U.S. Food and Drug Administration (FDA)-Approved Indications

For the treatment of generalized pustular psoriasis (GPP) flares in adults.

Spesolimab-sbzo is available as Spevigo (Boehringer Ingelheim Pharmaceuticals, Inc.). Spesolimab-sbzo is a humanized monoclonal immunoglobulin G1 antibody that inhibits interleukin-36 (IL-36) signaling by specifically binding to the interleukin 36 receptor (IL36R). Binding of spesolimab-sbzo to IL36R prevents the subsequent activation of IL36R by cognate ligands (IL-36 α, β and γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways. This interleukin-36 receptor antagonist has been evaluated for the treatment of generalized pustular psoriasis (GPP) flares in adults. The precise mechanism linking reduced IL36R activity and the treatment of flares of GPP is unclear.

Spevigo carries warnings and precautions for increased risk of infections; tuberculosis (TB); and hypersensitivity, including drug reaction with eosinophilia and systemic symptoms (DRESS), and infusion-related reactions. Live vaccines are not to be administered concurrently with Spevigo. During the one-week placebo-controlled period in the Effisayil-1 trial, infections were reported in 14% of subjects treated with spesolimab-sbzo compared with 6% of subjects treated with placebo. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in clinical trials with spesolimab-sbzo in subjects with GPP. Furthermore, Spevigo should not be administered to persons with active TB infection.

The most common adverse reactions (5% or more) include asthenia and fatigue, nausea and vomiting, headache, pruritus and prurigo, infusion site hematoma and bruising, and urinary tract infection.

Generalized Pustular Psoriasis

Generalized pustular psoriasis (GPP) is a rare, heterogenous, potentially life-threatening autoinflammatory neutrophilic skin disease characterized by episodes of widespread eruption of aseptic, macroscopically visible pustules, which can occur with or without plaque psoriasis, and may be accompanied by systemic inflammation (Choon et al, 2021).

GPP is traditionally classified as a variant of psoriasis; however, evidence suggests that genetic factors distinct from those associated with chronic plaque psoriasis contribute to GPP. In particular, mutations in the IL36RN gene that encodes the interleukin-36 receptor antagonist (IL-36Ra), an anti-inflammatory cytokine in the IL-1 family that inhibits proinflammatory signal pathways by preventing the binding of IL-36 to its receptor, have been detected in some patients with GPP. Pustular psoriasis has also been associated with mutations in caspase recruitment domain family member 14 (CARD14) and the adapter protein family 1 (AP1S3) (Kalb, 2022b).

The clinical course of GPP is usually unstable and prolonged without treatment, with periods of disease dormancy and recurrence over the course of years. Flares may occur upon re-exposure to a precipitating factor or for unknown reasons. Potential complications include sepsis; serious renal, hepatic (neutrophilic cholangitis) or respiratory (neutrophilic pneumonitis, acute respiratory distress syndrome) abnormalities; and death. Patients usually require continued therapy to avoid resurgence of flares (Kalb, 2022a, 2022b).

On September 1, 2022, the U.S. Food and Drug Administration (FDA) approved the first labeled treatment option, Spevigo (spesolimab-sbzo), a monoclonal antibody that inhibits IL-36 signaling, for the treatment of GPP flares in adults. FDA approval was based on positive outcomes from the Phase 2, randomized, double-blind, placebo-controlled Effisayil-1 study (NCT03782792), which found in the 12-week trial, that 54% of patients treated with Spevigo showed no visible pustules after one week compared to those who took a placebo (6%).

The Effisayil-1 study, conducted by Bachelez et al (2021), randomly assigned adult patients (n=53) with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab (n=35) or placebo (n=18). Patients were randomized if their flare was of moderate-to-severe intensity, as defined by: a Generalized Pustular Psoriasis Physician Global Assessment (GPPPGA) total score of at least 3 (moderate) [the total GPPPGA score ranges from 0 (clear) to 4 (severe)], the presence of fresh pustules (new appearance or worsening of pustules), GPPPGA pustulation sub score of at least 2 (mild), and at least 5% of body surface area covered with erythema and the presence of pustules. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a GPPGA pustulation subscore of 0 at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (p < 0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (p = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. The authors concluded that in a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. The authors state that longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis.

Due to the rarity, life-threatening potential, and limited treatment options for GPP flares, Spevigo was granted FDA Breakthrough Therapy Designation and Orphan Drug Designation in the U.S.

Other Indications

Atopic Dermatitis

Bissonnette et al (2022) noted that atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, and there is increasing evidence that the IL-36 pathway may play a role in the pathogenesis of AD. In a randomized, double-blind, placebo-controlled, multi-center, phase-IIa clinical trial, these researchers examined the safety and effectiveness of spesolimab in adult patients with moderate-to-severe AD. This study included 51 eligible patients; they were randomized 2:1 to receive IV doses of spesolimab 600 mg or placebo every 4 weeks. The primary endpoint was percentage change from baseline in Eczema Area and Severity Index (EASI) score at Week 16. Decrease in EASI score from baseline to Week 16 was - 37.9 % for spesolimab versus - 12.3 % for placebo (adjusted mean difference [MD] of -25.6 %, p = 0.149). A pre-defined sensitivity analysis, excluding data from patients who used restricted corticosteroids, resulted in an adjusted MD of -48.3 % (nominal p = 0.024). Spesolimab was well-tolerated, with no clinically relevant safety signals. The authors concluded that this was the 1st study to examine the IL-36 pathway inhibition in AD. These researchers stated that although not statistically significant, numerical improvements were observed in the primary endpoint of change from baseline in EASI score. Spesolimab had an acceptable safety profile, with no unexcepted safety concerns. These findings need to be validated in phase-III clinical trials.

Ulcerative Colitis

Ferrante et al (2022) stated that IL-36 signaling has been shown to be increased in ulcerative colitis (UC). In 3 phase-II clinical trials, these researchers examined the safety, immunogenicity, and effectiveness of IV spesolimab in patients with UC. Study 1: phase-II, randomized, placebo-controlled trial (300 mg, 1 dose; 450 mg every 4 weeks [q4w]; or 1,200 mg q4w, 3 doses). Study 2: phase IIa, randomized, placebo-controlled trial (1,200 mg q4w). Study 3: phase IIa, open-label, single-arm trial (1,200 mg q4w). Studies lasted 12 weeks, with a 12-, 24-, and 16-week safety follow-up, respectively. Adverse event (AE) rates were similar for spesolimab and placebo in Studies 1 (n = 98; 64.9 %; 65.2 %) and 2 (n = 22; 86.7 %; 71.4 %); all patients in Study 3 (n = 8) experienced AEs. The most frequent investigator-assessed drug-related (spesolimab; placebo) AEs were skin rash (5.4 %; 0 %) and nasopharyngitis (4.1 %; 0 %) in Study 1; acne (13.3 %; 0 %) in Study 2; 1 patient reported skin rash, nasopharyngitis, headache, and acne in Study 3. The authors concluded that spesolimab was generally well-tolerated, with no unexpected safety concerns; and the safety data were consistent with studies in other inflammatory diseases. However, effectiveness endpoints were not met.

: Requires Precertification:

Precertification of spesolimab-sbzo (Spevigo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of spesolimab-sbzo, call (866) 752-7021 (commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Prescriber Specialties

This medication must be prescribed by or in consultation with a dermatologist.

Criteria for Initial Approval

Aetna considers spesolimab-sbzo (Spevigo) medically necessary for treatment of generalized pustular psoriasis (GPP) flares in adult members when

the following criteria are met:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of spesolimab-sbzo (Spevigo) therapy medically necessary for treatment of generalized pustular psoriasis (GPP) flares when member meets all initial authorization criteria.

Other

For all indications: Member has had a documented negative TB test (which can include a tuberculosis skin test [PPD], an interferon-release assay [IGRA], or a chest x-ray)

within 6 months of initiating therapy for persons who are naïve to biologic drugs or targeted synthetic drugs associated with an increased risk of TB.

* If the screening testing for TB is positive, there must be further testing to confirm there is no active disease. Do not administer the requested medication to members with active TB infection. If there is latent disease, TB treatment must be started before initiation of the requested medication.

Related Policies

Dosage and Administration

Spesolimab-sbzo is available as Spevigo and supplied as 450 mg/7.5 mL (60 mg/mL) solution in a single-dose vial for intravenous (IV) use.

Per the Prescribing Information, Spevigo is administered as a single 900 mg dose by IV infusion over 90 minutes for adults with generalized pustular psoriasis (GPP). If GPP flare symptoms persist, an additional intravenous 900 mg dose (over 90 minutes) may be administered one week after the initial dose.

Source: Boehringer Ingelheim, 2022b

Experimental and Investigational

Aetna considers concomitant use of spesolimab-sbzo with any other biologic drug (e.g., adalimumab, anakinra, etanercept, infliximab, rilonacept, tocilizumab) or targeted synthetic drug (e.g. tofacitinib) experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers spesolimab-sbzo (Spevigo) experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established: