Spesolimab

12.1 Mechanism of Action 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.

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION Subcutaneous Dosage for Treatment of GPP When Not Experiencing a Flare Administer a subcutaneous loading dose of 600 mg, followed by 300 mg subcutaneously 4 weeks later and every 4 weeks thereafter. ( 2.3 ) Subcutaneous Use After Intravenous SPEVIGO for Treatment of GPP Flare: Four weeks after treatment with intravenous SPEVIGO, initiate or reinitiate subcutaneous SPEVIGO at a dose of 300 mg administered every 4 weeks. A loading dose is not required following treatment of a GPP flare with intravenous SPEVIGO. ( 2.3 ) See full prescribing information for preparation and administration instructions. ( 2.2 , 2.5 ) Intravenous Dosage for Treatment of GPP Flare Must be diluted before intravenous use. Administer as a single 900 mg dose by intravenous infusion over 90 minutes. If flare symptoms persist, may administer an additional intravenous 900 mg dose one week after the initial dose. ( 2.4 ) See full prescribing information for preparation and administration instructions and storage of the diluted solution. ( 2.2 , 2.5 ) 2.1 Testing and Procedures Prior to Treatment Initiation Evaluate patients for active or latent tuberculosis (TB) infection. SPEVIGO initiation is not recommended in patients with active TB infection. Consider initiating treatment of latent TB prior to initiation of SPEVIGO [see Warnings and Precautions (5.2) ] . Complete all age-appropriate vaccinations according to current immunization guidelines prior to initiating SPEVIGO for treatment of GPP [see Warnings and Precautions (5.4) ] . 2.2 Important Administration Information Subcutaneous Use for Treatment of GPP When Not Experiencing a Flare SPEVIGO prefilled syringes are for subcutaneous use for treatment of GPP when not experiencing a flare. When using SPEVIGO 300 mg/2 mL prefilled syringe: If the healthcare professional determines that it is appropriate, a patient 12 years of age or older may self-inject or the caregiver may administer the loading dose and the subsequent doses of SPEVIGO after proper training in subcutaneous injection technique. In pediatric patients 12 years of age and older, administer SPEVIGO under the supervision of an adult. When using SPEVIGO 150 mg/mL prefilled syringe: If required, the 600 mg subcutaneous loading dose of SPEVIGO is to be administered by a healthcare professional [see Dosage and Administration (2.3) ] . For subsequent 300 mg doses, if the healthcare professional determines that it is appropriate, a patient 12 years of age or older may self-inject or the caregiver may administer SPEVIGO after proper training in subcutaneous injection technique. In pediatric patients 12 years of age and older, administer SPEVIGO under the supervision of an adult. If a patient experiences a GPP flare while receiving subcutaneous SPEVIGO, the GPP flare may be treated with intravenous SPEVIGO [see Dosage and Administration (2.4) ] . Intravenous Use for Treatment of GPP Flare SPEVIGO vials are for intravenous use for treatment of GPP flare. Intravenous infusion of SPEVIGO is only to be administered by a healthcare professional in a healthcare setting. Prepare SPEVIGO intravenous infusion by diluting SPEVIGO single-dose vials [see Dosage and Administration (2.5) ] . Do not mix SPEVIGO with other medicinal products. 2.3 Recommended Subcutaneous Dosage for Treatment of GPP When Not Experiencing a Flare The recommended dosage of SPEVIGO for treatment of GPP when not experiencing a flare in adults and pediatric patients 12 years of age and older and weighing at least 40 kg is a loading dose of 600 mg followed by 300 mg administered subcutaneously 4 weeks later and every 4 weeks thereafter. Initiating or Reinitiating Subcutaneous SPEVIGO After Treatment of a GPP Flare with Intravenous SPEVIGO Four weeks after treatment of a GPP flare with intravenous SPEVIGO [see Dosage and Administration (2.4) ] , initiate or reinitiate subcutaneous SPEVIGO for treatment of GPP at a dose of 300 mg administered every 4 weeks. A subcutaneous loading dose is not required following treatment of a GPP flare with intravenous SPEVIGO. 2.4 Recommended Intravenous Dosage for Treatment of GPP Flare The recommended dosage of SPEVIGO for treatment of GPP flare in adults and pediatric patients 12 years of age and older and weighing at least 40 kg is a single 900 mg dose administered by intravenous infusion over 90 minutes. If GPP flare symptoms persist, an additional intravenous 900 mg dose (over 90 minutes) may be administered one week after the initial dose. 2.5 Preparation and Administration Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permits. SPEVIGO is a colorless to slightly brownish-yellow, clear to slightly opalescent solution. Do not use if the solution is cloudy, discolored, or contains large or colored particulates. Prefilled Syringe (Subcutaneous Use for Treatment of GPP When Not Experiencing a Flare) Before subcutaneous

6 ADVERSE REACTIONS 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 Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 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