Spesolimab

SPEVIGO is indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. SPEVIGO is an interleukin-36 receptor antagonist indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. ( 1 )

SPEVIGO is a colorless to slightly brownish-yellow, clear to slightly opalescent solution available as: For subcutaneous use: Injection: 300 mg/2 mL (150 mg/mL) solution in a single-dose prefilled syringe Injection: 150 mg/mL in a single-dose prefilled syringe For intravenous use: Injection: 450 mg/7.5 mL (60 mg/mL) in a single-dose vial for dilution prior to intravenous infusion For Subcutaneous Use Injection: 300 mg/2 mL (150 mg/mL) solution in a single-dose prefilled syringe ( 3 ) Injection: 150 mg/mL solution in a single-dose prefilled syringe ( 3 ) For Intravenous Use Injection: 450 mg/7.5 mL (60 mg/mL) solution in a single-dose vial ( 3 )

SPEVIGO is contraindicated in patients with severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO. Reported hypersensitivity reactions have included drug reaction with eosinophilia and systemic symptoms (DRESS) and anaphylaxis [see Warnings and Precautions (5.3) and Adverse Reactions (6) ] . Severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO ( 4 )

Infections: SPEVIGO may increase the risk of infections. Treatment with SPEVIGO is not recommended during any clinically important active infection. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur during or after treatment. If a clinically important active infection develops, discontinue SPEVIGO until the infection resolves or is adequately treated. ( 5.1 ) Risk of Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with SPEVIGO. ( 5.2 ) Hypersensitivity and Infusion-Related Reactions: Hypersensitivity reactions, including anaphylaxis and drug reaction with eosinophilia and systemic symptoms (DRESS), and infusion-related reactions may occur. Discontinue SPEVIGO immediately and initiate appropriate treatment if a serious hypersensitivity reaction occurs. ( 5.3 ) Vaccinations: Avoid use of live vaccines during and for at least 16 weeks after treatment with SPEVIGO. ( 5.4 )

5.1 Infections SPEVIGO may increase the risk of infections. During the one-week placebo-controlled period in the Effisayil-1 trial, infections were reported in 14% of subjects treated with SPEVIGO compared with 6% of subjects treated with placebo [see Adverse Reactions (6.1) ] . In patients with a chronic infection or a history of recurrent infection, consider the potential risks and expected clinical benefits of treatment prior to prescribing SPEVIGO. Treatment with SPEVIGO is not recommended in patients with any clinically important active infection until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur during or after treatment with SPEVIGO. If a patient develops a clinically important active infection, discontinue SPEVIGO therapy until the infection resolves or is adequately treated.

5.2 Risk of Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SPEVIGO. Avoid use of SPEVIGO in patients with active TB infection. Consider initiating anti-TB therapy prior to initiating SPEVIGO in patients with latent TB or a history of TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after SPEVIGO treatment.

5.3 Hypersensitivity and Infusion-Related Reactions Serious hypersensitivity reactions, including anaphylaxis and delayed reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during and following administration of SPEVIGO. These reactions can occur with the first dose or subsequent doses [see Adverse Reactions (6.1) ] . SPEVIGO is contraindicated in patients with severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO. If a patient develops signs of anaphylaxis or other serious hypersensitivity, discontinue SPEVIGO immediately and initiate appropriate treatment. If a patient develops mild or moderate hypersensitivity during an intravenous infusion or other infusion-related reactions, stop SPEVIGO infusion and consider appropriate medical therapy (e.g., systemic antihistamines and/or corticosteroids). Upon resolution of the reaction, the infusion may be restarted at a slower infusion rate with gradual increase to complete the infusion.

5.4 Vaccinations Prior to initiating SPEVIGO for treatment of GPP, complete all age-appropriate vaccinations according to current immunization guidelines. Avoid use of live vaccines in patients during and for at least 16 weeks after treatment with SPEVIGO. No specific studies have been conducted in SPEVIGO-treated patients who have recently received live viral or live bacterial vaccines.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Infections [see Warnings and Precautions (5.1) ] Hypersensitivity and Infusion-Related Reactions [see Warnings and Precautions (5.3) ] Treatment of GPP When Not Experiencing a Flare: SPEVIGO has been associated with an increased incidence (≥9 cases per 100 patient-years) of injection site reaction, urinary tract infection, arthralgia, and pruritus. ( 6.1 ) Treatment of GPP Flare: The most common adverse reactions (≥5%) are asthenia and fatigue, headache, nausea, pruritus and prurigo, infusion site hematoma and bruising, and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LEO Pharma, Inc. at 1-877-494-4536 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions with Intravenous SPEVIGO for Treatment of GPP Flare (Study Effisayil-1) SPEVIGO was studied in Study Effisayil-1, a randomized, double-blind, placebo-controlled study comparing a single intravenous 900 mg dose of SPEVIGO (n=35) with placebo (n=18) in subjects with generalized pustular psoriasis (GPP) flare. Subjects in either treatment group who continued to experience flare symptoms at Week 1 were eligible to receive a single open-label intravenous dose of 900 mg of SPEVIGO (second dose and first dose for subjects in the SPEVIGO and placebo groups, respectively). At Week 1, 12 (34%) subjects and 15 subjects (83%) in the SPEVIGO and placebo groups, respectively, received open-label SPEVIGO. After Week 1 to Week 12, subjects in either treatment group whose GPP flare reoccurred after achieving a clinical response were eligible to receive a single open-label rescue intravenous dose of 900 mg of SPEVIGO, with a maximum of 3 total doses of SPEVIGO throughout the study. Six subjects received a single open-label rescue dose of SPEVIGO. Thirty-six subjects received 1 dose of SPEVIGO, 13 subjects received 2 doses of SPEVIGO, and 2 subjects received 3 doses of SPEVIGO throughout the study [see Clinical Studies (14) ] . Subjects ranged in age from 21 to 69 years (mean age of 43 years); 45% were White and 55% were Asian; and 68% were female. Table 1 summarizes selected adverse reactions that occurred at a rate of at least 1% and at a higher rate in the intravenous SPEVIGO group than in the placebo group through Week 1. Table 1 Selected Adverse Reactions Occurring in ≥1% of the Intravenous SPEVIGO Group and More Frequently than in the Placebo Group through Week 1 in Subjects with GPP Flare (Study Effisayil-1) Adverse Reaction Intravenous SPEVIGO N = 35 n (%) Placebo N = 18 n (%) Asthenia and Fatigue 3 (9) 1 (6) Headache 3 (9) 1 (6) Nausea 2 (6) 0 Pruritus and prurigo 2 (6) 0 Infusion site hematoma and bruising 2 (6) 0 Urinary tract infection 2 (6) 0 Bacteremia 1 (3) 0 Bacteriuria 1 (3) 0 Cellulitis 1 (3) 0 Herpes dermatitis and oral herpes 1 (3) 0 Upper respiratory tract infection 1 (3) 0 Dyspnea 1 (3) 0 Eye edema 1 (3) 0 Urticaria 1 (3) 0 Specific Adverse Reactions Infections The most frequent adverse reactions that occurred in subjects treated with intravenous SPEVIGO were infections. During the 1-week placebo-controlled period in Study Effisayil-1, infections were reported in 14% of subjects treated with SPEVIGO compared with 6% of subjects treated with placebo. Serious infection (urinary tract infection) was reported in 1 subject (3%) treated with SPEVIGO and no subjects treated with placebo. Infections observed through Week 1 in Study Effisayil-1 in subjects treated with SPEVIGO were mild (29%) to moderate (71%). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Two cases of DRESS were reported in Study Effisayil-1 in subjects with GPP who were treated with intravenous SPEVIGO. RegiSCAR DRESS validation scoring (with the following categories: "no", "possible", "probable", or "definite" DRESS) was applied to the reported cases. Reported cases were assessed as "no DRESS" and "possible DRESS". Safety through Week 12 and 17 In Study Effisayil-1, additional adverse reactions that occurred through Week 12 in subjects treated with 1 single intravenous dose of randomized SPEVIGO were mild to moderate infections: device-related infection (3%), subcutaneous abscess (3%), furuncle (3%), and influenza (3%). Additional adverse reactions that occurred through Week 17 in subjects treated with a single intravenous dose of open-label SPEVIGO at Week 1 (second dose and first dose for subjects in the SPEVIGO and placebo groups, respectively) were mild to moderate infections: otitis externa (7%), vulvovaginal candidiasis (4%), vulvovaginal mycotic infection (4%), latent tuberculosis (4%), diarrhea (11%), and gastritis (4%). No new adverse reactions were identified for up to 16 weeks in subjects treated with a single intravenous dose of open-label rescue SPEVIGO from Week 1 to Week 12 (range 1-3 total doses). Adverse Reactions with Subcutaneous SPEVIGO for Treatment of GPP When Not Experiencing a Flare (Study Effisayil-2) Subcutaneous treatment with SPEVIGO was studied in Study Effisayil-2, a randomized, placebo-controlled, double-blind, parallel group study evaluating three dosages of SPEVIGO or placebo in subjects with generalized pustular psoriasis (GPP). Subjects were randomized (1:1:1:1) to receive a 600 mg loading dose (LD) of SPEVIGO followed by 300 mg every 4 weeks (n=30), one of two other dosages of SPEVIGO, or placebo (n=30) for up to 48 weeks [see Clinical Studies (14) ] . Subjects ranged in age from 14 to 75 years (mean age was 40 years); 64% of subjects were Asian and 36% were White; 62% of subjects were female. Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for injection site reaction (including erythema, pain, swelling, induration, urticaria, and warmth at the injection site) was 31.6 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 12.7 for the placebo cohort. Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for urinary tract infection was 18 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 0 for the placebo cohort. Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for pruritus was 8.8 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 0 for the placebo cohort. Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for arthralgia was 13.3 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 6 for the placebo cohort. For subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without flare, there were 3 subjects who discontinued subcutaneous SPEVIGO in the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) due to treatment emergent adverse events of psoriasis compared to no subjects in the placebo cohort who discontinued placebo for any treatment emergent adverse event. […]

8.1 Pregnancy Risk Summary The limited data on the use of SPEVIGO in pregnant women are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. Human IgG is known to cross the placental barrier; therefore, SPEVIGO may be transmitted from the mother to the developing fetus. In an animal reproduction study, intravenous administration of a surrogate antibody against IL36R in mice during the period of organogenesis did not elicit any reproductive toxicity (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Embryo-fetal development and pre- and postnatal development toxicity studies were performed in mice using a surrogate mouse specific IL36R antagonist monoclonal antibody. In the embryo-fetal development study, the surrogate was administered intravenously at doses up to 50 mg/kg to pregnant female mice twice weekly during the period of organogenesis. The surrogate was not associated with embryo-fetal lethality or fetal malformations. In the pre- and postnatal development toxicity study, the surrogate was administered intravenously at doses up to 50 mg/kg to pregnant female mice twice weekly from gestation day 6 through lactation day 18. There were no maternal effects observed. There were no treatment-related effects observed on postnatal developmental, neurobehavioral, or reproductive performance of offspring.

8.2 Lactation Risk Summary There are no data on the presence of spesolimab-sbzo in human milk, the effects on the breastfed infant, or the effects on milk production. Spesolimab-sbzo is a monoclonal antibody and is expected to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SPEVIGO and any potential adverse effects on the breastfed infant from SPEVIGO or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of SPEVIGO for the treatment of GPP have been established in pediatric patients 12 years of age and older and weighing at least 40 kg. Use of SPEVIGO for this indication is supported by data from a randomized, placebo-controlled study which included 6 pediatric subjects 14 to 17 years of age with a history of GPP treated with subcutaneous SPEVIGO (Study Effisayil-2) and evidence from an adequate and well-controlled study of intravenous SPEVIGO in adults with GPP (Study Effisayil-1), with additional pharmacokinetic analyses showing similar drug exposure levels in adults and pediatric subjects 12 years of age and older and weighing 40 kg or more [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . The safety and effectiveness of SPEVIGO in pediatric patients younger than 12 years of age or in pediatric patients weighing less than 40 kg have not been established.

8.5 Geriatric Use There were 2 (6%) intravenous SPEVIGO-treated subjects 65 to 74 years of age and no subjects 75 years of age or older in Study Effisayil-1. There were 6 (7%) subcutaneous SPEVIGO-treated subjects 65 to 74 years of age and 1 (1%) subject 75 years of age in Study Effisayil-2. Clinical studies of SPEVIGO did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Spesolimab-sbzo is a humanized monoclonal immunoglobulin G1 antibody that inhibits interleukin-36 (IL-36) signaling by specifically binding to the IL36R. Binding of spesolimab-sbzo to IL36R prevents the subsequent activation of IL36R by its ligands (IL-36 α, β and γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways. The precise mechanism linking reduced IL36R activity and the treatment of flares of GPP is unclear.