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

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 (four 150 mg injections) followed by 300 mg (two 150 mg injections) administered subcutaneously 4 weeks later and every 4 weeks thereafter.

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.

For subcutaneous use:

• 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

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

SPEVIGO-associated hypersensitivity reactions may include immediate reactions such as anaphylaxis and delayed reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS).

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in clinical trials with SPEVIGO in subjects with GPP [see Adverse Reactions (6.1)].

If a patient develops signs of anaphylaxis or other serious hypersensitivity, discontinue SPEVIGO immediately and initiate appropriate treatment. SPEVIGO is contraindicated in patients with severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO [see Contraindications (4)].

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.

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.

8.1 Pregnancy

8.2 Lactation

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.

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.

12.2 Pharmacodynamics

The pharmacodynamics of SPEVIGO in the treatment of patients with GPP have not been fully characterized.

12.3 Pharmacokinetics

A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP, and patients with other diseases. After a single intravenous dose of 900 mg of SPEVIGO, the population PK model-estimated AUC0-∞ (95% CI) and Cmax (95% CI) in a typical anti-drug antibody (ADA)-negative patient with GPP were 4750 (4510, 4970) mcg∙day/mL and 238 (218, 256) mcg/mL, respectively. After subcutaneous SPEVIGO 600 mg LD followed by 300 mg every 4 weeks, the mean steady-state trough concentration ranged from 33.4 mcg/mL to 42.3 mcg/mL.

When administered intravenously, spesolimab-sbzo AUC increased dose-proportionally from 0.3 to 20 mg/kg, and CL and terminal half-life were independent of dose. Following subcutaneous single dose administration, spesolimab-sbzo exposure increased slightly more than dose-proportionally across the dose range of 150 mg to 600 mg due to increased bioavailability at higher doses.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of spesolimab-sbzo or of other spesolimab products.

In subjects with GPP treated with intravenous SPEVIGO in Study Effisayil-1, ADAs formed with a median onset of 2.3 weeks. Following administration of 900 mg intravenous SPEVIGO, (12/50) 24% of subjects had a maximum ADA titer greater than 4000 and were neutralizing antibody (Nab)-positive by the end of the study (Weeks 12 to 17). In Study Effisayil-2, ADAs formed with a median onset of 8 weeks. Following administration of a 600 mg subcutaneous LD of SPEVIGO followed by 300 mg every 4 weeks for a total duration of 48 weeks, 24% of subjects had a maximum ADA titer greater than 4000 and were Nab-positive.

In Study Effisayil-1 following intravenous SPEVIGO, females appeared to have higher immunogenicity response; the percentage of subjects with ADA titer greater than 4000 was 30% in females, and 12% in males, respectively. In Study Effisayil-2 following administration of subcutaneous SPEVIGO, the data on immunogenicity response in males versus females were inconclusive.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with spesolimab-sbzo.

No adverse effects on fertility were observed in male or female mice that were intravenously administered a surrogate antibody to IL36R at doses up to 50 mg/kg twice weekly.

Intravenous SPEVIGO for Treatment of GPP Flare (Study Effisayil-1)

A randomized, double-blind, placebo-controlled study (Study Effisayil-1) [NCT03782792] was conducted to evaluate the clinical efficacy and safety of intravenous SPEVIGO in adult subjects with flares of generalized pustular psoriasis (GPP). Subjects were randomized if they had a flare of GPP 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.

Subjects were required to discontinue systemic and topical therapy for GPP prior to receiving study drug.

A total of 53 subjects were randomized (2:1) to receive a single intravenous dose of 900 mg SPEVIGO (N=35) or placebo (N=18) (administered over 90 minutes) during the double-blind portion of the study.

The study population consisted of 32% male and 68% female. The mean age was 43 years (range: 21 to 69 years); 55% of subjects were Asian and 45% were White. For ethnicity, there were no subjects that identified as Hispanic or Latino in the study. Most subjects included in the study had a GPPPGA pustulation sub score of 3 (43%) or 4 (36%), and subjects had a GPPPGA total score of 3 (81%) or 4 (19%). In this study, 25% of subjects had been previously treated with biologic therapy for GPP. At baseline acute flare, of the subjects with white blood cell count (WBC) assessments, 45% and 31% of subjects in the intravenous SPEVIGO and placebo groups, respectively, had (WBC) >12 × 109/L. Seventeen percent and 11% of subjects in the intravenous SPEVIGO and placebo groups, respectively, had temperature >38° Celsius. Of the subjects with WBC assessments, 12% and 6% of subjects in the SPEVIGO and placebo groups, respectively, had both WBC >12 × 109/L and temperature >38° Celsius [see Adverse Reactions (6.1)].

The primary endpoint of the study was the proportion of subjects with a GPPPGA pustulation sub score of 0 (indicating no visible pustules) at Week 1 after treatment.

Subcutaneous SPEVIGO for Treatment of GPP When Not Experiencing a Flare (Study Effisayil-2)

A randomized, double-blind, placebo-controlled study (Study Effisayil-2) [NCT04399837] evaluated the efficacy and safety of SPEVIGO for subcutaneous administration in adults and pediatric subjects (12 years of age and older and weighing at least 40 kg) with a history of at least two GPP flares of moderate-to-severe intensity in the past. Subjects were randomized if they had a GPPPGA total score of 0 or 1 at screening and randomization. Subjects were required to discontinue systemic and topical therapy for GPP prior to or at randomization. These subjects must have had a history of flaring while on concomitant treatment for GPP or a history of flaring upon dose reduction or discontinuation of these concomitant medications.

A total of 123 subjects were randomized (1:1:1:1) to one of four treatment arms:

• SPEVIGO: 600 mg subcutaneous loading dose (LD) followed by 300 mg subcutaneously every 4 weeks
• SPEVIGO: 600 mg subcutaneous LD followed by 300 mg subcutaneously every 12 weeks
• SPEVIGO: 300 mg subcutaneous LD followed by 150 mg subcutaneously every 12 weeks
• Placebo: subcutaneous LD followed by subcutaneous treatment every 4 weeks

While a 600 mg LD dose of SPEVIGO followed by 300 mg every 12 weeks dosage and a 300 mg LD of SPEVIGO followed by 150 mg every 12 weeks dosage were studied in Study Effisayil-2, these dosages are not approved. The recommended dosage of SPEVIGO for treatment of GPP when not experiencing a flare is a subcutaneous LD of 600 mg followed by 300 mg subcutaneously, administered every 4 weeks [see Dosage and Administration (2.3)]. The results summarized in Table 3 are those for the recommended dosage regimen.

The study population was 38% male and 62% female. The mean age was 40 years old (range: 14 to 75 years) with 8 (7%) pediatric subjects (2 per treatment arm); 64% of subjects were Asian and 36% were White. For ethnicity, 6% of subjects identified as Hispanic or Latino. Subjects included in the study had a GPPPGA pustulation sub score of 1 (28%) or 0 (72%), and subjects had a GPPPGA total score of 1 (86%) or 0 (14%). At the time of randomization, 75% of subjects were treated with systemic therapy for GPP, which was discontinued at the start of the randomized study treatment.

Subjects who experienced a GPP flare were eligible to receive up to two open-label intravenous doses of 900 mg SPEVIGO [see Dosage and Administration (2.4)]. Two (7%) subjects in the subcutaneous SPEVIGO 600 mg LD/300 mg every 4 weeks arm and 15 (48%) subjects in the placebo arm received intravenous SPEVIGO for treatment of GPP flare.

The primary endpoint of the study was the time to the first GPP flare up to Week 48 (defined by a GPPPGA pustulation sub score of ≥2 and an increase in GPPPGA total score by ≥2 from baseline). The key secondary endpoint was the occurrence of at least one GPP flare up to Week 48.

How Supplied

SPEVIGO (spesolimab-sbzo) injection is a sterile, preservative-free, colorless to slightly brownish-yellow, clear to slightly opalescent solution available as follows:

Storage and Handling

Infections

Inform patients that SPEVIGO may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any signs or symptoms of clinically important infection during or after treatment with SPEVIGO [see Warnings and Precautions (5.1)].

Hypersensitivity and Infusion-Related Reactions

Inform patients that hypersensitivity and infusion-related reactions may occur with SPEVIGO. Advise patients to seek immediate medical attention if they experience any symptoms of a serious hypersensitivity reaction [see Warnings and Precautions (5.3)].

Vaccinations

Advise patients to avoid receiving live vaccines during and for at least 16 weeks after treatment with SPEVIGO. Instruct patients to inform the healthcare provider that they are taking SPEVIGO prior to a potential vaccination [see Warnings and Precautions (5.4)].

Administration Instructions for Subcutaneous SPEVIGO for Treatment of GPP When Not Experiencing a Flare

If a patient 12 years of age and older or caregiver is to administer subcutaneous SPEVIGO, instruct them on injection technique and assess their ability to inject subcutaneously to ensure the proper administration of SPEVIGO. Provide training to patients or caregivers on preparation and administration of subcutaneous SPEVIGO and on proper needle and syringe disposal [see Dosage and Administration (2.5) and Instructions for Use].

Instruct patients or caregivers to subcutaneously administer two 150 mg/mL prefilled syringes to achieve a complete 300 mg dose of SPEVIGO [see Dosage and Administration (2.5) and Instructions for Use].