD (non-IBD interest group) (61.7 vs. 35.2%, respectively, P < 0.001). Gastroenterologists who were both young and have interest in IBD had more proportion of patients on combination therapy than those who were senior or had no interest in IBD for both infliximab (89.4 vs. 63.4%, respectively, P < 0.001) and adalimumab (75.9 vs. 33%, P < 0.001). The IBD interest group was also requesting more antidrug antibody level tests than those in the non-IBD interest group (41.4 vs. 12.3 tests, respectively, P < 0.001).Conclusion: Young gastroenterologists are more likely to prescribe anti-TNF infliximab and adalimumab combination therapy than senior gastroenterologists. In addition, gastroenterologists with IBD interest are more likely to prescribe adalimumab combination therapy than gastroenterologists with no IBD interest. Moreover, young gastroenterologists who have interest in IBD are more likely to prescribe both infliximab and adalimumab combination therapy than senior gastroenterologists or those with no IBD interest. In addition, gastroenterologists with IBD interest requested more anti-TNF serum drug concentrations and antidrug antibody level tests than those with no IBD interest.

A survey of pharmacokinetic bioanalytical methods in biosimilar biological license applications (BLAs) for the assessment of target and antidrug antibodies effects

The presence of circulating targets and antidrug antibodies can influence the ability of a bioanalytical method to measure therapeutic protein (TP) concentration relevant to exposure-response evaluations. This project surveyed biosimilar submissions for their bioanalytical methods. Survey results revealed that 97% of pharmacokinetic methods designed to measure theoretically free or partial-free TPs with respect to target indeed measured free or partial-free TPs when considering experimental testing results for target effects. Antidrug antibody effect is less often evaluated. The observed trend of measuring biologically active forms of TP is consistent with the scientific understanding that pharmacokinetics of biologically active forms is more likely to be relevant to the clinical responses and evaluation of clinically meaningful differences to contribute to biosimilarity assessments.

Leucine-Rich Alpha-2 Glycoprotein May Be Predictive of the Adalimumab Trough Level and Antidrug Antibody Development for Patients with Inflammatory Bowel Disease: A Sub-Analysis of the PLANET Study

<b><i>Introduction:</i></b> The aim of this study was to examine whether biomarkers are predictive of the adalimumab (ADA) trough level and antidrug antibody development in patients with Crohn’s disease (CD) and ulcerative colitis (UC). <b><i>Methods:</i></b> Using data obtained in a prospective, multicenter, observational study (PLANET), we assessed serial changes in a novel biomarker – leucine-rich alpha-2 glycoprotein (LRG) – during ADA treatment for patients with active CD and UC. We measured serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCAL) at weeks 0, 12, 24, and 52. The ADA trough level and anti-ADA antibody (AAA) were also measured at weeks 12 and 52. Correlations between the ADA trough level, AAA, and biomarkers were examined. <b><i>Results:</i></b> In all, 34 patients with CD and 47 patients with UC were enrolled. The ADA trough level at week 12 or at the time of ADA withdrawal was 8.5 ± 3.9 in the AAA-negative group (<i>n</i> = 70) and 2.9 ± 2.7 μg/mL in the AAA-positive group (<i>n</i> = 8) (<i>p</i> &#x3c; 0.0001). The ADA trough level at week 12 or at the time of ADA withdrawal was associated with pretreatment LRG (<i>p</i> = 0.0437 and <i>r</i> = −0.23). <b><i>Conclusion:</i></b> LRG, rather than CRP or fCAL, may be a marker for predicting the trough level of ADA for patients with CD and UC treated with ADA.

P001 What is the role of antidrug antibody and drug level testing in patients treated with infliximab and adalimumab?

Background/Aims Approximately 30-40% of rheumatology patients fail to respond to first-line biologics. Secondary inefficacy is mediated by immune complex formation between biologic agents and anti-drug antibodies. Anti-drug antibody testing has been undertaken at Sheffield Teaching Hospitals since October 2015. However, there are currently no national guidelines or consensus on what levels of anti-drug antibodies are clinically significant or what changes to therapy are suggested as a consequence of these tests. We aimed to review the reasons for and outcomes of anti-drug antibody levels tested at STH in patients on Adalimumab or Infliximab. Methods Retrospective review of records of all Rheumatology patients having antidrug antibody levels tested October 2015 - April 2019. Results 237 patients were included in this analysis. The mean age of patients was 48 years. 43% were male. The most common reasons for testing antibody levels were clinical evidence of a flare in disease (n = 92) and patient reported worsening of symptoms (n = 88). 66% (n = 157) of antibody levels tested were negative, 21% (n = 49) of tests were strongly positive (antibody titre &gt;50). Serum drug concentrations were subtherapeutic in 20 % (n = 47), therapeutic in 22% (n = 51) and supratherapeutic in 38% (n = 91). In 51% of patients (n = 119) the current treatment regime was continued. However, 38% (n = 90) changed biologics, and dosing schedule was changed in 2% (n = 6). Antibody titres were more likely to be strongly positive in patients who had clinically active disease compared to those who had symptoms but no clinical evidence of disease (30% vs 10% p = 0.009). Those with strongly positive antibodies were more likely to switch biologics than those with normal antibodies (84% vs 28%, p = 0.01). Patients with clinically active disease but normal antibodies and drug levels were more likely to switch biologics than patients with no evidence of active disease but positive antibodies (p = 0.03). Underlying diagnosis (p = 0.23) or concomitant DMARD use (p = 0.92) were not associated with positive autoantibodies. Of the 47 patients with subtherapeutic drug levels, 61% (n = 29) had strongly positive anti-drug antibodies and 73% (n = 34) subsequently switched biologics. 49% (n = 111) of patients had both therapeutic drug levels and normal antibodies. Of these, 22% (n = 25) switched biologics. Of the 25 patients that switched biologics 24% (n = 6) did not have evidence of active disease and 76% (n = 19) had active disease. Conclusion 33% of patients had positive autoantibodies. 39% of patients switched biologics following testing. There was no protective effect of DMARDs identified. Patients with active disease were more likely to have positive antibodies and to switch biologics than those with no clinical evidence of disease. 25% of patients had subtherapeutic drug levels. However, only 2% of patients had a dose schedule adjustment. Therefore, dosing schedule alterations could be considered in these patients prior to escalating to a more expensive biologic. Disclosure M. Cox: None. R. Smith: None. G. Wild: None. L. Dunkley: None.

rHuPH20-facilitated subcutaneous administration of monoclonal antibodies in cancer therapy

Aim: This meta-analysis aimed to evaluate the pharmacokinetics, efficacy, safety and immunogenicity of rHuPH20-facilitated subcutaneous (SC) administration of monoclonal antibody compared with intravenous (IV) administration for patients with cancer. Materials & methods: Outcomes included trough concentrations (Ctrough), overall response rate, adverse events, serious adverse events and antidrug antibody positivity rate. Subgroup analysis was also performed. Results: Five studies involving 1575 participants (788/787) were included. All studies met the non-inferiority criterion in Ctrough. No significant differences were observed in overall response rate (p = 0.12), adverse events (p = 0.05), and severe adverse events (p = 0.73) between SC and IV groups. The SC group also had lower immunogenicity than the IV group. Conclusion: rHuPH20-facilitated subcutaneous administration of monoclonal antibody is highly similar to IV administration in terms of pharmacokinetics, efficacy, and safety, but with lower immunogenicity.

Immunogenicity of antitumor necrosis factor therapy in patients with spondyloarthritis

ObjectivesTo evaluate the serum dosage of the biomedicine (DBM) and the incidence of antidrug antibody (ADA) against antitumor necrosis factor (TNF) in spondyloarthritis, and to demonstrate the influence of these parameters on the clinical efficiency.MethodsWe conducted a cross-sectional multicentric study including patients with spondylarthritis (SpA) under antiTNF (infliximab [INF], etanercept [ETA] and adalimumab [ADL]) for at least 6 months. A dosage of the ADA and DBM were practiced by the immuno-enzymatic essay.ResultSeventy one patients were recruited. Disease modifying antirheumatic drugs (DMARDs) were associated with anti-TNF in 30%. ADA was positive in 54% for INF, 33% for ADL and 0% for ETA with a significant difference(p<0.0001). Immunogenicity was correlated to a bad therapeutic response (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]≥4)(p=0.04). The DBM was inversely correlated with the rate of ADA for patients treated with INF(p<0.0001) and ADL(p<0.0001). The DBM was also inversely correlated with BASDAI of INF(p=0.03) and ADL (p=0.01). ADA was significantly associated with an anterior switch of anti TNF(p=0.04), the use of INF(p=0.002), presence of coxitis(p=0.01) and higher body mass index (BMI)(p=0.007). DMARDs associated with anti TNF were not a protective factor for positive ADA. In a multivariate study, only INF and BMI were independent factors of positive ADA.ConclusionThe ADA formation lowered the DBM and favored the therapeutic failure.

Infliximab concentrations in two non-switching cohorts of patients with inflammatory bowel disease: originator vs. biosimilar

Biosimilars are replacing originator compounds due to their similar effectiveness, safety and pharmacokinetics. Our objective was to compare the differences in pharmacokinetics and clinical outcomes between the originator infliximab (Ifx) and the biosimilar CT-P13 in a patient cohort with inflammatory bowel disease (IBD). Our cohort study included 86 patients from a historical and a prospective cohort from the start of infliximab treatment to 22 weeks later. Serum infliximab, antidrug antibody levels and other serum biomarkers were measured at weeks 0, 2, 6, 14 and 22. Remission outcomes were evaluated at weeks 14 and 22. Drug levels were measured prospectively and analysed using MANOVA. Of the 86 patients, 44 (51%) and 42 (49%) were administered the originator and CT-P13, respectively. Originator trough levels were higher than the biosimilar trough levels (35 vs. 21, 20.1 vs. 11, 6.6 vs. 2.9 and 4.3 vs. 1.7 μg/mL at weeks 2, 6, 14 and 22, respectively). A post-hoc analysis demonstrated changes in mean serum drug levels over time (p < 0.001) and according to the drug employed (p = 0.001). At week 22, 13 (81%) patients administered the originator achieved clinical remission compared with 5 (19%) patients with the biosimilar (p = 0.02). None of the patients administered the originator withdrew from the treatment compared with 7 for the biosimilar. During the study, there were significant differences in serum infliximab levels between the originator and the CT-P13 in the patients with IBD. The clinical outcomes were influenced by the type of compound administered.