Spesolimab for generalised pustular psoriasis

Background:
Generalised pustular psoriasis (GPP) is a rare and severe form of pustular psoriasis characterised by flares of widespread sterile pustules with erythematous, painful skin. GPP can be experienced at all ages but is most common in adults between 40 and 50 years. Several genetic mutations have been linked to GPP, particularly in the interleukin-36 (IL-36) subgroup of the interleukin-1 (IL-1) family. There is wide variation in the severity of GPP, both in the level of persistence and in the frequency and intensity of flares. GPP may cause serious morbidity, with constitutional signs and symptoms of systemic inflammation (fever, extreme fatigue, elevated C-reactive protein) and extra-cutaneous visceral involvement including liver, kidney failure and cardiovascular shock.¹ It is associated with increased mortality, which is directly attributable to either GPP or to treatment.¹

A range of drugs is used in the treatment of GPP, including retinoids, cyclosporin, methotrexate and biologic medicines;^1,2 however, there is limited evidence to support their use, mostly from uncontrolled observational studies.³ Spesolimab provides a new option to manage the flares that are such a debilitating and serious characteristic of GPP.¹

Mechanism of action:
Spesolimab is a humanised monoclonal IgG1 antibody that binds to IL-36 receptors.¹ Dysregulation of the IL-36 group is implicated in a range of autoimmune and inflammatory conditions,⁴ and has been specifically identified as central in the pathogenesis of GPP.⁵ Spesolimab blocks activation of IL-36 mediated inflammatory and profibrotic pathways, and is linked to improved clinical outcomes in GPP.

Clinical trials:
The main study demonstrating efficacy of spesolimab was Effisayil 1.⁶ This was a double-blind randomised controlled trial that recruited 53 patients (mean age 43 years). It compared a single 900 mg intravenous dose of spesolimab (n=35) with placebo (n=18) in patients with flares of GPP, as diagnosed using the European Rare and Severe Psoriasis Expert Network (ERASPEN) criteria, and irrespective of IL-36 gene mutation status. Severity of the flare was assessed at 1 week following treatment using the Generalised Pustular Psoriasis Physician Global Assessment (GPPGA) score, that assesses the cutaneous manifestations of GPP; erythema, scaling and pustulation, where scores range from 0 (clear) to 4 (severe).^7,8 After 1 week, 19 (54%) of the spesolimab-treated patients compared with one (6%) in the placebo group had no pustules; 15 (43%) of treated patients had a total GPPGA score of 0 or 1 compared with 2 (11%) in the placebo group.⁶

After 1 week, all patients were offered an open-label dose of spesolimab if flare symptoms persisted.⁶ Twelve patients in the spesolimab group received a second dose on day 8; at week 12, 25 (71%) had a GPPGA score of 0 or 1 and 21 (60%) had no pustules.

Adverse effects:
Safety data have been pooled across studies examining use of spesolimab for a range of clinical conditions, including other dermatological conditions and inflammatory bowel disease (which are not currently approved indications in Australia). The most serious adverse effect is an increase in the risk of infection. Most infections observed were of the urinary and upper respiratory tracts; these were mild to moderate. In the Effisayil 1 study, in the 1-week treatment period, 17% of patients treated with spesolimab compared with 5.6% in the placebo group reported an infection. One infection (urinary tract) in the treatment group was reported as serious.⁹ Other commonly reported adverse effects (1 to 10% occurrence) are fatigue and itch.⁹

Dosage and administration:
A single dose of 900 mg (2 × 450 mg/7.5 mL vials diluted in 85 mL of saline) is administered as an intravenous infusion over 90 minutes and not longer than 180 minutes. If flare symptoms persist, this dose may be repeated after 1 week.

Precautions:
Spesolimab should not be used in people with any active infection that is considered clinically important.⁹ Hypersensitivity reactions are a risk with all monoclonal antibody treatments.⁹ Spesolimab is not approved for treatment of life-threatening flares of GPP including when a patient requires intensive care treatment.⁹

Use in pregnancy and breastfeeding:
Spesolimab is a category B1 drug. Although no increase in fetal malformation or other direct or indirect harm has been observed, there are very limited safety data related to pregnancy. The recommendation is to avoid spesolimab in pregnancy and during breastfeeding.^1,9

Place in therapy:
Spesolimab has demonstrated clinical efficacy in the treatment of flares associated with GPP and is the first drug to be approved specifically for this indication. The potential role of spesolimab in prevention of flares is the subject of ongoing study.¹⁰

This new drug comment was finalised on 20 May 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Therapeutic Goods Administration. Australian Public Assessment Report for Spevigo. Department of Health and Aged Care; 2024. [cited 2025 May 15]
2. Psoriasis. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2025. [cited 2025 May 15]
3. Puig L, Choon SE, Gottlieb AB, Marrakchi S, Prinz JC, Romiti R, et al. Generalized pustular psoriasis: A global Delphi consensus on clinical course, diagnosis, treatment goals and disease management. J Eur Acad Dermatol Venereol 2023;37:737-52.
4. Queen D, Ediriweera C, Liu L. Function and Regulation of IL-36 Signaling in Inflammatory Diseases and Cancer Development. Front Cell Dev Biol 2019;7:317.
5. Sugiura K, Fujita H, Komine M, Yamanaka K, Akiyama M. The role of interleukin-36 in health and disease states. J Eur Acad Dermatol Venereol 2024;38:1910-25.
6. Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. Trial of Spesolimab for Generalized Pustular Psoriasis. N Engl J Med 2021;385:2431-40.
7. Burden AD, Bachelez H, Choon SE, Marrakchi S, Tsai TF, Turki H, et al. The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score: online assessment and validation study of a specific measure of GPP disease activity. Br J Dermatol 2023;189:138-40.
8. Burden AD, Bachelez H, Choon SE, Marrakchi S, Tsai TF, Turki H, et al. The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score: online assessment and validation study of a specific measure of GPP disease activity - supplementary materials. Br J Dermatol 2023;189.
9. Therapeutic Goods Administration. Australian Product Information - SPEVIGO spesolimab (rch) 450 mg in 7.5 mL concentrated solution for infusion vial. Department of Health and Aged Care; 2023. [cited 2025 May 19]
10. Morita A, Strober B, Burden AD, Choon SE, Anadkat MJ, Marrakchi S, et al. Efficacy and safety of subcutaneous spesolimab for the prevention of generalised pustular psoriasis flares (Effisayil 2): an international, multicentre, randomised, placebo-controlled trial. The Lancet 2023;402:1541-51.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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