Identification of strong correlations of clearance with clinical outcomes for inflammatory bowel disease

Abstract

BACKGROUND

Low drug concentrations have been linked to antidrug antibody (ADA) formation. High clearance is a major reason for low drug levels leading to treatment failure in patients with inflammatory bowel disease (IBD) receiving infliximab (IFX).

AIM

To explore the predictive value of initial IFX clearance on outcomes and assess the impact of Bayesian model (iDose)-guided IFX dosing on clearance and outcomes during induction and early maintenance treatment.

METHODS

Data from a Phase 3 study of 220 CT-P13/originator IFX-treated patients with Crohn’s disease were used to develop probability models for outcomes including mucosal healing (MHEAL), biomarker response [C-reactive protein (CRP)], ADA development, a composite endpoint and time to first ADA formation, based on initial clearance. Subsequently, patients with characteristics suggesting rapid initial clearance were enrolled in a ≤ 120-day (October 2018 to December 2019) compassionate use program of iDose-guided IFX treatment as a proof of concept to determine if the probabilities from initial clearance could be improved with individualized therapy. Serial serum IFX concentrations, clearance, outcome probabilities, and treatment outcomes were analyzed.

RESULTS

In the CT-P13 study, population pharmacokinetic was consistent with previously published models. Initial clearance was a significant predictor of several outcomes including MHEAL, CRP normalization, a composite endpoint ((1) CDAI at week 54 was at least 150 points less than baseline; (2) MHEAL at week 54; (3) CRP was in normal range at week 54; and (4) FCP was less than 250 at week 54) and ADA formation. In the proof-of-concept study, 10 patients received iDose-guided IFX treatment. Initial clearance ranged from 0.017 L/day to 1.11 L/day, prompting up to three IFX infusions within the first 2 weeks. Two patients were discontinued due to ADA. Generally, clearance slowed over time and inflammatory biomarker levels improved. There were no adverse effects.

CONCLUSION

Initial IFX clearance correlates with efficacy metrics and ADA formation. These probability curves may be useful to identify patients at risk of treatment failure or ADA who may benefit from individualized therapy. iDose-guided treatment successfully achieved targeted serum IFX concentrations, reducing risk of ADA formation. Proactive therapeutic drug monitoring and targeted dosing based on early IFX clearance may improve treatment outcomes for patients with IBD.

Keywords: Antidrug antibodies; Bayesian model-guided dosing; Clearance; Inflammatory bowel disease; Infliximab; Pharmacokinetics; Therapeutic drug monitoring

Core Tip: There have been several evaluations of the relationship between therapeutic antibody clearance and outcomes. Data from a large study in patients administered infliximab at the labeled dose were used to assess the probability of antidrug antibodies, C-reactive protein normalization, and mucosal healing based on baseline clearance. A compassionate use study further evaluated these correlations, and clearance often decreased from baseline due to individualized dosing, suggesting improvements in the probability of all outcomes. While this study was small, the results are encouraging and suggest that further research on the use of clearance as a therapeutic endpoint is warranted in this area.