The registration of the tumour necrosis factor-α inhibitor adalimumab in 2015 
was a major step forward in the treatment of hidradenitis suppurativa/acne 
inversa (HS). However, it soon became evident that the effectiveness of 
adalimumab in daily practice was highly variable. A significant unmet medical 
need of HS patients remained, and the search for novel therapeutic targets was 
intensified. During the 10th European Hidradenitis Suppurativa Foundation (EHSF) 
e.V. Conference, reknown international HS investigators virtually presented and 
discussed the published data on these potential target molecules for future HS 
treatment. This article addresses the most promising molecules currently under 
investigation from a pathophysiological and clinical point of view. With phase 
III trials ongoing, the anti- interleukin (IL)-17 biologics bimekizumab and 
secukinumab are in the most advanced stage of clinical development showing 
promising results. In addition, targeting IL-1α with bermekimab has shown 
encouraging results in two clinical trials. Directing treatment at neutrophil 
recruitment and activation by targeting IL-36 with spesolimab fits well in the 
pathogenic concept of HS and clinical phase II trial results are pending. In 
contrast to in situ evidence, Complement 5a (C5a) and C5a receptor blockade have 
only shown greater clinical benefit in patients with severe HS. Inhibition of 
Janus kinase (JAK) 1 signalling in HS showed clinical efficacy only in the 
highest dosage, highlighting that careful surveillance of the balance between 
safety and efficacy of JAK inhibition is warranted. Overall, clinical efficacies 
of all novel treatments reported so far are modest. To guide drug development, 
more and better-defined translational data on the pathogenesis of this severe 
and enigmatic inflammatory skin disease are required.