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Improving treatment outcomes for patients with chronic inflammatory diseases through identification of predictive biomarkers and therapeutic drug monitoring of new biologicals

Psoriasis and inflammatory bowel diseases (IBD), with Crohn’s disease (CD) and ulcerative colitis (UC) being the two main subtypes, are chronic inflammatory diseases of the skin and gastrointestinal tract, respectively. Together, these lifelong debilitating diseases affect up to 4% of the Western population and typically have a relapsing-remitting disease course that significantly impacts the patient’s quality of life. With the introduction of biologicals, including anti-TNF monoclonal antibodies and more recently, anti-integrin and anti-interleukin monoclonal antibodies, the treatment outcomes of patients with chronic inflammatory diseases significantly improved. However, the efficacy of these biologicals can vary greatly between patients. Some patients do not respond to treatment (primary non-responders), while others initially respond to treatment but lose response over time (secondary non-responders). An inadequate treatment response can be caused by insufficient exposure to the drug because of a high inflammatory burden or consequent to the development of anti-drug antibodies. Alternatively, mechanistic failure may be an underlying cause for non-response, which implies that other inflammatory pathways than those targeted by the biological, are the main drivers of the disease.

Therapeutic drug monitoring (TDM), i.e. the measurement of drug concentrations, has emerged as a valuable tool to optimize the management of patients with chronic inflammatory diseases. For anti-TNF biologicals (e.g. infliximab, adalimumab), multiple studies have shown that higher serum drug concentrations are associated with improved therapeutic outcomes including clinical, biological, and endoscopic response and fewer surgeries and hospitalizations. Consequently, monitoring drug concentrations could identify patients that are underexposed to the drug and who might benefit from treatment optimization. Furthermore, anti-drug antibodies have been linked to lower drug concentrations and loss of response. Therefore, the measurement of both drug and anti-drug antibody concentrations can shed light on what is happening with the drug in the patient and objectively evaluate potential reasons for treatment failure. For vedolizumab and ustekinumab, the value of monitoring drug and anti-drug antibody concentrations is underexplored because information on the relationship between serum drug concentrations and treatment response (i.e. concentration-response relationship) is still limited and questions concerning immunogenicity have yet to be elucidated. In this respect, the aim of this PhD project was to evaluate the value of monitoring drug and anti-drug antibodies in patients with chronic inflammatory diseases treated with vedolizumab or ustekinumab.

In chapter II, we developed a drug-tolerant assay to measure both free and drug-bound anti-vedolizumab (AVA) antibodies and evaluated the immunogenicity in vedolizumab-treated IBD patients who stopped treatment. Using the drug-tolerant assay, 3 (8%) out of 40 vedolizumab-treated IBD patients who discontinued therapy were AVA positive at week 6 of treatment, whereas no AVA were detected at the last infusion nor 12-20 weeks after treatment discontinuation. Considering the low prevalence and transient nature of AVA in this cohort of patients who discontinued vedolizumab therapy, these findings indicate that immunogenicity of vedolizumab is not the driving force of treatment failure. In this study, primary non-responders had numerically lower median vedolizumab concentrations at week 6 compared to patients with loss of response. Hence, underexposure during induction might partially be responsible for primary non-response.

In chapter III, we determined vedolizumab concentrations in gastrointestinal colonic tissue to evaluate whether insufficient tissue exposure could explain non-response in UC patients with adequate serum vedolizumab concentrations. A significant positive correlation was observed between vedolizumab serum and colonic tissue concentrations, regardless of the macroscopic inflammatory state of the tissue. In the full cohort, vedolizumab tissue concentrations were lower in non-responders than in responders. In the subgroup of patients with adequate vedolizumab serum concentrations, tissue vedolizumab was not significantly different between responders and non-responders. Hence, insufficient tissue exposure does not explain non-response in UC patients with adequate serum vedolizumab concentrations.

In chapter IV, we evaluated the concentration-response relationship of ustekinumab throughout the first 24 weeks of treatment in CD patients and explored the time points at which ustekinumab levels could identify patients achieving endoscopic remission. Concentration-time profiles showed that patients achieving endoscopic remission have a higher area under the curve, hence a higher ustekinumab exposure, than patients not achieving endoscopic remission. Ustekinumab concentrations were significantly higher in endoscopic remitters compared to non-remitters at trough and multiple intermediate time points. Therefore, monitoring ustekinumab concentrations at various trough and intermediate time points during the first 24 weeks of treatment, could help to identify patients achieving endoscopic (non)-remission.

In chapter V, we investigated the relationship between ustekinumab serum concentrations during maintenance at the intermediate time point 4-week postinjection and clinical response in moderate-to-severe psoriasis patients. A significant negative correlation was observed between absolute PASI score and ustekinumab concentrations up to 5.9 µg/mL. Ustekinumab concentrations were higher in optimal responders (PASI ≤ 2) than in suboptimal responders (PASI > 2). The ustekinumab concentration threshold associated with optimal response was determined to be 3.6 µg/mL. Only one patient (2%) had anti-ustekinumab antibodies measured with a drug-sensitive assay. These findings demonstrate the presence of a concentration-response relationship at week 4 after injection in ustekinumab-treated psoriasis patients. Monitoring 4-week postinjection ustekinumab concentrations could timely identify underexposed patients who might benefit from treatment optimization.

In conclusion, the immunogenicity of vedolizumab is low and not the driving force of treatment failure in vedolizumab-treated IBD patients. Monitoring drug concentrations in patients with IBD or psoriasis treated with vedolizumab or ustekinumab is useful and could guide clinicians in the treatment optimization of biologicals.

Date:28 Aug 2017 →  31 Dec 2021
Keywords:Therapeutic drug monitoring, Inflammatory bowel disease, Psoriasis, Immunogenicity, Vedolizumab, Ustekinumab, Biologicals
Disciplines:Dermatology, Gastro-enterology, Clinical trials, Diagnostics, Pharmacology not elsewhere classified, Biopharmaceuticals
Project type:PhD project