Patients With IBD Experience Nocebo Effect Post Mandatory Switch to Biosimilar

A prospective observational study of patients in Canada with inflammatory bowel disease (IBD) undergoing mandatory switching to an infliximab or adalimumab biosimilar reported rates of clinical remission and anti-drug antibodies did not differ from baseline to 24 weeks following the switch.However, they found 13% of patients experienced the nocebo effect during this time, and about one-fifth of those patients discontinued biosimilar therapy.

The authors wrote that despite the lack of significant changes in their study in remission rates, biomarkers, therapeutic drug levels, or anti-drug antibodies, “the nocebo effect has negative impacts on treatment adherence and outcomes in real-life clinical practice.”

Crohn disease (CD) and ulcerative colitis (UC), collectively referred to as IBD, are chronic inflammatory diseases of the gastrointestinal tract with significant negative effects on quality of life. According to the investigators, treatment with biologics “revolutionized the management of IBD,” however, biologic therapy is also “the main cost driver” in IBD care. Biosimilars referencing the tumor necrosis factor (TNF)-α inhibitors infliximab and adalimumab have been approved for IBD treatment. Quebec, Canada, has instituted a mandatory nonmedical switch policy for these biologics for all patients, new and currently being treated, who are covered by public insurance.

Despite clinical trials that have demonstrated similar efficacy and safety of infliximab and adalimumab biosimilars to their reference products, the authors said treatment discontinuation rates following a switch are frequently high in real-world studies, citing an approximate discontinuation rate of 21% after 2 years. One potential reason, they said, is the nocebo effect, a negative consequence from a treatment caused by a patient’s expectations. The nocebo effect is “an important clinical concern in the current era of biosimilars, since it has a detrimental influence on drug adherence, patient quality of life, and treatment outcomes,” they wrote.

Their study aimed to evaluate clinical remission, biomarkers, therapeutic drug levels, adverse events (AEs), and the nocebo effect in patients with IBD who underwent nonmedical switching to an adalimumab or infliximab biosimilar at a Canadian medical center in 2022 and 2023. A total of 210 patients were included, 81% of whom were being treated for CD; 44% were being treated with infliximab and 56% with adalimumab; the median duration of IBD prior to switch was 12 years (IQR, 8-22), and median duration of originator treatment was 3.8 years (IQR, 1.9-6.3). The infliximab originator (Remicade) was switched to either infliximab-dyyb (Inflectra) or ABP710 (Avsola), and the adalimumab originator (Humira) was switched to adalimumab-afzb (Abrilada), GP2017 (Hadlima), adalimumab-adaz (Hyrimoz), or adalimumab-fkjp (Hulio).

Clinical Remission Rate Remained “Unchanged” 24 Weeks After Switching

Rates of clinical remission at 8 weeks prior to switching, baseline, and 12 and 24 weeks after switching were 89%, 93%, 86%, and 91%, with no significant differences between time points. Corticosteroid-free remission rates also did not differ over time at 88%, 92%, 86%, and 90%.Median disease activity, as indicated by the Harvey-Bradshaw Index (HBI) for CD and the partial Mayo (pMayo) score for UC, also did not significantly change from before to after switching. Sustained clinical remission rates at week 12 and week 24 after switching were 80% and 70%. Rates of flares and the proportion of patients who needed new systemic corticosteroids for active symptoms or flares also did not differ significantly between time points.

Level of inflammation was evaluated with serum C-reactive protein (CRP) and fecal calprotectin (FCAL). There were no significant differences in the proportion of patients who were in remission as indicated by CRP or FCAL at 8 weeks prior, baseline, and 12 and 24 weeks after switch. Rates of endoscopic remission also did not change significantly over time.

Therapeutic Drug Monitoring and Immunogenicity

Median infliximab and adalimumab trough levels at baseline, 12 weeks, and 24 weeks, were not significantly different from those 8 weeks prior to switching, and there was no significant difference in the proportion of patients maintaining the therapeutic drug level over time, at 85%, 84%, 83%, and 85%. The prevalence of antidrug antibodies was “low,” the authors said, at 2.5% of patients receiving adalimumab and 2.2% of patients receiving infliximab, and the prevalence of antidrug antibodies was not significantly different across time points.

Discontinuation of Therapy and Nocebo Effect

The authors reported drug persistence was “high” in both infliximab and adalimumab treated patients. The discontinuation rate overall was 4.8%, and the probability of remaining on biosimilar treatment at 12 weeks was 97%, with no significant difference between CD and UC cohorts or between infliximab and adalimumab treatment.

The nocebo effect was defined in this study as new or worsening clinical symptoms in the absence of objective evidence of an increase in disease activity. The nocebo effect was observed in 13% (28) of patients.

Of the 10 patients who discontinued biosimilar treatment after switching, 5 were judged to have had a nocebo effect, 4 experienced loss of response, and 1 had an acute infusion reaction. Three of the 10 patients switched back to reference biologics, and 7 switched to different biologic molecules.

AEs were observed in 20 patients (9.5%) throughout the 24 weeks of biosimilar therapy, and the authors reported there were no new safety signals. They noted that their clinical remission results were consistent with previous studies of switching to anti-TNF biosimilars in IBD. Although their results demonstrate real-world effectiveness and safety of switching to anti-TNF biosimilars from originator drugs, they said, a “significant portion” of patients experienced the nocebo effect.

Reference

Wetwittayakhlang P, Karkout K, Wongcha-Um A, Tselekouni P, Al-Jabri R, Afif W, Wild G, Bitton A, Bessissow T, Lakatos PL. Clinical efficacy and nocebo effect following non-medical biosimilar switch in patients with inflammatory bowel disease: A prospective observational study. Dig Liver Dis. 2024;56(1):35-42. doi:10.1016/j.dld.2023.06.022