Abstract
The safety profiles and the efficacies of several biological drugs (biologics), including infliximab and vedolizumab, have been demonstrated in clinical trials as well as in real-life studies of inflammatory bowel disease (IBD) patients.1–3 Nonetheless, primary or secondary failure of a biologic may create the need to switch treatment, or even to add another biologic in a combination biologic therapy, as recently proposed. In contrast to the wealth of studies concerning the efficacies and safety profiles of biologics, there is a dearth of data regarding the optimal strategy for switching or combining biologics during the management of IBD patients.
In the current issue of the United European Gastroenterology Journal, Liefferinckx et al. 4 have addressed this very important and interesting topic, and explored the clinical and pharmacokinetic impact of the interval between stopping a biologic and commencing the next one. The authors have compared short and long washout times of switched treatment, defined as an interval <6 or >6 weeks, respectively, between the stopped monoclonal antibody (mAb) and the newly initiated one. Overall, 58 patients switched from infliximab to vedolizumab, and 13 patients switched from vedolizumab to infliximab. First, it was shown that, in terms of pharmacokinetics, the drugs' concentrations were similar in both switch-out groups, which indicates no influence of the residual mAB levels on the concentrations of the second-line mAB. Second, when assessing the efficacy of the drugs in both arms for a minimum period of 30 weeks, using parameters such as the Harvey–Bradshaw index score, the C-reactive protein level in Crohn’s disease (CD) patients and the partial Mayo score in ulcerative colitis patients, no significant differences could be documented in these efficacy parameters between the short and long washout groups. Finally, the safety profile appeared comparable between the short- and long-interval groups. However, caution should be exercised given the fact that the rate of infections in the short washout period group (30 per 100 patient-years) was numerically higher compared to 9.5 infections per 100 patient-years in the long washout period group (p = 0.12).
Very few studies have dealt with the impact of co-exposure to two biologics, either deliberately as part of combination therapy or coincidentally due to a short interval between treatments, which effectively co-exposes patients to the two agents. A previous study assessed the pharmacokinetics, efficacy and safety of vedolizumab therapy in patients, with a recent exposure to adalimumab or infliximab compared to a late exposure, with cut-offs for recent exposure of 1 and 3 months for adalimumab and infliximab, respectively. During a follow-up period of 14 weeks, no significant differences between the groups were found in number of adverse events (AEs), clinical efficacy or drug levels. 5
Another study has assessed the combination of natalizumab (anti-a4 integrin mAb) with infliximab in CD patients. Patients that received three infusions of 300 mg of natalizumab every 4 weeks, with ongoing treatment of infliximab, were compared to those treated with infliximab and placebo. Over a follow-up period of 10 weeks, no significant differences in AE incidence between the two groups were found. 6
Schiff et al. 7 compared the safety and efficacy of abatacept (cytotoxic T-lymphocyte-associated protein 4 fusion protein) for active rheumatoid arthritis in two groups of patients who stopped anti-tumour necrosis factor (TNF) drugs: the first group with a washout of at least 2 months, and the second group with a direct switch from anti-TNF to abatacept. During a follow-up time of 6 months, the safety and efficacy profiles in the two groups were comparable.
Therefore, the study by Liefferinckx et al., 4 together with the previously mentioned studies, provides important support for the management of IBD patients with a direct switch from infliximab to vedolizumab. This is also the first study to include a group of patients switching from vedolizumab to infliximab with a relatively long follow-up time. 4 It shows that a short washout period does not detrimentally affect the pharmacokinetics or efficacy of the second-line biologic. However, the study’s retrospective design, the small sample size of the group switching from vedolizumab to infliximab (n = 13) and the numeric (albeit not statistically significant) trend for higher infection rates in the shorter-interval switch group all indicate that these findings need to be interpreted with caution.
In summary, more studies like this one by Liefferinckx et al. are pertinent, in order to reassure clinicians of the safety and efficacy of a direct switch. This will not only prevent unnecessary long washout periods between biologics, but will also pave the way to new therapeutic options, such as treatment with dual biologics.