Spesolimab

The safety and efficacy of spesolimab in combination with immunosuppressants, including biologics, have not been evaluated systematically. In the GPP flare treatment clinical study, there was a washout period for most other treatments (biologics, other systemic immunomodulating treatments), while some treatments were discontinued before initiation of spesolimab treatment with no washout period required (methotrexate, cyclosporine, retinoids, topical treatments).

Concomitant use of other immunosuppressants and spesolimab is not recommended. At initiation of spesolimab treatment, other GPP treatments should be stopped and other treatments (e.g. with systemic immunosuppressants) should not be used concomitantly to treat the flare.

In patients with a chronic infection or a history of recurrent infection, the potential risks and expected clinical benefits of treatment should be considered prior to prescribing spesolimab.

There are no or limited data from the use of spesolimab in pregnant women. Non-clinical studies using a surrogate, mouse specific anti-IL36R monoclonal antibody do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Human immunoglobulin (IgG) is known to cross the placental barrier. As a precautionary measure, it is preferable to avoid the use of spesolimab during pregnancy.

No data are present on excretion of spesolimab in human milk. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Consequently, transfer of IgG antibodies to the newborns through milk, may happen during the first few days. In this short period, a risk to the breastfed child cannot be excluded. Afterwards, spesolimab can be used during breastfeeding if clinically needed. When treatment has occurred up to the last few months of pregnancy, breastfeeding can be started immediately after birth.

Fertility

There are no data available on the effect of spesolimab on human fertility. Studies in mice using a surrogate, mouse specific anti-IL36R monoclonal antibody, do not indicate direct or indirect harmful effects with respect to fertility from antagonism of IL36R.

Spesolimab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequent adverse reactions are infections (17.1%) with urinary tract infection reported as serious in 1 patient (2.9%).

Tabulated list of adverse reactions

Table 1 provides a list of the adverse reactions reported from clinical trials. The adverse reactions are listed by MedDRA System Organ Class (SOC) and frequency category using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (frequency cannot be estimated from the available data).

Table 1. Adverse reactions:

^a The most commonly reported infections were Urinary tract infection (Common) and Upper respiratory tract infection (Common)
^b Not reported in Effisayil 1

Description of selected adverse reactions

Infections

During the 1-week placebo-controlled period in Effisayil 1, infections were reported in 17.1% of patients treated with spesolimab compared with 5.6% of patients treated with placebo. Serious infection (urinary tract infection) was reported in 1 patient (2.9%) in the spesolimab group and no patients in the placebo group. Infections observed in clinical trials with spesolimab were generally mild to moderate with no distinct pattern regarding pathogen or type of infection.

Injection site reactions

Injection site reactions include injection site erythema, injection site swelling, injection site pain, injection site induration, and injection site warmth. Injection site reactions were typically mild-tomoderate in severity.

Immunogenicity

In patients with GPP treated with spesolimab in Effisayil 1, anti-drug antibodies (ADA) formed with a median onset of 2.3 weeks. Following intravenous administration of spesolimab 900 mg, 24% of patients had a maximum ADA titer greater than 4 000 and were Neutralising antibody-positive by end of the trial (weeks 12 to 17). Females appeared to have higher immunogenicity response; the percentage of patients with ADA titer greater than 4 000 was 30% in females, and 12% in males, respectively.

In some patients with ADA titer values >4 000, plasma spesolimab concentrations were reduced, with no apparent impact on pharmacokinetics at ADA titers below 4 000.

As the majority of patients did not experience a subsequent new flare in Effisayil 1, the data on re-treatment of patients with ADA (n=4) is limited. It is currently unknown if there is a correlation between the presence of ADA to spesolimab and maintenance of efficacy or hypersensitivity reactions upon re-treatment.