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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¹Department of Medicine, University of Toronto, ON, Canada
²Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
³Department of Dermatology, Women’s College Hospital, Toronto, ON, Canada
⁴Probity Medical Research, Peterborough, ON, Canada
⁵SKiN Center for Dermatology, Peterborough, ON, Canada
⁶Queen’s University, Kingston, ON, Canada

Conflict of interest: Karla Machlab has no conflicts of interest. Jensen Yeung has served as an investigator, speaker, and/or advisory board member for, and/or received grants/honoraria from: AbbVie, Amgen, Anacor, Astellas, Arcutis, Bausch Health, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, Incyte, Janssen, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, and Xenon. Melinda Gooderham serves as the Vice President of the Dermatology Association of Ontario and has served as an investigator, speaker, advisor and/or consultant for, and/or received grants/honoraria from: AbbVie, Akros, Amgen, Arcutis, Aslan, Aristea, AnaptysBio, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Meiji, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, and UCB. Funding sources: None.

Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease associated with psoriasis. Its major clinical domains include peripheral and axial arthritis, enthesitis, dactylitis and skin and nail involvement. Approximately 30% of patients with psoriasis develop psoriatic arthritis. The pathophysiology of PsA is complex and involves a dysregulated immune response. In particular, interleukin (IL)-23 is a major regulatory cytokine that has been implicated in PsA, including bone remodeling, enthesitis, synovitis and psoriatic lesions. Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that targets the p19 subunit of IL-23. It has been approved for the treatment of moderate-to-severe plaque psoriasis and, more recently, PsA. The efficacy and safety of risankizumab for the treatment of PsA has been demonstrated in phase 2 and phase 3 clinical trials. Risankizumab showed efficacy in decreasing the number of swollen and tender joints, clearing psoriatic plaque and improving quality of life. Treatment with risankizumab was well-tolerated, with the most common adverse event being upper respiratory tract infection. Overall, the current literature demonstrates that risankizumab is both a safe and effective therapeutic option for the treatment of PsA. Herein, week 24 and 52 results are reviewed.

Keywords: risankizumab, Skyrizi®, IL-23, psoriatic arthritis

Introduction

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease characterized by a range of clinical features including arthritic inflammation, dactylitis, enthesitis, and skin and nail changes. PsA may also be associated with multiple comorbidities including type 2 diabetes, hypertension, metabolic syndrome and cardiovascular disease.^1,2 Accordingly, PsA can greatly impair one’s quality of life (QoL) and therefore prompt intervention is crucial.^3,4

PsA affects males and females equally with an estimated prevalence of 1-2 in 1000.⁵ Approximately 30% of patients with psoriasis will develop PsA.^6-8sup> Given the high prevalence of PsA, it is important to continue to find effective and safe therapeutic options. This review focuses on the current literature regarding the efficacy and safety of risankizumab for the treatment of PsA up to 52 weeks of treatment.

Pathophysiology

The pathophysiology of PsA is complex and multifactorial. Although the exact mechanism is not completely understood, genetic and environmental factors interact to trigger immune pathways. PsA is associated with class II major histocompatibility complex (MHC) alleles, including HA-B*27, B*0801, B*3801 and B*3901.⁹ Risk factors include severe psoriasis, scalp, inverse or nail psoriasis, obesity and trauma (Koebner phenomenon).¹⁰ T-cells are major effectors in PsA and the role of CD8+ T-cells is supported by a strong association with HLA-1 alleles.¹¹ Type 17 T-cells, which include CD4+ type 17 helper T (Th17) cells, and type 3 innate lymphocytes, which produce interleukin (IL)-17 and IL-22, are increased in synovial fluid in patients with PsA.¹²

IL-23/IL-17 and tumor necrosis factor (TNF) pathways also play a central role and contribute to most domains of PsA, including synovitis, enthesitis, axial inflammation and psoriatic plaques. Dendritic cells produce IL-23, which triggers the differentiation and proliferation of Th17 cells, and activates other cytokine pathways including IL-17, IL-22 and TNF-α.¹³ These subsequently activate downstream effector cells, including keratinocytes, fibroblasts, osteoclast precursors, B-cells and macrophages. An inflammatory immune response is initiated resulting in keratinocyte proliferation, bone erosion and pathologic bone formation. Murine models have shown that administration of IL-23 leads to entheseal inflammation, inflammatory arthritis, bone erosion, periosteal bone formation, and increased production of IL-17.^14,15

Overview of Therapy

Treatment of PsA is initially guided by severity of disease and, importantly, the degree of activity in each of the domains. Mild PsA can be managed with non-steroidal anti-inflammatory drugs (NSAIDs) or intra-articular steroids. However, in moderateto- severe PsA, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, leflunomide or sulfasalazine are typically used first line. Newer novel agents, such as phosphodiesterase-4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, and biologic DMARDs (bDMARDs) are also approved efficacious agents. Biologics include TNF, IL-17, and IL-12/23 or IL-23 inhibitors.

TNF inhibitors were previously considered gold standard and are effective at improving clinical signs and symptoms of PsA and reducing radiographic progression of disease.¹⁶ Currently, five TNF inhibitors (etanercept, adalimumab, golimumab, certolizumab and infliximab) are approved for the treatment of PsA. The efficacy and safety of these agents are comparable;^17,18 ultimately, the choice of agent depends on factors such as patient preference for route and frequency of administration, physician experience, availability, and cost. Patients must be screened for latent tuberculosis and hepatitis B virus (HBV) infections and treated prophylactically if there is evidence of current or prior infection.¹⁹ Moreover, TNF inhibitors are contraindicated in patients with significant heart failure, recent malignancy or a family history of multiple sclerosis.^20,21 Newer classes of biologics have also been approved for the treatment of PsA and these include cytokine inhibitors anti-IL-17 (secukinumab and ixekizumab), anti-IL-12/23 (ustekinumab), and anti-IL-23 (guselkumab and risankizumab). These cytokine inhibitors have proven to be effective in treating PsA and are especially useful in patients who have contraindications to TNF inhibitors, but caution should be exercised with IL-17 inhibitors in patients with a history of inflammatory bowel disease.

Risankizumab for the Treatment of Psoriasis

Risankizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets the p19 subunit of IL-23. In 2019, it was approved for the treatment of moderate-to-severe plaque psoriasis. Administration follows a dosing schedule of 150 mg at week 0, week 4, and then every 12 weeks thereafter. Several clinical trials have established its ability to treat psoriasis with high efficacy and safety compared to biologics from each of the other classes. Two randomized, double-blinded phase 3 trials, UltIMMA-1 (n = 506) and UltIMMa-2 (n = 491), showed that risankizumab has significantly greater efficacy than ustekinumab and placebo.²² Skin clearance was seen as early as 4 weeks of treatment. Treatmentrelated adverse events (TEAEs) were comparable across all groups. Risankizumab was also proven superior to adalimumab in the phase 3 trial IMMvent (n = 605) where subjects were randomly assigned to a standard dosing regimen of risankizumab or adalimumab.²³ Efficacy was measured by the Psoriasis Area and Severity Index (PASI) and after 16 weeks of treatment 70% of patients on risankizumab achieved a 90% decrease in their PASI score from baseline (PASI90), compared to 44% those on adalimumab. In the phase 3b trial IMMerge, risankizumab was found to be superior to secukinumab at week 52 with PASI90 rates of 86.6% for risankizumab versus 57.1% for secukinumab.²⁴ These head-to-head studies have demonstrated risankizumab’s superior efficacy for plaque psoriasis when compared to adalimumab, ustekinumab and secukinumab.

Risankizumab for the Treatment of PsA

Given the critical role that IL-23 plays in the pathogenesis, risankizumab is an important therapeutic option for PsA. In a phase 2 trial, 185 subjects with active PsA were randomized into five groups: risankizumab 150 mg at week 0, 4, 8, 12 and 16 (arm 1); risankizumab 150 mg at week 0, 4 and 16 (arm 2); risankizumab at week 0 and 12 (arm 3); risankizumab 75 mg at week 0 (arm 4), or placebo.²⁵ The primary endpoint at week 16 was American College of Rheumatology 20 (ACR20) response. ACR20 is a composite measure defined as a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement in three or more of five variables: patient-assessed global activity, evaluator-assessed global activity, patient pain activity, functional disability, and acute phase response (ESR or CRP). Secondary endpoints included ACR50/70, dactylitis count, Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index, and health assessment questionnaire and disability index (HAQDI), a questionnaire designed to evaluate functional status and QoL in patients with arthritis. After 16 weeks of treatment, ACR20 was significantly higher across all treatment arms (57.1- 65.0%) compared to placebo (35.7%). ACR50 was higher across all treatment arms, and significant in arm 3 (39%) compared to placebo (12%). ACR70 was also higher across all treatment arms, and significant in arms 1, 1+2, 3 and 4 (14.3-25.6%) compared to placebo (0.0%). PASI75/90/100 responses were also significantly greater in all treatment groups (PASI75: 67-75%, PASI90: 52- 67%; PASI100: 33-56%) compared to placebo (10%; 10%; 7%, respectively). Dactylitis counts were similar across all groups, and improvements in enthesitis and HAQ-DI were greater in treatment groups compared to placebo but not statistically significant. Of the 185 subjects enrolled in the study, 145 continued in a 52-week single arm open-label extension (OLE). Subjects received 150 mg of risankizumab every 12 weeks for 36 weeks and continued to respond positively over all efficacy measures during this period. TEAEs were comparable in all arms and were similar in the 24- week study and OLE. Approximately 60% of subjects experienced a TEAE, with the most common being viral upper respiratory tract infection (11%). There was one serious adverse event (SAE) reported, but no malignancies, deaths or active cases of tuberculosis. Overall, risankizumab was well-tolerated and only 3.4% of patients discontinued due to side effects.

Notably, risankizumab was not found to be effective in the treatment of ankylosing spondylitis (AS)26 in a double-blinded phase 2 study. In this trial, 159 subjects were randomized to four treatment groups (risankizumab 18 mg one dose at week 0; risankizumab 90 or 180 mg at week 0, 8, 16 and 24; and placebo) over a 24-week period. The primary endpoint was Ankylosing Spondylitis Disease Activity Score (ASDAS) 40, a composite measure defined as a 40% improvement from baseline in three or more out of four variables: back pain, peripheral pain and swelling, duration of morning stiffness and patient global assessment. After 12 weeks of treatment, risankizumab failed to meet the primary endpoint as ASDAS40 responses were comparable and non-significant in treatment groups (15.0-25.0%) and placebo (17.5%). Similarly, in three multicentered, randomized, placebo-controlled studies, patients with AS were treated with ustekinumab.²² However, ustekinumab also did not demonstrate clinical efficacy in treating AS, as it failed to meet both primary and secondary endpoints including Assessment in Ankylosing Spondylitis (ASAS)20/40. These studies support the hypothesis that axial disease is driven by different mechanisms that are less reliant on IL-23.^27,28

Development Program for PsA

Pivotal phase 3 studies of risankizumab in PsA are currently ongoing. Two randomized, double-blinded studies compare risankizumab to placebo in subjects with active PsA who have failed to respond to at least one csDMARD (KEEPsAKE-1, NCT03675308) or bDMARD (KEEPsAKE-2, NCT03671148).^29,30 Subjects were randomized 1:1 to the treatment group (risankizumab at week 0, 4, 16 or 24) or placebo for a 24-week period. The study design for these trials is shown in Figure 1.

Similarly in KEEPsAKE-2, ACR20/50/70 response rates at week 24 were significantly higher with risankizumab (risankizumab: 51/26/12%; placebo:27/9/6%) (Figure 3). Subjects in the treatment group achieved greater resolution of enthesitis at week 24 (risankizumab: 43%, placebo: 30%) and dactylitis (risankizumab: 73%, placebo: 42%) and a greater change from baseline in HAQ-DI (risankizumab: -0.22; placebo: -0.05). In addition, PASI90 and MDA response rates were significantly higher with treatment (PASI90: 55%; MDA: 26%) compared to placebo (10%; 11%). Overall, in both trials, risankizumab produced more favorable outcomes in reducing disease activity, the number of affected joints, as well as improving psoriasis clearance and QoL.

After week 24, patients continued in an open label extension (OLE, Period 2) and received risankizumab 150 mg every 12 weeks until week 208. ACR 20/50/70 rates continued to improve to week 52 in KEEPsAKE-1 (risankizumab: 70/43/26% and placebo to risankizumab: 63/37/20%) and KEEPsAKE-2 (risankizumab: 59/32/17% and placebo to risankizumab: 56/32/21%) (Table 1b). Pooled data from both studies showed resolution of enthesitis in 55% of patients receiving risankizumab from baseline and in 57% of patients who transitioned from placebo to risankizumab in Period 2. Similarly, pooled data for resolution of dactylitis was reported in 76% of risankizumab patients and 73% of placebo to risankizumab patients in Period 2. The mean change in HAQ-DI at week 52 was -0.41 and -0.32 in risankizumab and placebo to risankizumab, respectively, in KEEPSaKE-1 and -0.26 and -0.34 in risankizumab and placebo to risankizumab, respectively, in KEEPSaKE-2. PASI90 responses were stable (risankizumab: 68% and placebo to risankizumab: 60%) in KEEPSaKE-1 and (risankizumab: 64% and placebo to risankizumab: 60%) in KEEPSaKE-2. The proportion of patients achieving MDA improved through week 52 (risankizumab: 38% and placebo to risankizumab: 27%) in KEEPSaKE-1 and (risankizumab: 27% and placebo to risankizumab: 34%) in KEEPSaKE-2 (Table 1b).

Adverse events were similar across all groups as of the data cut-off for week 52 analysis. By week 24, serious infection was reported in 2.7-2.9 events per 100 patient years (E/100PYs) of patients on risankizumab and did not increase in the long-term 52-week analysis (2.8 and 2.0E/100PY in KEEPsAKE-1 and -2, respectively). Serious TEAEs also did not increase from week 24 with 7.4E/100PY in KEEPsAKE-1 and 9.4E/100PY in KEEPSaKE-2 in the long-term. There were no reports of active tuberculosis or anaphylaxis in either study, but there was one case of oropharyngeal candidiasis in each study. There were no deaths in KEEPsAKE-2 but there were two deaths in KEEPsAKE-1; an 81-year-old male with dementia who was hospitalized with pneumonia and died of urosepsis and a 41-year-old male experienced sudden death on day 502. There were no reports of major cardiovascular events in KEEPsAKE-1 and three events in KEEPsAKE-2 which were reported as a non-fatal stroke in a patient with a history of hypertension and two non-fatal myocardial infarctions in patients with risk factors. Once again, risankizumab proved to be well-tolerated and discontinuation due to adverse events was low and occurred in 2.3E/100PY in KEEPSaKE-1 and 1.6E/100PY in KEEPSaKE-2.

Future Outlook

PsA is a multi-faceted, complex disease affecting multiple domains including skin, entheses, peripheral and axial joints. Although there are currently many options for treatment, there remains an unmet need for more efficacious and safer options. The addition of IL-23 inhibitors to the therapeutic landscape is welcomed given their tolerability, safety, and convenience of use. Conventional treatments for PsA including methotrexate, sulfasalazine, and leflunomide are burdened with tolerability issues, adverse effects, and end-organ toxicity. Newer oral agents also present challenges. Apremilast provides modest benefit but has issues with gastrointestinal intolerance and headaches. The JAK inhibitors are efficacious but have a boxed warning for serious infection and venous thromboembolism; more recent warnings for tofacitinib of cardiovascular events and malignancy, based on results from the ORAL Surveillance study,31 may make their use unsuitable in high-risk patients. The strength of IL-23 inhibition is the proven safety of this class in the psoriatic population. There is no signal for tuberculosis or other serious infections and can safely be used in patients with other comorbidities such as cardiac, renal, or hepatic disease. The convenient dosing schedule of injections as frequent as every 8 weeks to as infrequent as every 12 weeks will contribute favorably to QoL for patients by reducing the treatment burden and improving adherence. The current agents approved for use in PsA to target IL-23 are guselkumab, risankizumab and ustekinumab.

Risankizumab provides efficacy similar to that of other biologic agents for PsA, however the effect may take longer as we have not observed the early responses seen with other agents such as JAK inhibitors or IL-17 blocking agents. Guselkumab has shown in a network meta-analysis to have efficacy similar to IL-17 and TNF-α inhibiting biologic therapies supporting the important role of blocking IL-23 in the management of PsA.³² For patients with a prominent skin domain, targeting IL-23 may be preferred as it is very effective at clearing the skin in the majority of patients. Limiting its use will be the lack of efficacy in AS and further research will be required to understand the impact of risankizumab on axial PsA.

Conclusion

When choosing a treatment for PsA, ACR scores only tell part of the story, and we need to consider other disease measures such as enthesitis, dactylitis and QoL scores such as HAQ-DI, which were all shown to be significantly improved with risankizumab compared to baseline. Risankizumab has the potential to offer a treatment with a combination of efficacy, safety, convenience and overall improvement in QoL. However, more data is required and the complete long-term 208-week results from clinical studies for the management of PsA are eagerly anticipated.

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

Conflict of interest:
Abrahim Abduelmula has no relevant disclosures. Brian D. Rankin has no relevant disclosures. 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. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant.

Funding sources: None.

Abstract:
Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disease. Targeted treatment options remain limited. Tralokinumab (Adtralza^®) is a promising, new systemic therapy that inhibits interleukin-13. It was recently approved by Health Canada and the US FDA for the treatment of moderate-to-severe AD in adults and may be used alone or with topical corticosteroids. Herein, we review the efficacy and safety of tralokinumab in adults, as demonstrated in clinical trials.

Keywords:
Adtralza^®, tralokinumab, immunomodulator, therapeutics, biologic, atopic dermatitis, eczema, clinical trial

Introduction

Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disorder affecting between 5-10% of adults, with moderate-to-severe disease accounting for approximately 20-30% of cases.^1,2 This condition can have a significant negative impact on psychosocial well-being, health-related quality of life (QoL), and work/school productivity. In addition, uncontrolled AD is associated with a substantial financial burden on the patient and their family as well as the health care system.³

Topical therapies are employed as first-line treatment for the majority of AD cases, but lack of response can necessitate the use of phototherapy and/or systemic therapies. With respect to systemic therapies, recent advances have led to the development of new targeted treatments, of which four are now approved by Health Canada and the US FDA for moderate-to-severe AD. This includes two biologics (dupilumab [Dupixent^®], an interleukin (IL)-4/IL-13 inhibitor, and tralokinumab [Adtralza^®], an IL-13 inhibitor) and two small molecules (upadacitinib [Rinvoq^®] and abrocitinib [Cibinqo^®], both selective Janus kinase 1 [JAK1] inhibitors).

Background

Tralokinumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity to IL-13, thereby blocking its interaction with the IL-13Rα1/IL-4Rα1 heterodimer and IL-13Rα2 homodimer receptor complexes and subsequently leading to downstream STAT-6 inhibition.⁴ The latter results in reduced inflammation, improved skin barrier function (reductions in epidermal thickness and increased epithelial barrier integrity), as well as restoration of the microbiome (a near 10-fold reduction in Staphylococcus aureus colonization of the skin).^4,5

Tralokinumab may be given alone or in combination with a topical corticosteroid (TCS).^6,7 It was approved by both Health Canada and the US FDA in 2021 for the treatment of moderate-to-severe AD in adult patients whose disease is not adequately controlled with prescription topical therapies or when those prescription topical therapies are not advisable.⁶ Available as a single-use prefilled syringe containing 150 mg of tralokinumab in 1 mL solution (150 mg/mL), tralokinumab is administered as a subcutaneous (SC) injection.⁶ The recommended dosage for adult patients is an initial 600 mg loading dose followed by 300 mg maintenance doses every other week (Q2W). According to the product monograph, the prescriber may choose to administer tralokinumab every fourth week (Q4W) in adult patients who achieve clear or almost clear skin after 16 weeks of treatment; however, there is an increased probability that maintenance efficacy may be decreased with Q4W dosing.⁶

Non-medicinal ingredients of the product include acetic acid, polysorbate 80, sodium acetate trihydrate, sodium chloride, and water. No published data is currently available for its use in pediatric or pregnant patients, and, as such, tralokinumab has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended for pregnant women.⁶

Supporting Evidence from Clinical Trials (Figures 1-5)

Results from Pivotal Phase 3 Monotherapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=802) with moderate-to-severe AD (ECZTRA 1), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=603) versus placebo (n=199) was evaluated.⁸ At week 16: the primary endpoint of an Investigator Global Assessment (IGA) score of clear or almost clear (IGA 0/1) was achieved by 15.8% and 7.1% of patients treated with tralokinumab and placebo, respectively (p<0.002) (Figure 1); an improvement of ≥75% and ≥90% in the Eczema Area and Severity Index (EASI75 and EASI90, respectively) was achieved by 25.0% and 14.5% of patients treated with tralokinumab versus 12.7% and 4.1% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus Numerical Rating Scale (NRS) improved by 20.0% with tralokinumab versus 10.3% with placebo (p=0.002); and there was a reduction in Dermatology Life Quality Index (DLQI) scores by 7.1 with tralokinumab and 5.0 with placebo, respectively (p=0.002) (Figure 3). Safety evaluation revealed similar adverse event (AE) profiles between the tralokinumab and placebo groups, with the majority of treatment-emergent AEs (TEAEs) being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included viral upper respiratory tract infection (URTI) (23.1%), conjunctivitis (10.0%), and eczema herpeticum (0.5%). One case of conjunctivitis led to treatment discontinuation. No injection-site reactions (ISRs) were observed in either treatment group.⁸

In another phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=794) with moderate-to-severe AD (ECZTRA 2), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=593) versus placebo (n=201) was evaluated.⁸ At week 16: the primary endpoint of IGA 0/1 was achieved by 22.2% and 10.9% of patients treated with tralokinumab and placebo, respectively (p<0.001) (Figure 1); EASI75 and EASI90 were achieved by 33.2% and 18.3% of patients treated with tralokinumab versus 11.4% and 5.5% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus NRS improved by 25.0% with tralokinumab versus 9.5% with placebo (p<0.001); and there was a reduction in DLQI by 8.8 with tralokinumab and 4.9 with placebo, respectively (p<0.001) (Figure 3). Safety evaluation revealed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (8.3%), conjunctivitis (5.2%), and eczema herpeticum (0.3%). No cases of conjunctivitis led to discontinuation. In addition, no ISRs were observed in either treatment group.⁸

By week 52, IGA 0/1 responses achieved at week 16 with tralokinumab Q2W were maintained, without any rescue therapy (including TCS), by 51% (ECZTRA 1) and 59% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 47% (ECZTRA 1) and 25% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.60 and p=0.004, respectively) (Figure 4). In addition, by week 52, EASI75 responses achieved at week 16 with tralokinumab Q2W were maintained by 60% (ECZTRA 1) and 56% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 33% (ECZTRA 1) and 21% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.056 and p<0.001, respectively) (Figure 5).⁸ A subset of patients following week 16 were downdosed from Q2W to Q4W dosing of tralokinumab. By week 52, 39% (ECZTRA 1) and 45% (ECZTRA 2) of patients maintained their week 16 IGA 0/1 responses despite being switched from Q2W to Q4W dosing (Figure 4). In addition, by week 52, 49% (ECZTRA 1) and 51% (ECZTRA 2) of patients maintained their week 16 EASI75 responses despite being switched from Q2W to Q4W dosing (Figure 5).

Results from Pivotal Phase 3 Combination Therapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=380) with moderate-to-severe AD (ECZTRA 3), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=253) versus placebo + TCS (n=127) was evaluated. The TCS utilized was mometasone furoate 0.1% cream. At week 16: the primary endpoint of IGA 0/1 was achieved by 38.9% and 26.2% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.015) (Figure 1); EASI75 and EASI90 were achieved by 56.0% and 32.9% of patients treated with tralokinumab + TCS versus 35.7% and 21.4% of patients treated with placebo + TCS (p<0.001 and p<0.022, respectively) (Figure 2); pruritus NRS improved by 45.5% with tralokinumab + TCS versus 34.1% with placebo + TCS (p=0.037); and there was a reduction in DLQI by 11.7 with tralokinumab + TCS and 8.8 with placebo + TCS, respectively (p<0.001) (Figure 3). By week 32, in patients receiving tralokinumab Q2W + TCS, 89.6% and 92.5% maintained their week 16 IGA 0/1 and EASI75 responses, respectively (Figure 4 and 5, respectively). A subset of patients following week 16 were downdosed from tralokinumab Q2W to Q4W dosing. At week 32, 77.6% and 90.8% of patients maintained their week 16 IGA 0/1 and EASI75 responses, respectively, despite being switched from Q2W to Q4W dosing (Figure 4 and 5, respectively).⁹ Safety evaluation revealed similar AE profiles between the tralokinumab + TCS and placebo + TCS groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab + TCS included URTI (19.4%), conjunctivitis (13.1%), and eczema herpeticum (0.4%). Six patients permanently discontinued treatment with tralokinumab due to non-serious AEs, one of which was conjunctivitis.⁹ No ISRs were observed in either treatment group.

In another phase 3 multicenter, parallel, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=277) with moderate-to-severe AD (ECZTRA 7), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=140) versus placebo + TCS (n=137) was evaluated. The TCS utilized was mometasone furoate 0.1% cream.¹⁰ At week 16: the primary endpoint of EASI75 was achieved by 64.2% and 50.5% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.018) (Figure 2); EASI90 was achieved by 41.1% of patients treated with tralokinumab + TCS versus 29.3% of patients treated with placebo + TCS (p<0.001) (Figure 2); pruritus NRS was reduced by 4 with tralokinumab + TCS versus 3.1 with placebo + TCS (p<0.001); and there was a reduction in DLQI by 11.2 with tralokinumab + TCS and 9.6 with placebo + TCS, respectively (p=0.009) (Figure 3). By week 26, in patients receiving tralokinumab + TCS, 68.8% achieved EASI75 and 48.6% achieved EASI90, compared with 55.3% and 36.4% for placebo + TCS (p=0.014 and p=0.027, respectively) (Figure 5). Safety evaluation once again showed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (26.8%), conjunctivitis (9.4%), and eczema herpeticum (0.7%). One patient permanently discontinued treatment with tralokinumab due to an AE that was not deemed serious.¹⁰ No ISRs were observed in either treatment group.

Summary of Results from Pivotal Phase 3 Monotherapy and Combination Therapy Study Results and Additional Analyses

In summary, tralokinumab was more effective than placebo in both monotherapy and combination therapy studies, with tralokinumab demonstrating greater efficacy than placebo for patients with moderate-to-severe AD across all phase 3 clinical trials. Interestingly, rates of eczema herpeticum were higher in the placebo groups as opposed to the tralokinumab groups.^8-10 An additional pooled analysis (n=1605) of five completed double-blind, randomized, placebo-controlled, phase 2 and 3 clinical trials of tralokinumab in adult patients with moderateto- severe AD examined the rates of conjunctivitis within these studies; it was found that tralokinumab had a slightly higher incidence of conjunctivitis (7.5%) in comparison to placebo (3.2%), with the majority of cases being mild-to-moderate in severity and 75% of events resolving before the treatment period was over in both groups.¹¹

Tralokinumab was also shown to have a significant impact on health-related QoL in a phase 2b randomized, double-blind, placebo-controlled clinical trial involving adult patients (n=204) with moderate-to-severe AD. At week 6, a 5.4-point reduction in DLQI was observed with tralokinumab monotherapy, while a 2.3-point reduction in DLQI was observed with placebo (p=0.05). At week 16, a 6.8-point reduction in DLQI was observed with tralokinumab monotherapy, while a 3.5-point reduction in DLQI was observed with placebo (p=0.006) (Figure 3).¹²

Tralokinumab may also help resolve other IL-13-associated skin abnormalities. In a phase 2 randomized, double-blind, placebo-controlled study (n=204), adult patients with moderate-to-severe AD treated with tralokinumab had lower rates of Staphylococcus aureus colonization, fewer skin infections requiring systemic antimicrobial therapy, and a lower frequency of eczema herpeticum when compared to placebo groups.⁷ In another phase 2, 30-week, double-blind, randomized, placebo-controlled clinical trial (n=215), it was shown that tralokinumab did not impair vaccine-induced immune responses in adult patients receiving tetanus-diphtheria-pertussis (Tdap) or meningococcal vaccines.¹³

Special Populations

Tralokinumab has not been approved for utilization in children/ adolescents (<18 years of age), although a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial in adolescent patients (12-17 years of age) with moderate-to-severe AD is still ongoing.¹⁴ Tralokinumab is currently not recommended in pregnant or breastfeeding women. It remains unknown if the drug is excreted in breast milk. There were no differences in terms of efficacy or safety with use in elderly patients (≥65 years of age).⁶

Table 1. Summary of the efficacy and quality of life data for tralokinumab from pivotal phase 2 and 3 clinical trials in adult patients with moderate-to-severe AD

Counselling: Practical Tips to Optimize Administration

Tralokinumab is administered as an SC injection. Optimal anatomic sites for the SC injection include the lower limb (specifically thigh) or trunk (specifically abdomen, excluding a 5 cm radius around the navel); the upper limb (specifically lateral upper arm) may also be used if another individual can administer the medication. Multiple doses should be delivered in the same anatomic site but at different points within that anatomic site. Doses should be rotated to different anatomic sites with each subsequent set of SC injections. Tralokinumab should not be injected into tender or damaged skin. If a patient and/or a caregiver wishes to administer the SC injection, proper training should be provided. If a dose is missed, the missed dose should be administered as soon as possible and the scheduled dosing regimen continued.⁶

Conclusion

Tralokinumab is an effective and safe treatment for adult patients with moderate-to-severe AD. It may be used alone or in combination with TCS. This biologic can be considered first-line treatment after failure of or intolerance to topical therapies, and, as such, represents an important tool in our therapeutic armamentarium.

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¹Faculty of Medicine, University of Western Ontario, London, ON, Canada
²Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
³Department of Dermatology, McMaster University, Hamilton, ON, Canada
⁴Dermatrials Research Inc. & Venderm Innovations in Psoriasis, Hamilton, ON, Canada
⁵Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁶Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁷Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁸Probity Medical Research, Waterloo, ON, Canada
⁹Dermatology Research Institute, Calgary, AB, Canada
¹⁰Skin Health & Wellness Centre, Calgary, AB, Canada
¹¹Probity Medical Research, Calgary, AB, Canada
¹²Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
¹³Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹⁴Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest:
Abrahim Abduelmula and Brian D. Rankin have no relevant disclosures. Ronald Vender has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, Astellas, Celgene, Dermira, Eli Lilly, Galderma, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, and Takeda. 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, Tribute, UCB, and Valeant. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Funding sources: None.

Abstract:
A novel topical corticosteroid, halobetasol propionate (HP) 0.01% lotion (Bryhali™), has recently been introduced for the treatment of plaque psoriasis and corticosteroid-responsive dermatoses in adults. Once daily application of HP 0.01% lotion is indicated for use up to 8 weeks. Treatment success for plaque psoriasis in the pivotal phase 3 clinical trials (defined as an Investigator Global Assessment [IGA] of clear/almost clear [IGA 0/1] with ≥2-grade improvement from baseline) occurred in over one-third of patients by week 8. Treatment-emergent adverse events were typically mild-to-moderate in intensity and usually limited to the application site(s). No treatment-related cases of skin atrophy have been reported from the studies. Counselling should be considered to optimize treatment outcomes.

Key Words:
Bryhali™; halobetasol; topical; therapeutics; corticosteroid; psoriasis; clinical trial

Introduction

Topical corticosteroids are a mainstay in the management of plaque psoriasis and other corticosteroid-responsive dermatoses. Bryhali™ is a super-potent topical corticosteroid lotion with halobetasol propionate (HP) 0.01% as the active ingredient. It was approved by the US FDA in 2018 for plaque psoriasis and by Health Canada in 2021 for both plaque psoriasis and corticosteroid-responsive dermatoses. Available in 45 g, 60 g, and 100 g tubes containing 0.1 mg of HP 0.01% per gram, HP 0.01% lotion is applied once daily to affected areas (maximum dose of 50 g per week).^1,2 It has a safety profile allowing for extended use up to 8 weeks without physician re-evaluation (provided there are observed improvements in the condition being treated).³ Non-medicinal ingredients of this product include carbomer copolymer type b, carbomer homopolymer type a, diethyl sebacate, edetate disodium dihydrate, light mineral oil, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitan monooleate, and sorbitol solution 70%. No data is currently available for its use in pediatric or pregnant patients; therefore, HP 0.01% lotion has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended in pregnant women.¹

Background

Plaque psoriasis and certain corticosteroid-responsive dermatoses, such as atopic dermatitis, are chronic, immunemediated, inflammatory skin diseases that vary in severity. Topical corticosteroids are used across all severities, although moderate-to-severe disease often requires the addition of phototherapy or systemic therapies.⁴ Despite their efficacy, these conditions can quickly recur if treatment is discontinued; however, extended use of topical corticosteroids can also result in adverse events (AEs) that are either local (e.g., skin atrophy, folliculitis, striae, and telangiectasia) or systemic (e.g., hypothalamic-pituitary-adrenal [HPA] axis suppression).⁵

HP 0.05% cream or ointment (Ultravate^®) is a commonly prescribed topical corticosteroid applied once or twice daily per physician direction (maximum dose of 50 g per week).⁶ According to the product monograph, patients should limit use to a maximum of 2 weeks unless re-evaluated by a physician. However, considering the chronic nature of plaque psoriasis and many other corticosteroid-responsive dermatoses, such as atopic dermatitis, this limited treatment duration can become an issue for long-term utilization and compliance.⁶ Studies on HP 0.01% lotion have shown that despite demonstrating comparable efficacy to HP 0.05% cream, the safety profile allows it to be used for intervals longer than 2 weeks without the need for physician re-evaluation at 2 weeks.⁷

HP is a water-insoluble synthetic corticosteroid thought to act via the induction of lipocortins, a group of phospholipase A2 inhibitory proteins. It is theorized that these proteins act on pro-inflammatory mediators, such as prostaglandins and leukotrienes, via inhibition of the precursor arachidonic acid.⁸ HP has anti-inflammatory, anti-proliferative, antipruritic, and vasoconstrictive effects.^1,7

The once daily HP 0.01% lotion is formulated with proprietary PRISMATREX™ technology, a novel polymeric emulsification system that features oil droplets containing the active ingredient and other hydrating/moisturizing excipients dispersed evenly in an oil-in-water emulsion and separated by a 3-dimensional mesh matrix.^1,9 This allows for uniform distribution and enhanced penetration when applied onto the skin surface. The latter may provide rationale for the comparable efficacy of HP 0.01% lotion and HP 0.05% cream despite a 5-fold difference in the concentration of HP.⁷

Supporting Evidence from Clinical Trials (Table 1)

Table 1

Plaque Psoriasis

In a phase 2 multicenter, randomized, double-blind, vehicle-controlled clinical trial (n=150), the efficacy and safety of HP 0.01% lotion (n=60) versus HP 0.05% cream (n=57) was evaluated in adult patients with moderate-to-severe plaque psoriasis (Investigator Global Assessment [IGA] score: moderate [3] or severe [4]; affected body surface area [BSA]: 3% to 12%).⁷ At week 2: the primary endpoint of an IGA score of clear or almost clear (IGA 0/1) with ≥2-grade improvement from baseline (treatment success) was achieved by 30.0% and 31.6% of patients treated with HP 0.01% lotion and HP 0.05% cream, respectively (p=0.854); a 2-grade improvement from baseline in the 3 key signs of plaque psoriasis—erythema, elevation, and scaling—at the target lesion site (treatment success for specific psoriasis signs) was achieved by 38.3%, 40.0%, and 43.3% of patients treated with HP 0.01% lotion versus 31.6%, 36.8%, and 47.4% of patients treated with HP 0.05% cream, respectively (p=0.446, p=0.727, and p=0.663, respectively); and BSA improved by 22.3% with HP 0.01% lotion versus 20.9% with HP 0.05% cream (p=0.787). Both HP 0.01% lotion and HP 0.05% cream were more effective than vehicle at all time points, with HP 0.01% lotion demonstrating greater efficacy than HP 0.05% cream for patients with more severe disease (IGA=4) at baseline. Safety evaluation revealed AEs of treatment-related dermatitis (n=1) and severe itching (n=1) with HP 0.01% lotion as well as treatment-related severe itching (n=2) and severe burning/ stinging (n=1) with HP 0.05% cream. No treatment-related cases of skin atrophy, folliculitis, striae, or telangiectasia were observed in either treatment group.⁷ In summary, HP 0.01% lotion was comparable to HP 0.05% cream in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, and reduction in BSA, with both treatments demonstrating a favorable safety profile.

In a pooled analysis of 2 phase 3 multicenter, double-blind, randomized, parallel-group clinical trials (n=430), the efficacy and safety of HP 0.01% lotion (n=285) versus vehicle (n=145) was evaluated in adult patients with moderate-to-severe plaque psoriasis (IGA score: 3 or 4; affected BSA: 3% to 12%).⁹ At week 8: the primary endpoint of treatment success was achieved by 36.5% (Study 1) and 38.4% (Study 2) of patients treated with HP 0.01% lotion versus 8.1% (Study 1) and 12.0% (Study 2) of patients treated with vehicle (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (Study 1) and week 4 (Study 2); HP 0.01% lotion achieved treatment success for specific psoriasis signs at the target lesion site in 46.7% (Study 1) and 56.3% (Study 2) of patients for erythema, 52.5% (Study 1) and 62.7% (Study 2) of patients for elevation, as well as 54.9% (Study 1) and 63.1% (Study 2) of patients for scaling (p<0.001 for all comparisons versus vehicle); BSA improved by 34.2% (Study 1) and 36.2% (Study 2) with HP 0.01% lotion (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (both Study 1 and Study 2); mean Dermatology Life Quality Index (DLQI) score was reduced by 57.7% (Study 1) and 58.7% (Study 2) with HP 0.01% lotion (p=0.001 and p=0.004, respectively, versus vehicle); mean IGAxBSA composite score (calculated by multiplying the IGA by the BSA; range: 9-48) was reduced by 49.5% with HP 0.01% lotion versus 13.4% with vehicle (p<0.001), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2; and the proportion of patients achieving ≥50%, ≥75%, and ≥90% reduction in IGAxBSA composite score from baseline (IGAxBSA-50, IGAxBSA-75, and IGAxBSA-90, respectively) was 56.8%, 39.3%, and 19.3% with HP 0.01% lotion versus 17.2%, 9.7%, and 2.8% with vehicle (p<0.001 for all comparisons versus vehicle).^3,9 Safety evaluation revealed similar rates of AEs between the treatment groups: 21.5% with HP 0.01% lotion and 23.9% with vehicle. Most AEs (90.2%) were mild-to-moderate in intensity. No cases of treatment-related skin atrophy, folliculitis, or striae were reported.¹⁰ There was one AE of telangiectasia with HP 0.01% lotion, not deemed to be treatment-related. In summary, HP 0.01% lotion was superior to vehicle in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, reduction in BSA, as well as improvements in mean DLQI and mean IGAxBSA composite scores, with HP 0.01% lotion demonstrating a favorable safety profile.

Corticosteroid-Response Dermatoses

There are no clinical trials investigating the efficacy and safety of HP 0.01% lotion for corticosteroid-responsive dermatoses.

Dosage and Administration

The on-label recommendation is to apply a thin layer of Bryhali™ once daily to areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses until disease control is achieved.¹ The total amount used should not exceed 50 g per week due to the concern for HPA axis suppression. Uninterrupted treatment beyond 8 weeks is not recommended.¹

Counselling: Practical Tips to Optimize Use

A thin layer of HP 0.01% lotion should be applied, just enough to cover the areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses. It is essential to rub in gently and inform patients that applying excessive amounts will not improve treatment efficacy. If HP 0.01% lotion is applied after bathing, the treatment site(s) should be dry before application.

It is also important to allow sufficient time for the medication to dry before putting clothes on to prevent inadvertent spread onto unaffected skin. HP 0.01% lotion should not be used with occlusive dressings unless recommended by a physician. It is for external use only and must be kept away from the eyes, nose, mouth, and other mucosal sites. HP 0.01% lotion should not be applied to the scalp or sensitive sites, such as the face, groin, and axillae, nor on ulcers or wounds.¹ It is also advised to avoid application on areas affected by untreated bacterial, tubercular, fungal and viral infections involving the skin.¹

Conclusion

Once daily application of HP 0.01% lotion (Bryhali™) is a convenient topical therapy with comparable efficacy to HP 0.05% cream (Ultravate^®), despite a 5-fold difference in concentration of HP. One of the main advantages is its ability to be used safely for up to 8 weeks without concern for AEs (especially skin atrophy) and the requirement for physician re-evaluation (provided there are observed improvements in the condition being treated). Counselling with application tips should be considered for all patients.

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