New and Emerging Therapies for Patients with Psoriasis

Due to a better understanding of the pathogenesis of psoriasis, many novel therapies have been developed (Figure 1). Today, psoriasis is not seen as a skin disease but a systemic inflammatory disease with both IL-17A and IL-17F being key drivers of pathogenesis.

The most effective way to achieve complete clearance

Bimekizumab is an agent that blocks both IL-17A and IL-17F. A recently published meta-analysis, dedicated to systemic treatments for patients with plaque psoriasis, revealed that patients treated with bimekizumab are most likely to achieve a PASI 100 response, equivalent to complete skin clearance. As Prof. Puig pointed out, bimekizumab is superior to substances like ixekizumab and secukinumab than only address IL-17A. “The beauty of bimekizumab is that it can tackle IL-17A and IL-17F. By blocking these cytokines, we are able to provide a high degree of a complete clearance,” Prof. Puig said.

Prof. Puig’s explanation for the superiority of bimekizumab lies in the fact that in psoriasis, IL17F levels are 30-fold higher than IL-17A levels. This applies not only to lesional skin but also to serum of patients with psoriasis.

According to Prof. Puig, other advantages of the dual specific antibody bimekizumab are its speed of action and maintenance of the degree of response, with close to 80% of the patients remaining on PASI 100.

Another way to block IL-17A and F

The trivalent nanobody sonelokimab is also able to block IL-17A and IL-17F. The agent is currently under investigation in phase-2b trials. It has an N-terminal moiety that specifically binds to IL-17F, a central moiety binding to serum albumin for stabilization and a C-terminal moiety binding at IL-17A and IL-17F.

Prof. Puig pointed out another potential advantage of this substance: After therapy is stopped, there is only a very slow decrease in efficacy, but 78% of participants re-achieved an investigator´s global assessment score (IGA) of 0 corresponding to completely clear skin when the drug was restarted. “Retention of skin clearance after seven half-lives following randomised withdrawal is a commonality of all drugs that can provide remission”, Prof. Puig said. Maintenance of skin clearance for seven half-lives was observed in 50% of patients taking sonelokimab, and even in 70% of patients treated with the IL-23 inhibitor risankizumab. Time to relapse seems to correlate with the ability of agents to lower tissue resident memory cells, he added. This is also an explanation why super-responders to treatment are patients with a short disease duration.

A drug which is also in phase-2 trials in psoriasis is izokibep. It has IL-17A/F + albumin + IL-17F binding domains and has been tried in several indications. It is characterized by good penetration into tissue. PASI 90 was achieved in up to 70% of patients in a phase 2 trial.

Spesolimab, a humanized monoclonal antibody, that binds to the IL-36 receptor and prevents binding of IL-36, is the only approved agent to treat generalised pustular psoriasis flares in adults. Unfortunately, therapy was disappointing in palmoplantar pustular psoriasis that is often refractory to treatment.

Oral therapy with a very good safety profile

Deucravacitinib is a highly selective, allosteric TYK2 (tyrokinase) inhibitor that has been approved by the European authorities (EMA) in 2023 as a first selective TYK2-inhibitor for treatment of adult patients with moderate to severe plaque psoriasis. The substance selectively inhibits the TYK2 pathway (> 50% inhibition) and has only minimal effects on JAK1-3 pathways (< 2% inhibition), which explains its good safety profile. Deucravacitinib inhibits IL-12/IL-23 and type 1 interferon pathways. “The drug tends to be relatively slow during onset, but the response keeps on climbing”, Prof. Puig said . More TYK2 inhibitors are expected to enter the therapeutic arena in psoriasis.