Kennedy NA, et al. - Given that anti-TNF drugs are efficacious for managing Crohn's disease, but treatment failure is common, researchers identified clinical and pharmacokinetic issues predicting primary non-response at week 14 following treatment onset, non-remission at week 54, and adverse events that necessitate withdrawal of the drug. The results of this prospective, multicenter, cohort study indicate that anti-TNF treatment failure is common and forecast by low drug concentrations, which immunogenicity partly mediates. Clinical trials are necessary to examine if results can be improved via personalized induction regimens and intensification of treatment-to-target.

Methods

• The personalized anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study.
• Between March 7, 2013 and July 15, 2016, anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab were enrolled; patients were assessed for 12 months or until the withdrawal of the drug.
• At baseline, demographic data, smoking status, age at diagnosis, disease duration, location, and behavior, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded; disease activity score, weight, therapy, and adverse events were recorded at every visit, as were drug and total anti-drug antibody concentrations.
• The endpoints of treatment failure were primary non-response at week 14, non-remission at week 54 and adverse events leading to the withdrawal of the drug..
• Regression analyses was used to identify which factors were related to treatment failure.

Results

• According to findings, 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab were enrolled.
• Primary non-response occurred in 295 (23.8%, 95% CI 21.4–26.2) of 1,241 patients who were assessable at week 14.
• At week 54, non-remission occurred in 764 (63.1%, 60.3–65.8) of 1,211 patients who were assessable, and adverse events curtailed treatment in 126 (7.8%, 6.6–9.2) of 1,610 patients.
• In multivariable analysis, the only factor independently related to primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0.35 [95% CI 0.20–0.62], p=0.00038; adalimumab: 0.13 [0.06–0.28], p<0.0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab.
• Investigators found that continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12.4% [95% CI 6.9–19.9]) of 113 patients entered remission by week 54.
• In similar, week 14 drug concentration was also independently linked to non-remission at week 54 (0.29 [0.16–0.52] for infliximab; 0.03 [0.01–0.12] for adalimumab; p<0.0001 for both).
• Data reported that the proportion of patients who developed anti-drug antibodies (immunogenicity) was 62.8% (95% CI 59.0–66.3) for infliximab and 28.5% (24.0–32.7) for adalimumab.
• Suboptimal week 14 drug concentrations predicted immunogenicity and the development of anti-drug antibodies predicted subsequent low drug concentrations for both drugs.
• They observed that combination immunomodulator (thiopurine or methotrexate) therapy reduced the risk of developing anti-drug antibodies (hazard ratio 0.39 [95% CI 0.32–0.46] for infliximab; 0.44 [0.31–0.64] for adalimumab; p<0.0001 for both).
• In the case of infliximab, the multivariate analysis of the use of immunododulators and the concentration of drugs and anti-drug antibodies in week 14 showed an independent effect of the use of immunomodulators in week 54 (odds ratio 0.56 [95% CI 0.38-0.83], p=0.004).