Tuba Bukhari, BSc, MBT1*; Mariya Markovina, BSc, MSc1*; Abrahim Abduelmula, BScN2; Brian D. Rankin, MD, PhD3; Ronald Vender, MD, FRCPC4,5; Jensen Yeung, MD, FRCPC6-9; Alim R. Devani, MD, FRCPC1,9,10; Vimal H. Prajapati, MD, FRCPC1,3,9-12
*Co-first authors

1Dermatology Research Institute, Calgary, AB, Canada
2Faculty of Medicine, University of Western Ontario, London, ON, Canada
3Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
4Department of Dermatology, McMaster University, Hamilton, ON, Canada
5Dermatrials Research Inc. & Venderm Consulting, Hamilton, ON, Canada
6Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
7Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
8Sunnybrook Health Sciences Centre, Toronto, ON, Canada
9Probity Medical Research, Waterloo, ON, Canada
10Skin Health & Wellness Centre, Calgary, AB, Canada
11Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
12Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest: Ronald Vender has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, Aralez, Arcutis, Astellas, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Centocor, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Innovaderm, Janssen, Kabi-Care, LEO Pharma, Merck, Novartis, Palladin, Pfizer, Regeneron, Sandoz, Sun Pharma, Takeda, UCB, and Viatris-Mylan. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Alim R. Devani has been an advisor, consultant, speaker, and/ or investigator for AbbVie, Amgen, AnaptysBio, Arcutis, Arena, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Takeda, Tribute, UCB, and Valeant. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Apogee Therapeutics, Aralez, Arcutis, Arena, Asana, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, RAPT Therapeutics, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Takeda, Tribute, UCB, and Valeant. Tuba Bukhari, Mariya Markovina, Abrahim Abduelmula, and Brian D. Rankin have no relevant disclosures. Funding sources: None.

Abstract: Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations. Mutations in the interleukin-36 receptor antagonist (IL36RN) gene have been implicated in its pathogenesis. Spesolimab is a novel systemic biologic therapy that selectively inhibits interleukin-36. It was recently approved by Health Canada and the US FDA for the treatment of GPP flares in adults. Results from phase 1 and 2 studies have been promising. Herein, we review the efficacy and safety of spesolimab for the treatment of GPP flares, as demonstrated in clinical trials.

Keywords: spesolimab, generalized pustular psoriasis, clinical trial, biologics, interleukin-36

Introduction

Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations, which, if left untreated, can be life-threatening in certain instances.1,2 According to the European Rare and Severe Psoriasis Expert Network (ERASPEN) criteria, GPP is defined by the presence of “primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques)”, with 3 subclassifications, including “with or without systemic inflammation”, “with or without psoriasis vulgaris”, and “either relapsing (>1 episode) or persistent (>3 months)”.3 The prevalence of GPP varies with geographic location, where it was reported to be higher in Italy, impacting 180 cases per million, but lower in Japan, Germany, and France with 7.5, 5.0, and 1.8 cases per million, respectively.4,5 GPP can have a pediatric- or adult-onset, and there is a slight female predilection.3 GPP adversely affects patient quality of life (QoL) and can also have a profound negative impact on families.6

Homozygous, heterozygous, and compound heterozygous lossof- function mutations in the interleukin (IL)-36 (IL-36) receptor antagonist gene (IL36RN), as well as mutations in other genes involved in the IL-36 signaling pathway, including, CARD14, AP1S3, and SERPINA3, have been identified in a proportion of patients with GPP.7-9 Moreover, genotype-phenotype studies revealed that 24% of patients with GPP had IL36RN gene variants. The latter was associated with earlier age of onset/diagnosis, a greater degree of inflammation, and more severe disease.10,11

Presently, there are no universally-accepted international consensus guidelines regarding the management of GPP. In the majority of countries, current first-line systemic therapies are being used offlabel. These include non-biologics, such as acitretin, cyclosporine, methotrexate, and apremilast, as well as biologics, including inhibitors of tumor necrosis factor-alpha, IL-12/23, IL-23, and IL-17.12-14 Thus, there remains a significant unmet need for an advanced targeted systemic therapy that effectively treats acute GPP flares. Recently, Health Canada and the US FDA approved spesolimab, a novel IL-36 inhibitor, for the latter indication in adults.1 This biologic is the first commercially available IL-36 inhibitor for any indication.

Background

Spesolimab (Spevigo®) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively inhibits the IL-36 receptor (IL-36R), thereby preventing activation of the IL-36 signaling pathway which leads to release of the pro-inflammatory cytokines (IL-36A, IL-36B, and IL-36G) that cause GPP.1 By inhibiting the overexpression of IL-36 cytokines, clinical resolution of acute flares can be observed.15

Available as single-use vials containing 450 mg of spesolimab in a 7.5 mL solution (60 mg/mL), spesolimab is administered as an intravenous (IV) infusion.6 The recommended dosage for adult patients is a single 900 mg IV dose over 90 minutes.1

Non-medicinal ingredients of the spesolimab product include arginine hydrochloride, glacial acetic acid, polysorbate 20, sodium acetate, sucrose, and water. No data is currently available for its use in pediatric or pregnant patients; therefore, spesolimab has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended in pregnant or nursing women.1

Supporting Evidence from Clinical Trials

Results from Phase 1 Studies

In a phase 1, multicenter, single-arm, open-label, proof-of-concept clinical trial, a single 10 mg/kg IV dose of spesolimab (formerly named BI 555130) was evaluated in adult patients (n=7) with a GPP flare.2 The latter was defined as adult patients with an overall Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 3 or greater (GPPGA total score ≥3) and a GPPGA pustulation subscore of 2 or greater (GPPGA pustulation subscore ≥2). Safety and tolerability were the primary endpoints, with efficacy, including improvements in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) and GPPGA, as the secondary endpoints.

At week 2, improvements in GPPASI were achieved by all patients, with 73.2% of patients achieving a score of clear (GPPASI 0) and pustules being completely cleared (GPPGA pustulation subscore of 0) in 85.7% of patients. In addition, the proportion of patients achieving a GPPGA total score of clear or almost clear (GPPGA 0/1) was achieved by 71.4% of patients by week 1 and 100% of patients by week 4. There were also improvements seen in patient-reported outcomes (PROs) at week 2, with the mean (standard deviation [SD]) change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F) being 12.3 (10.1) and mean (SD) change from baseline in the Visual Analog Scale for pain (Pain-VAS) being -45.9 (32.3). Safety evaluation revealed that by week 20, four patients experienced treatment-emergent adverse events (TEAEs), all of which were mild or moderate in intensity. The most commonly reported TEAEs included eosinophilia and upper respiratory tract infection in two patients each. There were no serious AEs or deaths.2

In this study, patients underwent screening for mutations in genes thought to be involved in the pathogenesis of GPP, including IL36RN, CARD14, and AP1S3. Genetic testing revealed that two patients had homozygous loss-of-function mutations in IL36RN, and one patient had a homozygous mutation in IL36RN as well as a heterozygous mutation in CARD14. Treatment responses were consistent across all patients, irrespective of genetic mutation status.2

Table 1: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 1 clinical trial.

PHASE 1 WEEK 1 WEEK 2 WEEK 4
Proportion of patients achieving GPPGA total score 0/1 71.4% NR 100%
Proportion of patients achieving GPPASI50 85.7% NR NR
Proportion of patients achieving GPPASI75 NR NR 71.4%
Percent change in mean GPPASI from baseline NR 73.2% 79.8

Percent of patients achieving GPPGA pustulation subscore of 0a

71.4% 85.7% NR
Percent reduction in mean GPPASI subscores (erythema/scaling) from baseline

27.8%/38.1%b

53.5%/49.6%b

53.5%/57.1%b

Change in mean FACIT-F score from baseline NR 12.3-point improvement 12.3-point improvement
Change in mean pain-VAS score from baseline NR 45.9-point reduction 45.9-point reduction

Table 1: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 1 clinical trial.2

aDefined as complete clearance of pustules.
bRefers to erythema and scaling respectively.
Abbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; GPPGA, Generalized Pustular Psoriasis Physician Global Assessment; GPPASI, Generalized Pustular Psoriasis Area and Severity Index; NR, not reported; VAS, Visual Analogue Scale.

Results from Phase 2 Studies

In a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial (Effisayil™ 1), the efficacy and safety of a single 900 mg IV dose of spesolimab (n=35) versus placebo (n=18) were evaluated in adult patients with a GPP flare.16 The latter was defined as a GPPGA total score ≥3, GPPGA pustulation subscore ≥2, and affected body surface area (BSA) ≥5%. All patients were followed for 12 weeks.

At week 1, the primary efficacy endpoint of GPPGA pustulation subscore of 0 (clearance of pustules) was achieved by 54% and 6% of patients treated with spesolimab and placebo, respectively (p<0.001); in addition, the GPPGA total score 0/1 was achieved by 43% and 11% of patients treated with spesolimab and placebo, respectively (p=0.02). On day 8, in addition to patients who received spesolimab on day 1 (n= 35), including those who received a second, optional dose of spesolimab on day 8 (n=12), a proportion of placebo-treated patients also received open-label spesolimab (n=15). The secondary efficacy endpoint of 75% improvement in GPPASI (GPPASI75) was achieved by 51.4% of patients by week 4 and 57% of patients by week 12.16 PROs also improved by week 4, with a median (interquartile range [IQR]) change from baseline in Pain-VAS score of -53.4 (-77.9, -20.2), a median (IQR) change from baseline in the Psoriasis Symptom Scale (PSS) score of -7.0 (-10.0, -3.0), and a median (IQR) change from baseline in FACIT-F score of -22.0 (1.0, 31.0). In addition, patients from the placebo group who received open-label spesolimab on day 8 had comparable positive outcomes in physician-rated outcomes and PROs to those who received spesolimab at the start of the study.16

After one week, safety evaluations revealed similar rates of AEs between the treatment groups (spesolimab: 66%; placebo: 56%). In addition, TEAEs were similar between the spesolimab (29%) and placebo (28%) treatment groups. Among AEs in the spesolimab-treated group, infections (17%) were the most common AE reported after week 1, with the incidences increasing by week 12 (47.1%). After week 1, infections included: urinary tract infection (n=2), bacteremia (n=1), bacteriuria (n=1), cellulitis (n=1), herpes dermatitis (n=1), oral herpes (n=1), pustule (n=1), and upper respiratory tract infection (n=1). Serious AEs were reported in 6% and 12% of spesolimab-treated patients by week 1 and week 12, respectively. Two patients receiving spesolimab reported drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome; however, based on the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring criteria (score <2: no DRESS; score of 2 or 3: possible DRESS; score of 4 or 5: probable DRESS; score >5: definite DRESS), these diagnoses and casual associations are not certain. In the first patient, the RegiSCAR score was 1, suggesting that the diagnosis was not compatible with DRESS. In the second patient, the RegiSCAR score was 3, indicating possible DRESS; yet, in addition to spesolimab, the patient received concomitant spiramycin and paracetamol (acetaminophen), then experienced a recurrence of the same signs/symptoms with a spiramycin rechallenge months after resolution of the first episode, suggesting spiramycin as a potential causative agent. No AEs led to treatment or study discontinuation.16

Table 2: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 2 clinical trial.

PHASE 2 (Effisayil-1™)
WEEK 1 Spesolimab Placebo P-Value
Proportion of patients achieving GPPGA pustulation subscore of 0 54% 6% <0.001

Proportion of patients achieving GPPGA total score 0/1a

43.4% 11% 0.02
WEEK 4 Spesolimab Placebo P-Value
Proportion of patients achieving GPPASI75 51.4% NR NR
Change in mean pain-VAS score from baseline 53.4-point reduction NR NR
Percent change in mean FACIT-F score from baseline 22-point improvement NR NR
Change in mean PSS score from baseline 7-point reduction NR NR
WEEK 12 Spesolimab Placebo P-Value
Percent of patients achieving GPPASI75 57% NR NR

Table 2: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 2 clinical trial.16

aDefined as clear or almost clear with respect to a GPPGA total score of 0 as clear and 1 as almost clear.
Abbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; GPPGA, Generalized Pustular Psoriasis Physician Global Assessment; GPPASI, Generalized Pustular Psoriasis Area and Severity Index; PSS, Psoriasis Symptom Scale; NR, not reported; VAS, Visual Analogue Scale.

Summary of Results from Phase 1 and Phase 2 Studies

In summary, clinical trial results suggest that IL-36 inhibition with spesolimab leads to rapid and sustained improvements in GPP flares in adult patients with a favorable safety profile. Results from both the phase 1 and phase 2 studies demonstrated rapid clearance of pustules, with many patients experiencing clear or almost clear skin after one dose of spesolimab. The safety profile of spesolimab revealed slightly higher rates of infection compared to placebo. There were also two reports of DRESS in the phase 2 clinical trial, although both cases were determined to be non-definitive. Larger sample sizes are required to confirm the safety risks associated with spesolimab use in GPP; in addition, given that this is a rare condition, long-term efficacy and safety data from clinical trials and real-world studies will be of utmost importance in order to elucidate spesolimab’s place in the therapeutic paradigm for GPP.

Spesolimab was also shown to have a positive impact on PROs in GPP patients, including pain, fatigue, and QoL in both phase 1 and phase 2 studies. In the phase 2 clinical trial, PROs particularly improved after one week in comparison to the placebo, with scores continuing to improve past week 4 and maintained until the end of the study at week 12. Despite the individual differences in the clinical progression of GPP, there were rapid and maintained overall improvements in PROs.

Specific Populations

Data on the treatment of GPP using spesolimab is not yet available in children or adolescents (<18 years of age); however, a phase 2b, multicenter, double-blind, placebo-controlled clinical trial (Effisayil™ 2) evaluating the efficacy and safety of maintenance treatment with subcutaneous spesolimab in patients aged 12-75 years is currently ongoing.17 Although 6% of patients were aged 64-75 years in the phase 2 clinical trial, due to insufficient sample size, efficacy and safety have not been determined in elderly populations.1

Counselling: Practical Tips to Optimize Use

In preparation for injection, spesolimab must be diluted with 15 mL of sterile 0.9% sodium chloride solution and promptly used. Spesolimab is administered as a single 900 mg dose by continuous IV infusion over a period of 90 minutes in an outpatient setting by a healthcare provider. If the infusion is slowed or interrupted, the total infusion time should not exceed 180 minutes. Pre-existing IV lines may be used as long as they are flushed with a sterile 0.9% sodium chloride solution prior to and after spesolimab administration. If GPP flare signs/symptoms continue, this dosing regimen can be repeated one week after the initial dose.1

Patients must be informed about the importance of disclosing their complete history of chronic and recurrent infections to their healthcare provider, as spesolimab can increase the risk of infection. Patients should be advised to seek immediate medical attention if they develop new signs/symptoms of infection or infusion-related hypersensitivity reactions, such as anaphylaxis or DRESS after spesolimab use. Patients should also be advised against receiving live vaccines after spesolimab treatment has started, as no studies have been conducted in spesolimab-treated patients that have previously received live bacterial or viral vaccines.1

Conclusions

A single IV dose of spesolimab is an effective and safe treatment for adult patients presenting with GPP flares. Results of clinical trials using spesolimab indicate that medications targeting the IL-36 pathway can be successful therapeutic interventions to improve the clinical signs and symptoms of GPP. Further long-term studies with larger sample sizes, the inclusion of more pediatric and elderly patients, and the exploration of various dosing regimens for maintenance treatment are required to more accurately assess the efficacy and safety of spesolimab.

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