Spevigo

Clear to slightly opalescent, colourless to slightly brownish-yellow solution.
Each vial contains 450 mg spesolimab in 7.5 mL.
Each mL of concentrate for solution for infusion contains 60 mg spesolimab.
After dilution, each mL of the solution contains 9 mg spesolimab (see Special precautions for disposal and other handling under Cautions for Usage).
Spesolimab is produced in Chinese hamster ovary cells by recombinant DNA technology.
Excipients/Inactive Ingredients: Sodium acetate trihydrate (E262), Glacial acetic acid (E260) (for pH adjustment), Sucrose, Arginine hydrochloride, Polysorbate 20 (E432), Water for injections.

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors. ATC code: L04AC22.
Pharmacology: Pharmacodynamics: Mechanism of action: Spesolimab is a humanised antagonistic monoclonal immunoglobulin G1 (IgG1) antibody blocking human IL36R signalling. Binding of spesolimab to IL36R prevents the subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways. IL-36R signalling is differentiated from TNF-α, integrin and IL-23 inhibitory pathways by directly and simultaneously blocking both inflammatory and pro-fibrotic pathways. Genetic human studies have established a strong link between IL36R signalling and skin inflammation.
Pharmacodynamic effects: Following treatment with SPEVIGO in patients with GPP, reduced levels of C-reactive protein (CRP), interleukin (IL)-6, T helper cell (Th1/Th17) mediated cytokines, keratinocyte-mediated inflammation, neutrophilic mediators, and proinflammatory cytokines were observed in serum and skin at week 1 compared to baseline and was associated with a decrease in clinical severity. These reductions in biomarkers became more pronounced at the last measurement at week 8 in Effisayil 1.
Clinical efficacy and safety: 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 Generalized Pustular Psoriasis (GPP), as diagnosed per European Rare And Severe Psoriasis Expert Network (ERASPEN) criteria, regardless of IL36RN mutation status. Patients were randomised if they had a flare of GPP of moderate-to-severe intensity, as defined by a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) total score (which ranges from 0 [clear] to 4 [severe]) of at least 3 (moderate), presence of fresh pustules (new appearance or worsening of pustules), GPPGA pustulation sub score of at least 2 (mild), and at least 5% of body surface area (BSA) covered with erythema and the presence of pustules. Patients were required to discontinue systemic and topical therapy for GPP prior to receiving study drug.
The primary endpoint of the study was the proportion of patients with a GPPGA pustulation sub score of 0 (indicating no visible pustules) at Week 1 after treatment. 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. Additional secondary endpoints at Week 4 were the proportion of patients with a 75% reduction in the Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI 75), and patient-reported outcomes including change from baseline in Pain Visual Analog Scale (VAS) score, change from baseline in Psoriasis Symptom Scale (PSS) score, and change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score.
A total of 53 patients were randomised (2:1) to receive a single intravenous dose of 900 mg SPEVIGO (n= 35) or placebo (n=18). Patients in either treatment arm who still experienced flare symptoms at Week 1 were eligible to receive a single intravenous dose of open-label 900 mg SPEVIGO, resulting in 12 patients (34%) in the SPEVIGO arm receiving a second dose of SPEVIGO and 15 patients (83%) in the placebo arm receiving one dose of SPEVIGO on Day 8. In addition, 6 patients (4 SPEVIGO arm; 2 placebo arm) received rescue treatment with a single 900 mg dose of intravenous SPEVIGO for reoccurrence of a flare after Day 8.
The study population consisted of 32% men and 68% women. The mean age was 43 (range: 21 to 69) years; 55% of patients were Asian and 45% were Caucasian. Most patients included in the study had a GPPGA pustulation sub score of 3 (43%) or 4 (36%), and patients had a GPPGA total score of 3 (81%) or 4 (19%). 24.5% of patients had been previously treated with biologic therapy for GPP.
At Week 1, there was a statistically significant difference in the proportion of patients achieving a GPPGA pustulation sub score of 0 (indicating no visible pustules) and GPPGA total score of 0 or 1 (clear or almost clear skin) in the SPEVIGO arm compared with placebo (see Table 1).

Click on icon to see table/diagram/image

In patients randomized to SPEVIGO, pustular clearance (GPPGA pustulation sub score of 0) was achieved as early as one day after treatment in 11.4% (4/35) of patients. The effect of up to two doses of SPEVIGO on GPPGA pustulation sub score and GPPGA total score was sustained until Week 12 (see Figures 1 and 2).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

The results of the primary and key secondary endpoints were consistent across subgroups including sex, age, race, GPPGA pustulation sub score at baseline, GPPGA total score at baseline, mutation status in IL36RN, and irrespective of any GPP treatment prior to randomization.
At Week 4, 16 patients (46%) randomized to SPEVIGO achieved a GPPASI 75.
In patients randomized to SPEVIGO, improvements in the pain VAS score, PSS score (measuring symptoms of pain, redness, itching, and burning), and FACIT Fatigue score were observed at Week 4 (median change from baseline: -22.45, -2.00 and 3.00, for the pain VAS score, PSS score, and FACIT Fatigue score, respectively).
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 i.v. dose of 900 mg, the population PK model-estimated AUC0-∞ (95% CI) and Cmax (95% CI) in a typical ADA-negative patient with GPP were 4750 (4510, 4970) μg·day/mL and 238 (218, 256) μg/mL, respectively.
Distribution: Based on the population pharmacokinetic analysis, the typical volume of distribution at steady state was 6.4 L.
Biotransformation: The metabolic pathway of spesolimab has not been characterized. As a humanized IgG1 monoclonal antibody, spesolimab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Elimination: In the linear dose range (0.3-20 mg/kg), based on the population PK model, spesolimab clearance (95% CI) in a typical GPP patient without ADA, weighing 70 kg was 0.184 (0.175, 0.194) L/day. The terminal-half-life was 25.5 (24.4, 26.3) days.
Linearity/non-linearity: At low doses, spesolimab exhibited target-mediated drug disposition (TMDD) kinetics after single i.v. dose administration. At doses from 0.01 to 0.3 mg/kg, both clearance (CL) and terminal half-life were dose dependent, and systemic exposure (AUC) increased more than dose proportionally with dose.
The saturation of the nonlinear elimination pathway occurred at about 0.3 mg/kg as spesolimab AUC increased approximately linearly with dose from 0.3 to 20 mg/kg, and CL and terminal half-life were independent of dose.
Elderly/Gender/Race: Based on population pharmacokinetic analyses, age, gender and race do not have an effect on the pharmacokinetics of spesolimab.
Hepatic and renal impairment: As a monoclonal antibody, spesolimab is not expected to undergo hepatic or renal elimination. No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of spesolimab was conducted.
Population PK analysis did not identify mild hepatic impairment or mild or moderate renal impairment as having an influence on the systemic exposure of spesolimab.
Body weight: Spesolimab concentrations were lower in subjects with higher body weight. The impact of body weight on spesolimab plasma concentrations is not expected to be clinically meaningful.
Paediatric population: The pharmacokinetics of spesolimab in paediatric patients has not yet been studied.
Drug-Drug Interactions (studies): No formal drug interactions studies have been conducted with spesolimab. Population PK analyses indicated that concomitant use of immunosuppressants or oral corticosteroids did not have a direct impact on the pharmacokinetics of spesolimab.
Toxicology: Preclinical safety data: Pre-clinical data reveal no special hazard for humans.
Repeat dose toxicology studies were conducted in mice using a surrogate, mouse specific anti-IL36R monoclonal antibody by twice weekly intravenous injection for 26 weeks at a dose (50 mg/kg) that was 5 fold higher than the dose that was protective in an experimental mouse colonic inflammation model. No adverse changes in body weight, food consumption or clinical observations were noted at this dose. No adverse effects on clinical pathology parameters including haematology, immunophenotyping, clinical chemistry and histopathology, including lymphoid tissues, have been observed.
The binding specificity of spesolimab to human tissues was evaluated in a tissue cross-reactivity study. No unexpected tissue binding was observed.
Developmental and Reproductive Toxicity: Pre-clinical studies conducted in mice using a surrogate antibody directed towards murine IL-36R do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development or fertility, at intravenous doses up to 50 mg/kg twice weekly.
Genotoxicity: Genotoxicity studies have not been conducted with spesolimab.
Carcinogenicity: Carcinogenicity and mutagenicity studies have not been conducted with spesolimab.

SPEVIGO is indicated for the treatment of generalized pustular psoriasis (GPP) flares in adults.

Treatment with SPEVIGO should be initiated and supervised by physicians experienced in the management of patients with inflammatory skin diseases.
Posology: The recommended dose of SPEVIGO is a single dose of 900 mg (2 x 450 mg/7.5 ml vials) administered as an intravenous infusion.
If flare symptoms persist, an additional 900 mg dose may be administered 1 week after the initial dose.
Elderly patients: No dose adjustment is required.
There is limited information in patients aged 65 years and older.
Renal and/or hepatic impairment: SPEVIGO has not been studied in these patient populations. These conditions are generally not expected to have any clinically relevant impact on the pharmacokinetics of monoclonal antibodies and no dose adjustments are considered necessary.
Paediatric population: The safety and efficacy of SPEVIGO in children below the age of 18 years have not been established. No data are available.
Method of administration: SPEVIGO must be diluted before use (see Instructions for use/handling as follows).
SPEVIGO is administered as a continuous intravenous infusion through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron) over 90 minutes.
In the event that the infusion is slowed or temporarily stopped, the total infusion time (including stop time) should not exceed 180 minutes (see Precautions).
Instructions for use/handling: Prior to use, the unopened vial may be kept at room temperature (up to 30°C) for up to 24 hours, if stored in the original package in order to protect from light.
The vial should be visually inspected before use. SPEVIGO is a colourless to slightly brownish-yellow, clear to slightly opalescent solution. If the solution is cloudy, discoloured, or contains large or coloured particulates, the vial should be discarded.
Aseptic technique must be used to prepare the solution for infusion. Draw and discard 15 ml from a 100 ml container of sterile 0.9% sodium chloride solution and replace slowly with 15 ml SPEVIGO (complete content from two vials of 450 mg/7.5 ml). Mix gently before use. The diluted SPEVIGO infusion solution should be used immediately.
SPEVIGO must not be mixed with other medicinal products. A pre-existing intravenous line may be used for administration of SPEVIGO. The line must be flushed with sterile 0.9% sodium chloride solution prior to and at the end of infusion. No other infusion should be administered in parallel via the same intravenous access.
SPEVIGO is for single-use only and does not contain preservatives.
Chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at 2-30°C followed by 3 hours infusion time.
From a microbiological point of view the diluted solution for infusion should be used immediately. If not used immediately, in use storage conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions. For the time between preparation and start of administration the solution for infusion should be protected from light following local standard procedures.
No incompatibilities have been observed between SPEVIGO and infusion sets composed of polyvinylchloride (PVC), polyethylene (PE), polypropylene (PP), polybutadiene and polyurethane (PUR), and in-line filter membranes composed of polyethersulfone (PES, neutral and positively charged) and positively charged polyamide (PA).

There is no clinical experience with overdoses of SPEVIGO.
The highest dose of SPEVIGO administered in clinical trials was 1200 mg. Adverse events observed in subjects receiving single or repeated doses up to 1200 mg were consistent with the known safety profile of SPEVIGO.
In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and symptomatic treatment be instituted as appropriate.

Severe or life-threatening hypersensitivity to SPEVIGO or to any of the excipients listed in Description (see Precautions).

Traceability: In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.
Infections: SPEVIGO may increase the risk of infections. During the 1-week placebo-controlled period in the Effisayil-1 trial, infections were reported in 17.1% of patients treated with SPEVIGO compared with 5.6% of patients treated with placebo (see Adverse Reactions).
In patients with a chronic infection or a history of recurrent infection, the potential risks and expected clinical benefits of treatment should be considered prior to prescribing SPEVIGO. Treatment with SPEVIGO should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be instructed to seek medical advice if signs or symptoms of clinically important infection occur after treatment with SPEVIGO.
Pre-treatment evaluation for tuberculosis: Patients should be evaluated for tuberculosis (TB) infection prior to initiating treatment with SPEVIGO. SPEVIGO should not be administered to patients with active TB infection.
Anti-TB therapy should be considered prior to initiating SPEVIGO in patients with latent TB or a history of TB in whom an adequate course of treatment cannot be confirmed. After SPEVIGO treatment, patients should be monitored for signs and symptoms of active TB.
Hypersensitivity and infusion-related reactions: Hypersensitivity and infusion-related reactions may occur with monoclonal antibodies such as SPEVIGO. Hypersensitivity may include immediate reactions such as anaphylaxis and delayed reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS).
If a patient develops signs of anaphylaxis or other serious hypersensitivity, SPEVIGO should be discontinued immediately and appropriate treatment should be initiated (see Contraindications).
If a patient develops mild or moderate infusion-related reaction, SPEVIGO should be stopped and appropriate medical therapy should be considered (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 (see Dosage & Administration).
Immunisations: No specific studies have been conducted in patients who have recently received live viral or live bacterial vaccines. The interval between live vaccinations and initiation of SPEVIGO therapy should be at least 4 weeks. Live vaccines should not be administered for at least 16 weeks after treatment with SPEVIGO.
Peripheral neuropathy: The potential for peripheral neuropathy with SPEVIGO is unknown. Cases of peripheral neuropathy have been reported in clinical trials with spesolimab. Physicians should be vigilant for symptoms potentially indicative of new-onset peripheral neuropathy.
Excipients: This medicinal product contains less than 1 mmol sodium (23 mg) per 900 mg dose, that is to say essentially 'sodium free'.
Effects on ability to drive and use machines: SPEVIGO has no or negligible influence on the ability to drive and use machines.

Pregnancy: There are limited data from the use of spesolimab in pregnant women. Pre-clinical studies using a surrogate, mouse specific anti-IL36R monoclonal antibody do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Human immunoglobulin (IgG) is known to cross the placental barrier. As a precautionary measure, it is recommended to avoid the use of SPEVIGO in pregnancy, unless the expected clinical benefit clearly outweighs the potential risks.
Breast-feeding: It is unknown whether spesolimab is excreted in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. Spesolimab is a monoclonal antibody and is expected to be present in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from SPEVIGO therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: There are no data available on the effect of spesolimab on human fertility. Pre-clinical studies in mice using a surrogate, mouse specific anti-IL36R monoclonal antibody, do not indicate direct or indirect harmful effects with respect to fertility from antagonism of IL36R.

Summary of the safety profile: The safety data provided in the following are based on Effisayil-1, a double-blind, randomised trial comparing a single intravenous 900 mg dose of SPEVIGO (n=35) with placebo (n=18) in patients with generalized pustular psoriasis for up to 12 weeks after treatment and four double-blind, placebo-controlled trials of 254 spesolimab-treated patients who received doses up to 1200 mg intravenous or subcutaneous spesolimab for other diseases.
The most frequent adverse reactions associated with SPEVIGO are infections.
Tabulated summary of adverse reactions: (See Table 2.)

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Description of selected adverse reactions: Infections: During the 1-week placebo-controlled period in Effisayil-1, infections were reported in 17.1% of patients treated with SPEVIGO compared with 5.6% of patients treated with placebo. Serious infection (urinary tract infection) was reported in 1 patient (2.9%) in the SPEVIGO group and no patients in the placebo group. Infections observed in clinical trials with spesolimab were generally mild to moderate with no distinct pattern regarding pathogen or type of infection.
Injection site reactions: Injection site reactions include injection site erythema, injection site swelling, injection site pain, injection site induration, and injection site warmth. Injection site reactions were typically mild-to-moderate in severity.
Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
In patients with GPP treated with Spesolimab in Effisayil-1, anti-drug antibodies (ADA) formed with a median onset of 2.3 weeks. Following administration of i.v. spesolimab 900 mg, 24% of patients had a maximum ADA titer greater than 4000 and were Neutralising antibody (Nab)-positive by end of the trial (Weeks 12 to 17).
Females appeared to have higher immunogenicity response; the percentage of patients with ADA titer greater than 4000 was 30% in females, and 12% in males, respectively.
In some patients with ADA titer values greater than 4000, plasma spesolimab concentrations were reduced, with no apparent impact on pharmacokinetics at ADA titers below 4000. There are limited data on the impact of ADAs on safety and efficacy upon retreatment as the majority of subjects did not experience a subsequent, new flare in an open-label extension trial. There was no apparent correlation between the presence of ADA to spesolimab and hypersensitivity reactions.

No interaction studies have been performed.
Live vaccines should not be given concurrently with SPEVIGO (see Precautions).

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Special precautions for disposal and other handling as follows.
Special precautions for disposal and other handling: This medicinal product is compatible with infusion sets composed of polyvinylchloride (PVC), polyethylene (PE), polypropylene (PP), polybutadiene and polyurethane (PUR), and in-line filter membranes composed of polyethersulfone (PES, neutral and positively charged) and positively charged polyamide (PA).
Handling instructions: The vial should be visually inspected before use. If the solution is cloudy, discoloured, or contains large or coloured particulates, the vial should be discarded.
Spevigo is for single use only.
Aseptic technique must be used to prepare the solution for infusion. Draw and discard 15 mL from a 100 mL container of sodium chloride 9 mg/mL (0.9%) solution for injection and replace slowly with 15 mL spesolimab sterile concentrate (complete content from two vials of 450 mg/7.5 mL). Mix gently before use. The diluted spesolimab infusion solution should be used immediately.
Spevigo must not be mixed with other medicinal products. A pre-existing intravenous line may be used for administration of diluted spesolimab infusion solution, if the compatibility information as previously mentioned is considered. The line must be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection prior to and at the end of infusion. No other infusion should be administered in parallel via the same intravenous access.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Shelf life: Unopened vial: 3 years.
After opening: From a microbiological point of view, once opened, the medicinal product should be diluted and infused immediately.
After preparation of infusion: Chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at 2°C to 30°C.
From a microbiological point of view, the diluted solution for infusion should be used immediately. If not used immediately, in use storage conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions. For the time between preparation and start of administration the solution for infusion should be protected from light following local standard procedures.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original package in order to protect from light.
Prior to use, the unopened vial may be kept at temperatures up to 30°C for up to 24 hours, if stored in the original package in order to protect from light.
For storage conditions after opening and dilution of the medicinal product, see Shelf life as previously mentioned.

Immunosuppressants

L04AC22 - spesolimab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.

POM