Another anti‐interleukin ( IL )‐17 inhibitor: is there an advantage of blocking IL‐17A and IL‐17F ?

Linked Article: Oliver et al. Br J Dermatol 2022; 186:652–663. Bimekizumab is the fourth biologic inhibiting interleukin (IL)-17 that has been approved for the treatment of plaque-type psoriasis in Europe.1 Do we need it? IL-17 inhibitors are more heterogeneous than the group name implies. Secukinumab and ixekizumab directly inhibit IL-17A, while brodalumab blocks IL-17-receptor alpha and as a consequence inhibits IL-17A, IL-17C, IL-17E and IL-17F.2 Bimekizumab finds a middle way, and selectively inhibits IL-17A and IL-17F.1 One could assume that these marginal differences do not have a clinical impact, but the study by Oliver and colleagues3 published in this issue of the BJD helps us to better understand the molecular mechanisms of bimekizumab. The study preceded the published phase III studies, but gives us insight into the basis on which successful dosing intervals were chosen. This elegant trial of 49 randomized patients showed nicely that two doses of bimekizumab 4 weeks apart almost normalized the transcriptome of lesional skin to nonlesional levels. The effect was not limited to inflammatory parameters, but the 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100) peaked at week 12, that is 8 weeks after the second dose. This response, in combination with the transcriptome data, permitted comparison of 4-week and 8-week dosing intervals, while the 12-week dosing interval could be eliminated based on the poor response in this study.3 One of the subsequent phase III studies was a head-to-head comparison of secukinumab and bimekizumab.4 It showed clear clinical superiority of bimekizumab for PASI 100 regardless of the maintenance dosing interval (every 4 weeks vs. every 8 weeks) over time. However, the significantly increased effectiveness came at the expense of clinical safety. Oral candidiasis was found in 19·3% of the bimekizumab patients while oral candidiasis was found in only 3% of secukinumab patients.4 Although predominantly mild to moderate in severity, this increase in candida infections is concerning because IL-17A and probably even more in combination with IL-17F is thought to protect skin and mucosa from yeast and fungal infections.5 So, beyond the clinical effectiveness these mechanistic differences may have implications for clinical safety, particularly as risk factors for candida infections like obesity and diabetes are common in the psoriasis population.6 At the same time, mucocutaneous candidiasis is often easily treated, and may be more of a nuisance than a threat. A recent review has not found published cases of deep fungal infections in patients on other IL-17 inhibitors.7 In conclusion, this elegant study gives us new insight into molecular proof of concept and definition of dosing intervals for psoriasis medications, and is well worth reading. If nothing else it is a beautiful piece of clinical and molecular investigation. The study demonstrates that inhibiting IL-17F increases efficacy and extends dosing intervals. Given the problem of candidiasis, patients and physicians have to decide what they find more important. This is best done based on real-world data.