Spesolimab

Spesolimab is a humanized monoclonal immunoglobulin G1 (IgG1) antibody that specifically inhibits the interleukin-36 receptor (IL-36R). Through this specific blockade, it modulates inflammatory processes and is used to treat flare-ups in adult patients with generalized pustular psoriasis. In the pivotal ^EFFISAYIL® 1 study, there was a numerical advantage of spesolimab for the GPPASI 75 response at week 1. The ^EFFISAYIL® 1 study was a multicentre, randomized, placebo-controlled, double-blind, confirmatory study that investigated spesolimab versus placebo in adult patients with a GPP relapse (evidence level 1b). For the pustules subdomain, there was a statistically significant benefit of spesolimab at week 1 with a reduction in pustules of at least 75% before application.

By binding to the IL36R receptor, spesolimab inhibits the activation of the interleukin-36 receptor by its natural ligands, namely IL36 alpha, beta and gamma. This prevents the subsequent signal transduction that would otherwise activate pro-inflammatory signaling pathways. The result of this interaction is a reduction in inflammatory responses mediated by the IL36R signaling pathway.

Spesolimab is administered intravenously. The typical volume of distribution at steady state is 6.4 liters.

The exact metabolic pathway of spesolimab has not yet been characterized. Since spesolimab is a humanized monoclonal IgG1 antibody, it is expected to be degraded into small peptides and amino acids via catabolic pathways similar to endogenous IgG. The terminal half-life of spesolimab is 25.5 days. It was found that the clearance of spesolimab was increased in some patients with ADA titre values > 4,000.

Spesolimab is used as monotherapy for the treatment of relapses in adult patients with generalized pustular psoriasis (GPP).

There are only limited data on the use of spesolimab in pregnant women. Non-clinical studies have shown no evidence of reproductive toxicity. Nevertheless, spesolimab should only be used during pregnancy if clinically necessary and if the potential benefit outweighs the potential risk to the fetus. It is known that human immunoglobulins can cross the placental barrier.

Lactation: It is not known with certainty whether spesolimab passes into breast milk. However, it is known that human immunoglobulins (IgG) may be excreted in breast milk during the first few days after birth. There is therefore a potential risk for the breastfed child during this short phase.

The recommended dose is 900 mg as a single dose, administered as an intravenous infusion. If relapse symptoms persist, a further dose of 900 mg can be administered one week after the first dose.

The most common side effects of spesolimab reported in clinical trials are:

• Infections: These occurred in 17.1% of patients treated with spesolimab. Of particular note is a urinary tract infection reported as serious in one patient (2.9%). Most reported infections were urinary tract infections and upper respiratory tract infections
• Reactions at the injection site: These include symptoms such as redness, swelling, induration, warmth or pain at the injection site
• Pruritus (itching)
• fatigue

No specific studies have been conducted to detect interactions with spesolimab.

Spesolimab is not expected to cause cytokine-mediated CYP interactions.

Live vaccines should not be administered concomitantly with spesolimab.

There is limited experience with the use of spesolimab in combination with immunosuppressants in patients with GPP.

Spesolimab must not be used in:

• Severe or life-threatening hypersensitivity to the active substance
• Clinically significant active infection (e.g. active tuberculosis)

Spevigo ^®

Since August 29, 2023, spesolimab has been withdrawn from the market in Germany by the manufacturer due to a lack of cost-effectiveness ( see: https://www.deutsche-apotheker-zeitung.de/news/artikel/2023/08/31/spevigo-spesolimab-in-deutschland-nicht-mehr-im-handel)

1. Bachelez H et al. (2021) Effisayil 1 Trial Investigators. Trial of Spesolimab for Generalized Pustular Psoriasis. N Engl J Med 385:2431-2440.
2. Hawkes JE et al. (2023) The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab. Front Immunol 14:1292941
3. Morita A et al. (2023) Efficacy and safety of spesolimab in Asian patients with a generalized pustular psoriasis flare: Results from the randomized, double-blind, placebo-controlled Effisayil™ 1 study. J Dermatol 50:183-194.