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.

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.

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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¹Rush University Medical Center, Department of Dermatology, Chicago, IL, USA
²SkinCare Physicians, Chestnut Hill, MA, USA
³Yale University School of Medicine, Department of Dermatology, New Haven, CT, USA

Conflict of interest: Julie Bittar and Perry Hooper have no conflicts to disclose. Jeffrey Dover has received funding for research and consulting from Cutera Inc.

Abstract: The treatment of acne vulgaris traditionally consists of a combination of topical and oral medications. The use of lasers to treat this condition has been an area of increasing research, and several types have previously been used in the treatment of acne. New 1726 nm lasers specifically target the sebaceous gland, which is known to be pivotal in acne pathophysiology. This laser wavelength demonstrates substantial potential as a safe and effective therapeutic option for moderate to severe acne without the risks of systemic therapy. This paper reviews the 1726 nm lasers for acne vulgaris.

Keywords: 1726 nm laser, acne laser, laser acne treatment, laser treatment, contact cooling, forced-air cooling, acne vulgaris, acne scarring, acne severity, acne skin types, acne treatment, sebaceous glands, selective photothermolysis

Introduction

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit. The pathophysiology of acne formation is multifactorial. Elevation of androgen levels, associated with puberty, lead to increased production of sebum in the pilosebaceous unit. This is accompanied by proliferation of Cutibacterium acnes (C. acnes) and resultant inflammation. While several factors have been associated with acne formation and progression, the sebaceous gland has long been known to play an essential role in the disease.

Various treatments are typically used in the management of acne vulgaris. Standard treatments for moderate to severe acne use a combination of topical and systemic medications, light-based therapy, lasers, photodynamic therapy, radiofrequency devices, and other physical modalities, but supporting studies of their effectiveness have been limited.¹ Use of lasers is an area of increasing research as several devices have shown promise in the reduction of acne lesions and improvement of the overall appearance of skin (Table 1).² Very recently, two new 1726 nm lasers which target sebaceous glands were approved by the US FDA for the treatment of acne.

The efficacy of these devices is based on the theory of selective photothermolysis.³ Selective photothermolysis is the precise and localized injury of microscopic tissue targets through a combination of selective light absorption and a pulse duration less than or equal to the thermal relaxation time (TRT) of a target chromophore. Simply stated, different structures preferentially absorb specific wavelengths of light. By using these “absorption peaks”, specific chromophores (e.g., sebaceous gland) can be targeted while sparing other structures. The result is an increased efficacy and safety profile. In 2012, Sakomoto et al. studied the absorption spectrum of sebum to determine feasibility of selective photothermolysis of sebaceous glands.² They found that at 1726 nm, in vivo sebum has 1.2x the optical absorption of water. Further, laser-induced heating was approximately 1.5x higher in sebaceous glands than water at 1710 nm and 1720 nm. Thermal imaging showed focal heating near sebaceous follicles. Histologic evaluation demonstrated selective thermal damage to sebaceous glands while the epidermis remained undamaged.⁴

Supporting Data

1726 nm lasers have been tested in all skin types and, because of low absorption in pigment, these systems have been found to be safe in all skin types. The two FDA approved 1726 nm devices are the AviClear Laser System (Cutera, Inc.) and Accure Laser System (Accure Acne Inc.) (Table 2).

The AviClear device is a 1726 nm laser that treats acne via selective photothermolysis of the sebaceous gland. It is FDA approved to treat mild to severe inflammatory acne in all skin types. AviClear uses a 3 mm spot size and contact cooling to prevent damage to other surrounding structures. As there is no visible clinical endpoint for the 1726 nm lasers, the AviClear laser treats to a target fluence, which correlates to sebaceous gland destruction. The Accure laser treats to a target epidermal temperature, which also correlates to sebaceous gland destruction. The duration of each treatment is approximately 30 minutes. In a study by Scopelliti et al., the authors tested the 1726 nm AviClear device at a fluence of 20.5 J/cm² on human facial skin around the ear and then biopsied the site 5 days post treatment. Histology showed total necrosis of the sebaceous gland with complete sparing of the epidermis and follicular epithelium.

Early evidence for this device is promising. Goldberg et al. studied the AviClear device in 17 patients and performed three treatments, spaced up to 7 weeks apart. All patients tolerated the treatment without anesthetic (discomfort score of 4.9± 1.5 out of 10). Patients had statistically significant reductions in acne with a 52% reduction in inflammatory lesion count within 1 month of treatment and a 97% reduction 24 months after the last treatment.⁵ A larger, non-randomized, open label study by Alexiades et al. enrolled 104 patients with moderate to severe acne, allowed for a 30-day washout of all acne products, and then performed 3 monthly treatments utilizing the 1726 nm AviClear laser. Three dermatologists assessed patients at baseline and post-treatment at 4-, 12-, and 26-week timepoints utilizing Investigator’s Global Assessment (IGA) scale. An IGA score of 0 correlates to clear skin, IGA 1 is almost clear, IGA 2 is mild, IGA 3 is moderate, and IGA 4 indicates severe acne. The authors found that at 3 months, 87% of patients achieved a score of IGA 1+, 47% achieved IGA 2+, and 36% were clear or almost clear. Additionally, at the 12 month follow-up, 93% of patients had achieved IGA 1+, 79% with IGA2+, and 68% were clear/almost clear.⁶ Furthermore, there is no available data on the differences in outcomes for facial versus truncal acne outcomes with this device, however, AviClear is currently developing a truncal handpiece.

The Accure device is another FDA approved 1726 nm laser that treats mild to severe inflammatory acne vulgaris via selective photothermolysis of the sebaceous gland. This device employs an infrared camera for real-time, continuous, epidermal temperature monitoring. This allows for a peak epidermal temperature (PET) of 40°C-46°C depending on body site to serve as the objective clinical endpoint. The PET correlates with selective sebaceous gland damage. The epidermis is protected via highly controlled, forced air cooling. These therapeutic and safety measures also allow use in all skin types. There are two “modes” on the device, “Standard Mode” and “Boost Mode”. The primary difference in these two modes lies in the anesthetic used. The Standard Mode utilizes injectable anesthesia (lidocaine/1% epinephrine/saline/sodium bicarbonate mixture) while the Boost Mode uses a topical anesthetic. The Boost Mode also utilizes a unique proprietary pulsing method. A single-use patient treatment kit contains a one-time-use device tip as well as template grids that guide the spacing of injection points. Using a marker, the markings are spaced 13 mm apart for the first treatment then 11.5 mm apart for the following treatments. The primary investigators found that this spacing interval provided safe and optimal results.⁷ The duration of each treatment is approximately 45 minutes.

To date, 10 institutional review board-approved clinical trials with more than 180 patients with mild to severe acne have been treated. It should be noted that all data described below is preliminary and unpublished.

In a previously presented study of 12 patients treated using the standard mode by Tanghetti et al., there was an 80% reduction in acne lesions noted 12 weeks after a fourth monthly treatment.⁸ An additional 30 patients treated in Standard Mode were enrolled in Accure’s facial acne trial. In this trial, there was a 100% responder rate, defined as a 50% reduction in active lesions, noted at 4, 8, 12, and 24 weeks after four monthly treatments post-treatment for patients with more than 5 acne lesions. There was an 82% average lesion reduction at 12 weeks following four monthly treatments and a 90% decrease at 12 months. The most commonly reported side effects with the Accure laser are post-treatment erythema, edema, and acne flares. Dryness and crusting are also possible, but rare.⁹

Initial data from Accure’s ongoing Boost Mode clinical trials showed a median reduction of inflammatory acne lesion counts of 79%, 68%, 75%, and 90% at 12, 26, 39, and 52 weeks, respectively, after four monthly treatments. However, only 17 of 35 patients were available for long-term data collection. The authors also showed a 100%, 83%, 80% and 88% responder rate, defined as a 50% reduction or greater in acne lesions, at 12, 26, 39, and 52 weeks.

Additionally, there is no available data for the difference in outcomes for facial versus truncal acne with the Accure device. This device currently uses the same single-use patient tip for all treatment areas and different target PET settings depending on body site.

Conclusion

1726 nm lasers appear to be effective and well tolerated therapeutic options for the treatment of mild to severe inflammatory acne vulgaris while eliminating the risks of systemic agents. The results from studies demonstrate significant reduction of inflammatory lesion count and do not report on comedonal lesions. The effects of both of these devices on comedonal acne still need to be investigated. As these devices are used in non-study settings, more will be learned about their effectiveness and how to best incorporate them into our acne therapeutic armamentarium. To date, no direct clinical comparisons have been made between the AviClear and Accure lasers.

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