It is caused by the accumulation of neutrophils in the skin, causing painful sterile pustules to develop all over the body. Some patients will experience a relapsing disease with recurrent flares, whereas others will have a more persistent form with intermittent flares.
Left untreated, complications such as sepsis and multisystem organ failure can develop. Although rare, it is more prevalent in women than men.
Boehringer Ingelheim has developed spesolimab, a first-in-class treatment for the disease.
The drug is a humanised monoclonal antibody that inhibits interleukin-36 signalling, blocking the activation of the IL-36 receptor. This is a key part of the signalling pathway involved in GPP. Skin and blood samples collected from GPP patients taking part in a Phase I trial were compared with those from healthy volunteers.1
This showed that the antibody caused a rapid modulation of commonly dysregulated pathways in the disease. In a pivotal Phase II trial, 52 patients with a GPP flare were randomised to receive a single 900 mg intravenous dose of spesolimab or a placebo.2
Patients in both groups were able to receive an open label dose on day 8 or an open label dose as a rescue medication after day 8 and were followed for 12 weeks.
The primary endpoint was a GPP physician global assessment pustulation subscore of 0 at the end of the first week, in which 0 is no visible pustules and 4 is severe pustulation. At baseline, 46% of those in the spesolimab group and 39% of those given the placebo had a score of 3, whereas 37% and 33% had a score of 4.
At the end of the first week, 19 of the 35 patients in the active group had a score of 0 (compared with just one of the 18 patients given the placebo). However, it was associated with both infections and systemic dose reactions.
After 12 weeks, 84.4% of treated patients had no visible pustules and 81.3% had clear or almost clear skin. The antibody is also being investigated for the treatment of another chronic inflammatory skin disease, palmoplantar pustulosis (PPP), in which pustules develop on the palms of the hands and soles of the feet — and for which there is a high unmet clinical need.
In a Phase IIa double-blind, randomised, placebo-controlled pilot study, patients with PPP were given intravenous 300 mg or 900 mg doses of spesolimab or a placebo every 4 weeks until week 12.3
At week 16, 31.6% of patients in both spesolimab dose groups achieved a 50% reduction from baseline in the PPP area and severity index compared with 23.8% of the placebo group. It was well tolerated and trials continue.
References
- P. Baum, et al., J. Allergy Clin. Immunol. 149, 1402 (2022).
- H. Bachelez, et al., NEJM 385, 2431 (2021).
- U. Mrowietz, et al., Dermatol. Ther. (Heidelb.) 11, 571 (2021).
