TRIALISTMD ยท Drug Intelligence Platform
FDA APPROVED 2022
IL-36R Antagonist ยท Dermatology ยท Generalized Pustular Psoriasis
Spesolimab
SPEVIGOยฎ ยท Boehringer Ingelheim Pharmaceuticals, Inc.
The first and only FDA-approved interleukin-36 receptor (IL-36R) antagonist โ and the first therapy specifically approved for generalized pustular psoriasis (GPP) flares in adults. Spesolimab-sbzo is a humanized monoclonal IgG1 antibody that blocks IL-36ฮฑ, ฮฒ, and ฮณ signaling, offering rapid pustular clearance in a rare, potentially life-threatening inflammatory skin disease with previously no approved treatments.
Drug Overview
BLA 761179Indication
GPP Flares
Generalized Pustular Psoriasis in adults
Mechanism
IL-36R Antagonist
Humanized monoclonal IgG1 antibody (~146 kDa)
Approved Dose
900 mg IV
Single infusion over 90 min; optional 2nd dose at Week 1
Disease Rarity
First-in-Class
No prior FDA-approved GPP-specific therapy
Mechanism of Action
Spesolimab-sbzo is a humanized monoclonal IgG1 antibody that inhibits interleukin-36 (IL-36) signaling by specifically binding to the IL-36 receptor (IL36R). By occupying IL36R, spesolimab prevents the binding of all three cognate ligands โ IL-36ฮฑ, IL-36ฮฒ, and IL-36ฮณ โ thereby blocking downstream activation of pro-inflammatory and pro-fibrotic pathways. In GPP, dysregulated IL-36 signaling is central to the sterile neutrophilic pustule cascade involving keratinocyte activation, neutrophil recruitment, and systemic inflammation.
Genetic context: Loss-of-function mutations in IL36RN (encoding IL-36Ra, the endogenous IL-36R antagonist) are found in a subset of GPP patients, creating a hyper-activated IL-36 signaling state that spesolimab is uniquely positioned to counter. The drug is effective regardless of IL36RN mutation status.
Mechanistic note: The precise mechanism linking reduced IL36R activity and the treatment of GPP flares is not fully elucidated per the label (Section 12.1). Downstream targets include NF-ฮบB and MAPK pathways, which regulate cytokine amplification, keratinocyte hyperproliferation, and neutrophil trafficking characteristic of GPP flare pathophysiology.
Competitive Landscape
| Drug | Target | Approval / Status | Route | Population |
|---|---|---|---|---|
| Spesolimab (SPEVIGO) | IL-36R antagonist | September 1, 2022 | IV (900 mg) | Adults โ GPP flares |
| Imsidolimab (ANB019) | IL-36R antagonist | NDA submitted (AnaptysBio) | SC | Adults โ GPP flares (investigational) |
| Acitretin / Cyclosporine | Non-specific immunosuppression | Off-label use | Oral | Conventional systemic therapy |
| TNF-ฮฑ inhibitors | TNFฮฑ | Off-label use | SC / IV | Used off-label in severe GPP |
Sources: FDA prescribing information (BLA 761179, Ref ID: 5039554). Imsidolimab status based on published pipeline data. Spesolimab is the only FDA-approved IL-36R antagonist for GPP flares as of the label date (September 2022).
Clinical Efficacy
Study Effisayil-1 ยท NCT03782792Primary Endpoint
GPPPGA Pustulation = 0
No visible pustules at Week 1 post-treatment
Trial Design
RCT, DB, Placebo-Ctrl
2:1 randomization (SPEVIGO:placebo); 12โ17 week follow-up
Population (N)
53
Randomized (35 SPEVIGO ยท 18 Placebo)
Eligibility (GPPPGA)
โฅ 3
Moderate-to-severe GPP flare with fresh pustules
Primary Endpoint Results
EFFISAYIL-1 (NCT03782792) โ GPPPGA Pustulation Sub Score = 0 at Week 1
Risk difference vs placebo: 49% (95% CI: 21%โ67%) ยท N=35 vs N=18 ยท p statistically significant
GPPPGA Pustulation Score Over Time
Effisayil-1 โ Weeks 0 through 12
SPEVIGO 900 mg IV
Placebo
Proportion achieving GPPPGA pustulation sub score of 0 (no visible pustules) across timepoints. Placebo subjects who did not achieve a response at Week 1 received open-label SPEVIGO. Values estimated from Effisayil-1 published data. Source: FDA prescribing information, BLA 761179.
Key Secondary Endpoints
| Endpoint | SPEVIGO (N=35) | Placebo (N=18) | Note |
|---|---|---|---|
| GPPPGA pustulation = 0 at Week 1 | 54% (19/35) | 6% (1/18) | Primary Endpoint |
| GPPPGA total score = 0 or 1 at Week 1 | ~43โ54% | ~6% | Key Secondary |
| Second dose required at Week 1 (symptoms persist) | 34% (12/35) | 83% (15/18) | Open-label rollover |
| GPPPGA pustulation = 0 at Week 2 (2nd dose recipients) | 42% (5/12) | โ | 2nd dose responders |
| Rescue dose required (Weeks 1โ12, flare recurrence) | 6 subjects total across both groups received rescue dose | Open-label rescue | |
Baseline Population Characteristics (Effisayil-1)
| Characteristic | SPEVIGO (N=35) | Placebo (N=18) |
|---|---|---|
| Mean Age (range) | 43 years (21โ69) | 43 years |
| Female | 68% | 68% |
| Race: Asian | 55% | 55% |
| Race: White | 45% | 45% |
| GPPPGA pustulation sub score 3 | 43% | โ |
| GPPPGA pustulation sub score 4 | 36% | โ |
| GPPPGA total score 3 (moderate) | 81% | โ |
| GPPPGA total score 4 (severe) | 19% | โ |
| Prior biologic therapy for GPP | 25% | โ |
| WBC >12 ร 10โน/L at baseline | 45% | 31% |
| Temperature >38ยฐC at baseline | 17% | 11% |
Study did not include sufficient numbers to determine differential response by sex, age, race, or baseline GPPPGA score. Source: FDA Prescribing Information, Section 14 (BLA 761179, Ref ID: 5039554).
Safety & Adverse Drug Reactions
Effisayil-1 ยท Weeks 1, 12 & 17Safety Population
53
Randomized (35 SPEVIGO ยท 18 Placebo)
Clinical Development Exposure
~750
Subjects exposed across all spesolimab trials
Infection Rate (Week 1)
14%
vs 6% placebo โ most mild-to-moderate
DRESS Cases
2
1 “no DRESS” + 1 “possible DRESS” by RegiSCAR
Adverse Reactions โฅ1% (Week 1 Placebo-Controlled Period)
| Adverse Reaction | SPEVIGO (N=35) | Placebo (N=18) |
|---|---|---|
| Asthenia and Fatigue | 9% (3/35) | 0% |
| Nausea and Vomiting | 9% (3/35) | 6% |
| Headache | 9% (3/35) | 6% |
| Pruritus and Prurigo | 6% (2/35) | 0% |
| Infusion site hematoma and bruising | 6% (2/35) | 0% |
| Urinary tract infection | 6% (2/35) | 0% |
| Bacteremia | 3% (1/35) | 0% |
| Bacteriuria | 3% (1/35) | 0% |
| Cellulitis | 3% (1/35) | 0% |
| Herpes dermatitis / oral herpes | 3% (1/35) | 0% |
| Upper respiratory tract infection | 3% (1/35) | 0% |
| Dyspnea | 3% (1/35) | 0% |
| Eye edema | 3% (1/35) | 0% |
| Urticaria | 3% (1/35) | 0% |
Notable Safety Signals
Infections (Week 1)
14% SPEVIGO vs 6% placebo. Severity: 29% mild, 71% moderate. Serious infection (UTI) in 1 subject (3%).
DRESS (Drug Reaction with Eosinophilia)
2 reported cases; RegiSCAR: “no DRESS” and “possible DRESS”. Monitor closely. Listed as contraindication trigger.
Extended Follow-up Infections (Week 12)
Device-related infection (3%), subcutaneous abscess (3%), furuncle (3%), influenza (3%) โ all mild-to-moderate.
Extended Follow-up โ Week 17 (open-label 2nd dose)
Otitis externa (7%), vulvovaginal candidiasis (4%), VV mycotic infection (4%), latent TB (4%), diarrhea (11%), gastritis (4%).
Guillain-Barrรฉ Syndrome
3 cases across ~750 subjects in clinical development (various doses and indications โ not from the GPP approval trial).
Infusion-Related Reactions
Injection site reactions (erythema, swelling, pain, induration, warmth) observed in clinical development. Manage with rate reduction.
Anti-Drug Antibody (ADA) Immunogenicity
24% of subjects developed ADA titer >4000 with neutralizing activity by Week 12โ17. Females: 30%; Males: 12%.
ADA Impact on PK
ADA titer <4000: No PK impact. ADA titer >4000: Significant reduction in spesolimab plasma concentrations observed in most subjects.
Clinical context: Effisayil-1 enrolled only 53 subjects, reflecting the rarity of GPP as a disease. Adverse event rates should be interpreted in the context of confounding by the underlying GPP flare itself (systemic inflammation, fever, leukocytosis), which makes attribution of individual events to spesolimab vs disease activity challenging.
Pharmacokinetics
Section 12.3 โ Prescribing InformationRoute
IV Infusion
900 mg over 90 minutes; 100% bioavailable
Cmax (ADA-negative GPP)
238 mcg/mL
95% CI: 218โ256 mcg/mL after single 900 mg dose
AUCโโโ
4750 mcgยทday/mL
95% CI: 4510โ4970 in ADA-negative GPP patients
Volume of Distribution (Vss)
6.4 L
Consistent with vascular compartment distribution
Clearance
0.184 L/day
95% CI: 0.175โ0.194 L/day (70 kg, ADA-negative)
Terminal Half-Life
25.5 days
95% CI: 24.4โ26.3 days; independent of dose
PK Properties Summary
| PK Parameter | Value / Finding |
|---|---|
| Dose proportionality | AUC increases proportionally from 0.3 to 20 mg/kg |
| CL dose-dependence | CL and tยฝ independent of dose (linear range) |
| Body weight effect | Lower concentrations in higher-weight subjects; clinical impact unknown |
| Age / Gender / Race | No clinically relevant effect on PK in population PK analysis |
| Hepatic impairment | No formal study conducted; IgG1 not expected to undergo hepatic elimination |
| Renal impairment | No formal study; IgG1 not expected to undergo renal elimination |
| Drug interactions | No formal DDI studies conducted |
| Metabolism | Not characterized; expected degradation to peptides/amino acids via catabolic pathways (as for endogenous IgG) |
Immunogenicity
ADA development: In Effisayil-1, anti-drug antibodies (ADAs) developed with a median onset of 2.3 weeks after infusion. By Weeks 12โ17, 24% (12/50) of subjects had maximum ADA titers >4000 with neutralizing activity. Females had substantially higher immunogenicity rates (30% vs 12% in males). High-titer ADA (>4000) was associated with significantly reduced plasma spesolimab concentrations.
Mechanism of Action
Section 12.1| Feature | Detail |
|---|---|
| Antibody class | Humanized monoclonal IgG1 (~146 kDa) |
| Target | IL-36 receptor (IL36R) |
| Ligands blocked | IL-36ฮฑ, IL-36ฮฒ, IL-36ฮณ (all three cognate ligands) |
| Downstream effect | Blocks NF-ฮบB and MAPK-driven pro-inflammatory and pro-fibrotic gene expression |
| Production | Chinese hamster ovary (CHO) cells; recombinant DNA technology |
| Formulation pH | 5.0โ6.0 |
| Excipients | Arginine HCl, glacial acetic acid, polysorbate 20, sodium acetate, sucrose, WFI |
Pharmacodynamics
The pharmacodynamics of spesolimab in GPP have not been fully characterized (Section 12.2). Rapid onset of pustular clearance โ with 54% of patients achieving a GPPPGA pustulation score of 0 by Day 7 โ suggests effective IL-36 pathway suppression within one week of administration. The relationship between receptor occupancy, IL-36 biomarker suppression, and clinical response remains an area of ongoing characterization.
Dosing & Administration
Section 2 โ Prescribing InformationInitial Dose
- 900 mg IV as a single infusion over 90 minutes
- Dilute in 100 mL NS (draw and discard 15 mL; replace with 15 mL SPEVIGO from two vials)
- Administer through 0.2 micron low-protein-binding in-line filter
- Flush line with 0.9% NaCl before and after infusion
- Total infusion time (including stop time) must not exceed 180 minutes
Optional 2nd Dose
- If GPP flare symptoms persist at Week 1, a second 900 mg IV dose may be administered
- Administered one week after the initial dose
- Maximum of 3 total doses throughout study (including rescue dosing)
- Open-label rescue dose permitted for recurrent flares (Weeks 1โ12)
Preparation
- Use aseptic technique
- Two vials (450 mg/7.5 mL each) = 900 mg total
- Do not shake; mix gently
- Colorless to slightly brownish-yellow; discard if cloudy or particulate
- Diluted solution: use immediately or refrigerate โค4 hours at 2ยฐโ8ยฐC; protect from light
Pre-Treatment Evaluation
- Evaluate for active or latent tuberculosis before initiation
- Do not initiate during any clinically important active infection
- Consider anti-TB therapy before starting if latent TB or unconfirmed TB history
- No live vaccines concurrent with or after treatment
Dosage Forms & Strengths
| Parameter | Detail |
|---|---|
| Concentration | 60 mg/mL (450 mg in 7.5 mL per vial) |
| Vials per carton | 2 single-dose vials (NDC 0597-0035-10) |
| Appearance | Sterile, preservative-free, colorless to slightly brownish-yellow, clear to slightly opalescent |
| Storage (unopened) | Refrigerate 2ยฐโ8ยฐC; protect from light; do not freeze. May store at room temperature (20ยฐโ25ยฐC) โค24 hrs before use. |
Contraindications
- Severe or life-threatening hypersensitivity to spesolimab-sbzo or any SPEVIGO excipients, including reactions that have included DRESS
Warnings & Precautions
Infections (5.1)
May increase infection risk. Do not initiate during active infection. Infections in 14% SPEVIGO vs 6% placebo at Week 1. Evaluate and monitor throughout.
Tuberculosis (5.2)
Evaluate all patients for TB before starting. Do not administer to patients with active TB. Consider anti-TB therapy for latent TB before initiation. Monitor during and after treatment.
Hypersensitivity & Infusion Reactions (5.3)
Includes immediate (anaphylaxis) and delayed (DRESS) reactions. Discontinue immediately for serious reactions. For mild-to-moderate IRR: stop, treat with antihistamines/steroids, restart at slower rate.
Vaccinations (5.4)
Avoid live vaccines during and after treatment with SPEVIGO. No formal studies of live vaccines in SPEVIGO-treated patients.
Use in Specific Populations
| Population | Guidance |
|---|---|
| Pregnancy | Limited human data; IgG crosses placental barrier. Animal studies (mouse surrogate) showed no embryo-fetal or postnatal toxicity at 50 mg/kg. Use with caution; risk/benefit discussion required. |
| Lactation | No data on presence in human milk. Monoclonal antibodies expected to be present. Consider benefits of breastfeeding vs. maternal need. |
| Pediatric Use | Safety and effectiveness not established in patients <18 years. |
| Geriatric Use | Only 2 subjects (6%) aged 65โ74 in Effisayil-1. Insufficient data to determine differential response in โฅ65 years. |
| Body Weight | Higher body weight associated with lower plasma concentrations. Clinical impact unknown. |
Regulatory History
BLA 761179 ยท Boehringer IngelheimReview Designation
Priority Review
Granted due to serious unmet need in rare GPP disease
Application Type
BLA
Biologics License Application (novel biologic)
Approval Date
Sep 1, 2022
First-in-class IL-36R antagonist; first GPP-specific approval
Label Revision
09/2022
Initial approval label โ check FDA for updates
Regulatory Timeline
2018โ2020
Phase 1 / Early Clinical Development
Spesolimab entered clinical development for GPP and other inflammatory indications including hidradenitis suppurativa and psoriatic arthritis.
NCT03782792 ยท 2019โ2021
Effisayil-1 Phase 2 Trial
Randomized, double-blind, placebo-controlled trial in 53 adults with moderate-to-severe GPP flares. 2:1 randomization; primary endpoint: GPPPGA pustulation score = 0 at Week 1.
2022 ยท Pre-Approval
BLA 761179 Submission
Boehringer Ingelheim submitted BLA for spesolimab-sbzo under the name SPEVIGO for GPP flares in adults. Priority Review designation granted.
September 1, 2022
FDA Approval โ SPEVIGO (spesolimab-sbzo)
First drug approved specifically for GPP flares in adults. First-in-class IL-36R antagonist. Approved dose: 900 mg IV ร 1 (with optional 2nd dose at Week 1). NDC: 0597-0035-10.
September 2022
Prescribing Information Issued (Ref ID: 5039554)
Initial U.S. prescribing information published. Label includes Effisayil-1 data only. Patients should be screened for TB and active infections prior to use.
Ongoing
Effisayil-2 / Post-Marketing Studies
Continued clinical development including maintenance dosing regimens and pediatric GPP indications. Subcutaneous formulation and chronic suppression data anticipated from ongoing trials.
Key Regulatory Reference Documents
| Document | Reference / Source |
|---|---|
| Prescribing Information (Label) | BLA 761179 ยท Ref ID: 5039554 ยท Revised 09/2022 |
| Drugs@FDA | BLA 761179 Approval Letter |
| Clinical Trial (Effisayil-1) | NCT03782792 ยท ClinicalTrials.gov |
| Manufacturer | Boehringer Ingelheim Pharmaceuticals, Inc. ยท Ridgefield, CT ยท US License #2006 |
| Licensed From | Boehringer Ingelheim International GmbH ยท Ingelheim, Germany |
| NDC | 0597-0035-10 (carton of 2 ร 450 mg/7.5 mL single-dose vials) |
Nonclinical Toxicology Summary
| Study | Finding |
|---|---|
| Carcinogenicity | Not conducted with spesolimab-sbzo |
| Mutagenicity | Not conducted with spesolimab-sbzo |
| Fertility (mice, surrogate IL36R mAb) | No adverse effects on male or female fertility at doses up to 50 mg/kg twice weekly IV |
| Embryo-fetal development (mice, surrogate) | Twice weekly IV up to 50 mg/kg during organogenesis: no embryo-fetal lethality or malformations |
| Pre-/postnatal development (mice, surrogate) | GD6โLD18 dosing: no maternal effects; no effects on postnatal development, neurobehavior, or reproductive performance of offspring |
Data sourced from FDA Prescribing Information (BLA 761179, Ref ID 5039554) and FDA label dated September 2022. For current labeling, visit https://www.fda.gov/drugsatfda. TrialistMD provides clinical research intelligence for educational purposes only.
