Regulatory Decision Summary for Spevigo

Generalized pustular psoriasis (GPP) is a rare, severe skin disease. There are no GPP-specific therapies authorized. Spesolimab is a first-in-class, monoclonal antibody therapy that blocks human IL-36R activation leading to suppression of inflammation.

A randomised, double-blind, placebo-controlled study (EFFISAYIL-1) was conducted to evaluate the clinical efficacy and safety of Spevigo in adult patients with flares of GPP of moderate-to-severe intensity. Patients were required to discontinue systemic and topical therapy for GPP prior to receiving study drug. A total of 53 patients were randomised to receive a single intravenous dose of 900 mg Spevigo (n = 35) or placebo (n = 18).

The primary endpoint of the study was the proportion of patients with a GPPGA pustulation subscore of 0 (indicating no visible pustules) at Week 1. The key secondary endpoint of the study was the proportion of patients with a GPPGA total score of 0 or 1 (clear or almost clear skin) at Week 1. The efficacy of Spevigo was demonstrated in the target patient population. The study met the pre-specified objectives at Week 1 for both GPPGA pustulation subscore and GPPGA total score. The results were clinically meaningful and statistically significant.

In total, 36 subjects received 1 dose of Spevigo, 13 subjects received 2 doses of Spevigo, and 2 subjects received 3 doses of Spevigo throughout the study.

The most common adverse events (AEs) that occurred ≥5%, and at a higher rate in the Spevigo group through Week 1, were asthenia and fatigue, nausea and vomiting, headache, pruritus and prurigo, infusion site hematoma and bruising, and urinary tract infection. The most frequent AE that occurred in subjects treated with Spevigo overall corresponded to infections of mild to moderate intensity. One subject in the Spevigo group experienced a serious infection (urinary tract infection). The risk of infection has been appropriately labelled in the Product Monograph (PM).

Two cases of drug reaction with eosinophilia and systemic symptoms (DRESS) were reported in subjects treated with Spevigo. In both cases, there was a close temporal relation to a GPP flare which can share many of the same signs and symptoms as DRESS, as well as the use of possible trigger concomitant medications. This risk of DRESS has been labelled in the PM.

Of note, among approximately 750 subjects exposed to Spevigo during clinical development, Guillain-Barré syndrome (GBS) was reported in 3 subjects who received various doses of Spevigo in clinical trials for other indications. A certain diagnosis of GBS could not be verified in any of the cases. As per the Sponsor, there is no indication from the literature, that the inhibition of the interleukin-36 (IL-36) pathway is linked to an increased risk of treatment-emergent peripheral neuropathy. Nonetheless, the risk of peripheral neuropathy has been adequately labelled in the PM.

High-level review of supportive Phase 1 and 2 studies did not indicate any new safety signals at this time. One potential important difference in how the drug was administered and used in the pivotal clinical trial (i.e., rescue treatment with study drug could be administered up to 12 weeks with a limit of 3 total doses during the trial) versus its expected use in the post-market setting that could lead to increased risk, is the potential for multiple, repeat dosing for GPP reoccurrence and the unknown effect of immunogenicity on efficacy and safety. This has also been labelled in the PM.

Based on the data evaluated as part of this assessment, no significant safety concerns were identified that would preclude the approval of the study drug for the treatment of GPP flares in adults, particularly given the seriousness and rarity of a disease such as GPP. Risk mitigation strategies can be utilized through labeling and in the post-market setting. There is sufficient evidence of safety to support an authorization of Spevigo for the treatment of adults with GPP presenting with an acute flare of moderate to severe intensity.

Overall, the benefits of Spevigo outweigh its risks in adult patients with GPP flares. The benefit/risk profile of the drug is considered favourable in the target patient population.