Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflict of interest: The authors have no conflicts of interest to declare. Funding: None.

Abstract:
The pathogenesis of psoriasis has been linked to autoimmune and autoinflammatory traits that result in atypical cytokine and keratinocyte activation and proliferation. Many cytokine pathways are involved in the development of inflammation with interleukin-23 (IL-23) playing a significant role in plaque-type psoriasis. Biologic agents that target specific cytokines have shown to be effective therapies in the treatment of plaque-type psoriasis over other conventional treatments such as systemic retinoids. Tildrakizumab is an immunoglobulin G1-kappa monoclonal antibody that inhibits the IL-23/IL-17 pathway and has demonstrated through two three-part randomized Phase 3 clinical trials (reSURFACE 1 and reSURFACE 2) and their extension trials to be an efficacious and safe therapy for the targeted treatment of moderate-to-severe plaque-type psoriasis.

Keywords: psoriasis, tildrakizumab, IL-23/IL-17 pathway, targeted therapy, re-SURFACE trials, Ilumya®

Introduction

Psoriasis is a chronic inflammatory skin disease that affects 2% of the population. The pathogenesis of psoriasis is multifactorial and associated with a polygenic genetic predisposition and various triggers, leading to an abnormal type 1 immune response stimulating abnormal keratinocyte proliferation and differentiation.^1-3 Among the various cytokines implicated in the development of psoriasis, interleukin-23 (IL-23) has shown to play a significant role via induction of IL-17 and regulation of T memory cells and activation of macrophages that contribute to chronic inflammation (Figure 1).² The development of co-morbidities such as joint and vascular inflammation, and an increased risk of cardiometabolic, gastrointestinal, and chronic kidney diseases, can lead to psychological and quality of life impairments for many patients.¹ A systematic review and meta-analysis showed that the risk of developing depression is greater in patients with psoriasis, which may result from factors such as stigma and social isolation, physical pain from pruritus and bleeding, and co-morbidities, as well as associations with pro-inflammatory biomarkers.⁴ An increased prevalence of depression, anxiety and suicide ideation amongst the psoriatic population reveals a high burden of disease.¹

While phototherapy continues to be used in the sphere of psoriasis, other therapies such as immunosuppressive and immunomodulatory treatments, including methotrexate, carry long-term risk of adverse effects.⁵ With an improved safety and efficacy profile over conventional treatments, biologics are increasingly emerging as standard of therapy for the management of psoriasis.

Novel Therapy

In March 2018, tildrakizumab, a high-affinity, humanized immunoglobulin G1-kappa (IgG1/k) monoclonal antibody targeting the p19 unit of IL-23, was approved by the US FDA for the treatment of patients with moderate-to-severe chronic plaque psoriasis.⁶ Health Canada approval followed in May 2021. Data from two randomized Phase 3 trials (reSURFACE 1 and reSURFACE 2, n=772 and n=1090) and their extension trials showed favorable efficacy and tolerability of tildrakizumab.^7,8

Mechanism of Action

Tildrakizumab binds to the p19 subunit on IL-23 and inhibits the binding of IL-23 with the IL-23 receptor (IL-23R) on Th-17 cells.⁶ When the IL-23p19 subunit binds to the IL-23 receptor, it results in tyrosine phosphorylation of JAK2 within Th-17 cells, thereby inducing phosphorylation of STAT3 and TYK2 and gene expression of RORγt, leading to Th17 cell differentiation. Th17 cell differentiation releases proinflammatory cytokines (IL-17A/F) that in turn induce keratinocyte activation and proliferation.^9-11 By blocking the binding of IL-23p19 to IL-23R, the release of IL-17A/F cytokines is inhibited.

Clinical Trials

The efficacy and safety of tildrakizumab was assessed in two three-part randomized Phase 3 trials (reSURFACE 1 and reSURFACE 2).⁷ The two trials spanned 250 sites globally and included sites in Australia, Canada, the UK, the US, Europe, Israel, and Japan. Enrolled participants were aged 18 years or older with moderate-to-severe chronic plaque psoriasis as defined by body surface area ≥10%, Physician’s Global Assessment (PGA) score ≥3 and Psoriasis Area and Severity Index (PASI) score ≥12. Baseline characteristics were similar across all groups and included a higher percentage of male (65%-73%) and White (65%-92%) participants with average PASI scores of 19.3-20.7. Two co-primary endpoints were evaluated in the trials and included: achieving PASI 75 and PGA response (score of 0 (“clear”) or 1 (“minimal”) with ≥2 grade score reduction from baseline) at week 12. Secondary endpoints were PASI 90 and PASI 100 at week 12 in both studies. In reSURFACE 2, PASI 75 and PGA response at week 28 were also secondary endpoints. In reSURFACE 1, 772 subjects were randomized to receive 200 mg (n=308), 100 mg (n=309), or placebo (n=155). In reSURFACE 2, 1090 subjects were randomized to receive 200 mg (n=314), 100 mg (n=307), placebo (n=156), or etanercept (n=313). Tildrakizumab was administered at week 0 and 4 during part 1 and at week 16 during part 2. Etanercept was administered twice weekly in part 1 and once weekly during part 2 of the reSURFACE 2 trial.

At week 12, subjects assigned to 100 mg or 200 mg of tildrakizumab groups showed significant clinical improvement in both re-SURFACE 1 and 2 trials compared to vehicle controls. Table 1 shows efficacy results for the two co-primary efficacy endpoints and the two secondary endpoints (p<0.0001 for comparisons of both tildrakizumab groups vs. placebo in both trials).

Two extension studies of the reSURFACE 1 and 2 Phase 3 trials were conducted up until 148 weeks (2 years) and 244 weeks (5 years). In the 148-week extension, efficacy was assessed for responders (PASI 75) to 100 mg and 200 mg tildrakizumab, partial responders (PASI 50-75) to 100 mg and 200 mg tildrakizumab, and partial/non-responders (PASI 50-75/PASI 0-50) to etanercept at week 28. Tildrakizumab responders (100 mg, n=329; 200 mg, n=227) and partial responders (100 mg, n=40; 200 mg, n=201) were maintained on the same dose and partial/non-responders to etanercept 50 mg were switched to tildrakizumab 200 mg dosing (n=121), administered every 12 weeks, until week 148.⁸ In the 244-week extension study, the tildrakizumab 100 mg and 200 mg week 28 responders (100 mg, n=302; 200 mg, n=213) and partial/non-responders to etanercept who were switched to tildrakizumab 200 mg at week 28 (n=107) were maintained on the same dose, administered every 12 weeks, until week 244.¹² The efficacy results for both extension studies are shown in Table 2.

Overall, the reSURFACE trials 2-year extension study demonstrated that 80% of patients who initially responded to tildrakizumab maintained PASI 75 efficacy up to week 148 with continued tildrakizumab treatment.⁸ The 5-year extension study showed improved PASI 75, 90, and 100 responses from week 128 to week 244 across tildrakizumab responders and etanercept partial/nonresponders groups, demonstrating sustained psoriasis control with tildrakizumab treatment in moderate-to-severe psoriasis patients.¹²

Safety Profile

Phase 3 trials of tildrakizumab showed an overall safety profile similar to vehicle. The most common adverse event in these investigations was nasopharyngitis (200 mg 6%, 100 mg 8%, and vehicle 5% in reSURFACE 1; 200 mg 11%, 100 mg 13%, and vehicle 8% in reSURFACE 2) and upper respiratory tract infection (200 mg 5%, 100 mg 3%, and vehicle 6% in reSURFACE 1). The proportion of patients with serious adverse events or who discontinued were low across both reSURFACE 1 and 2 trials (2%, 1% in the 200 mg tildrakizumab group; 0%, 1% in the 100 mg tildrakizumab group; 1%, 1% in the placebo group for reSURFACE 1 and reSURFACE 2, respectively). Notably, many side effects associated with other psoriasis medications, such as Candida infections, commonly seen in anti-IL 17A antibodies medications, were infrequent in reSURFACE trials. No new cases of inflammatory bowel disease or exacerbation of pre-existing disorders was reported in these studies. Suicidal ideation and behavior that have been observed with brodalumab, an IL-17A antibody, were not reported in any of the reSURFACE trials. Only one major adverse cardiovascular (CV) event, a side effect that has been linked to briakinumab, an IL-12 and IL-23p40 antibody, was reported in the trials.⁷

In the 2-year and 5-year extension study, there were no apparent dose-dependent safety signals or unexpected adverse events. Nasopharyngitis remained the most common treatment-emergent adverse event. The safety profile for 2- and 5-year extension trials for adverse events occurring in greater than 5% of patients is shown in Table 3.⁸

In the 5-year extension study, the cumulative incidence for major adverse CV events (0.5, 0.7 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively), malignancy excluding non-melanoma skin cancer (0.7, 0.6 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively), and severe infections (1.2, 1.3 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively) were generally comparable with Psoriasis Longitudinal Assessment and Registry (0.22, 0.55, 1.45 per 100 PYs). No dosage-related differences in frequency of severe infections or malignancies were noted.¹²

An additional pooled analysis of the 5-year extension study data compared the safety profile of tildrakizumab in younger (<65 years: 100 mg, n=303; 200 mg, n=211) and older (≥65 years: 100 mg, n=26; 200 mg, n=16) patients with psoriasis. Both age groups showed similar profiles, with nasopharyngitis and upper respiratory tract infections being the most common treatment-emergent adverse events. While older patients showed higher incidence than younger patients of CV events (100 mg/200 mg 14/21 per 100 PYs vs. 1/3 per 100 PYs), nonmelanoma skin cancer (6/10 vs. 8/6), and other malignancies (17/11 vs. 4/6), these increases were likely attributable to aging and longer psoriatic disease duration, and not as a result of psoriasis treatment. Overall, tildrakizumab demonstrated similar efficacy across both age groups, with comparable improvements in quality of life, and without major safety issues.¹³ These results further support the favorable safety profile of tildrakizumab.

Conclusion

Tildrakizumab is a promising target therapy to treat moderate-to-severe plaque psoriasis. Evidence from the Phase 3 clinical investigations and their extension trials has demonstrated that tildrakizumab is efficacious and well-tolerated by patients and maintains a reassuring safety profile. The most common side effects from the trials (up to 5 years), were nasopharyngitis and upper respiratory tract infection. Adverse effects that have been linked to other biologic agents, such as Candida infections, CV events, and suicide ideation, were not identified or were uncommon in the 5-year trials. While the reSURFACE 1 and 2 trials and their extensions have provided evidence of the longer-term safety profile of tildrakizumab, pharmacovigilance remains important through real-world and/or prolonged experience.

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Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflict of interest: Ayaa Alkhaleefa, Taylor Evart Woo, and Laurie Parsons have no relevant disclosures. Funding sources: None.

Abstract: Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Dupilumab was approved by the US Food and Drug Administration in September 2022 and Health Canada in July 2023 for the treatment of PN. Dupilumab is a human monoclonal immunoglobulin G4 antibody that binds the interleukin (IL)-4 receptor alpha subunit, blocking intercellular signalling of IL-4 and IL-13. Inhibition of these cytokines downregulates the inflammatory response and improves disease severity and pruritus. Two randomized controlled trials have shown dupilumab to be effective in reducing pruritus and lesion count in patients with PN. The approval of dupilumab for PN represents the first approved therapy for PN and may indicate a paradigm shift in the way this condition is treated.

Keywords: dupilumab, Dupixent®, immunomodulator, biologic, prurigo nodularis, nodular prurigo, clinical trial

Introduction

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by prurigo nodules, a cutaneous reaction pattern in which pruritus is a central component.^1,2 It presents with papulonodules distributing along the trunk and extensor surfaces and ranges from few to hundreds of lesions.^2,3 It is among the dermatoses that demonstrate the “butterfly sign”, where skin on the upper back is spared.⁴ The mean age of patients with PN is 50.9 years, and it is slightly more common in females who have darker skin phototypes.⁴ PN may be associated with underlying systemic diseases, including chronic obstructive pulmonary disease, congestive heart failure, chronic nephritis, type 2 diabetes mellitus, or the human immunodeficiency virus (HIV) infection. Clinical features of PN include intense pruritus that is present constantly, intermittently, or paroxysmally for ≥6 weeks. The diagnostic workup for PN includes a complete blood cell count with differential, liver and renal function tests, diabetes screening, thyroid function testing, infectious etiologies including viral hepatidies, and excluding other systemic etiologies.³

The pathogenesis of PN involves immune and neural dysregulation.^3-5 Biopsy of prurigo lesions show dense dermal, interstitial, and perivascular infiltrates in the dermis.³ These infiltrates primarily consist of increased numbers of T-lymphocytes, mast cells, and eosinophilic granulocytes. These collections of immune cells generate a robust inflammatory response releasing interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins, and neuropeptides causing an intractable itch. In addition, there is upregulation of several neuropeptides such as calcitonin gene-related peptide and substance-P. Upregulation of neuropeptides promotes their secretion into cutaneous tissue via nerve fibers, ultimately causing neurogenic inflammation.

Treatment options for PN involve addressing potential underlying causes, providing symptomatic relief, and breaking the itchscratch cycle.^3,6 The first-line topical therapy for PN is high potency topical corticosteroids, such as betamethasone valerate 0.1% tape.³ Other treatment options include topical calcineurin inhibitors, topical capsaicin, neuromodulators (gabapentinoids, cannabinoids, or anesthetics), antidepressants, phototherapy, and immunosuppressants. However, many treatments for PN are commonly used off-label and there exists variability in dosing regimens, leading to varying degrees of efficacy and clearance rates.⁷

Dupilumab represents the first and only US FDA and Health Canada approved medication for the treatment of PN.⁸ Dupilumab is a human monoclonal immunoglobulin G4 antibody that works by binding the IL-4 receptor alpha subunit shared by the IL-4 and IL-13 receptor complexes (Figure 1). Binding to this subunit inhibits both the inflammatory and pruritic processes, which are integral components in managing the itch-scratch cycle. IL-31 is a cytokine that is associated with the immune cascade and is believed to contribute towards symptoms of intense pruritus in PN.^4,6

Supporting Evidence for Dupilumab Monotherapy

The clinical trials involved in the regulatory approvals of dupilumab for PN, PRIME and PRIME2, showed significant improvement in the treatment of extreme pruritus and reduction in lesion count. The clinical investigations included two 24-week randomized, double-blind, placebo controlled, multicenter, parallel-group trials.^9,10 Adults aged 18-80 years (n=311) with ≥20 nodules and pruritus were included. Pruritus was graded using the Worst-Itch Numeric Rating Scale (WI-NRS), where 0 indicated no itch and 10 indicated insupportable itch. Only patients with WI-NRS score of ≥7 prior to commencement of dupilumab were investigated. Additional inclusion criteria included a history of failing a 2-week course of medium-to-superpotent topical corticosteroid or when topical corticosteroids were not medically advisable. Both clinical trials assessed the effect of dupilumab in reducing the number of lesions along with pruritus improvement. Efficacy was assessed by a reduction in WI-NRS by ≥4 points and Investigator’s Global Assessment PN-Score (IGA PN-S) of 0-1, which is equivalent to a reduction in the number of nodules down to 0-5. Patients received either dupilumab 600 mg subcutaneously on day 1 followed by 300 mg once every other week for 24 weeks on a background therapy of topical corticosteroids/topical calcineurin inhibitors at a stable dose, or a matching placebo drug. The mean age of patients was 49.5 years, and 65% of subjects were female. At baseline, the WI-NRS score was 8.5, and 66% of patients had 20-100 nodules while 34% had more than 100 nodules. In addition, 43% of patients had a history of atopy.

The first clinical trial (PRIME) showed that 38.7% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 9.2% of patients who received placebo (Table 1).⁹ The second clinical trial (PRIME2) showed that 32.1% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 8.5% of patients who received placebo (Table 2).¹⁰ Overall, dupilumab demonstrated efficacy in treating both the extreme pruritus and for reducing the number of PN nodules over a 24- week period.

Safety

Dupilumab appears to be safe for the treatment of PN. The most common side effects include 1-2% of patients who developed injection site reactions, which was more likely to occur with the initial loading dose. In addition, 8.6% of patients (n=152) had headache, 5.3% of patients (n=152) had nasopharyngitis, 4% (n=152) of patients developed conjunctivitis, and 3% (n=152) of patients developed herpes infection, dizziness, myalgias, and diarrhea.^9,10 Serious adverse events, including neurodermatitis occurred in 1.3% of patients (n=152). The following serious adverse events occurred in <1% of the patient sample: coronavirus disease of 2019 pneumonia, musculoskeletal chest pain, papillary thyroid cancer, asthma, interstitial lung disease, pelvic inflammatory disease, acute pyelonephritis, lipoma, and uterine leiomyoma. The aforementioned adverse effects were not considered related to the study intervention, except for sepsis and mesenteritis which occurred in one patient in the placebo group.¹¹

Combination Therapy Studies

Studies exploring combination therapies with dupilumab are limited. Kabbani et al. shared a case study of a 49-year-old woman who had psoriasis and PN and was successfully treated with a combination of dupilumab and ustekinumab.¹² Ustekinumab is a human monoclonal antibody that is used to treat plaque psoriasis, psoriatic arthritis, and inflammatory bowel disease.¹³ It specifically inhibits the inflammatory response caused by IL-12 and IL-23. After 3 months of ustekinumab 45 mg every 12 weeks and dupilumab 600 mg loading dose followed by 300 mg every 2 weeks, the patient had complete resolution in her pruritus. After 10 months on this combination therapy, she achieved complete clearance of her nodules. The patient has been on this combined therapy for 4 years, and has maintained her clinical response in remission. The combination therapy has been well tolerated, and there have been no safety concerns reported.

Special Populations

Safety and efficacy of dupilumab for pediatric patients younger than 18 years of age with PN have not been established.^9,10 PN has an incidence of 21.6 per 100,000 children and is commonly associated with atopic dermatitis.¹⁴ Few case reports have highlighted the use of dupilumab in pediatric patients. For example, a 7-year-old boy who had PN was treated with dupilumab 400 mg followed by 200 mg every 2 weeks. He was also using topical corticosteroids at the time. After 4 weeks of dupilumab therapy, the patient noted improvement in his prurigo lesions and no new lesions developed. By 12 weeks, the patient reported resolution of pruritus, and at the 1 year follow-up there were only a minimal number of active skin lesions and almost no excoriations. Overall, further clinical trials are required to determine the efficacy and safety of using dupilumab for PN in the pediatric population.

Conclusion

Dupilumab is an effective treatment for adult patients who have PN. Most notably, therapy improves the severe pruritus associated with this condition. Dupilumab has been shown to have a promising safety-profile and represents a paradigm shift in the way patients with PN are treated. However, further research is also required to determine the efficacy and safety of dupilumab for PN in the pediatric population.

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Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflict of interest:
The authors have no conflicts of interest to declare.

Abstract:
The pathogenesis of acne is multifactorial and involves inflammation, bacterial dysbiosis, and androgen stimulation. Existing systemic therapies target hormonal pathways to mitigate acne lesions; however, their use is limited to the female population and associated with systemic adverse effects. Clascoterone is the first topical therapy to target the hormonal pathogenesis of acne approved to treat acne vulgaris. In two identical phase 3 trials, clascoterone showed favorable efficacy over placebo in treating acne, with higher treatment success and a greater reduction in acne lesions. Large scale trials are required to assess the efficacy of clascoterone against its comparators and in combination with existing acne therapies; however, results from the current phase 3 trials support the therapeutic value of clascoterone, suggesting that this novel topical androgen inhibitor represents a valuable addition to the catalogue of acne therapy.

Key Words:
acne, clascoterone, androgen inhibitor, topical acne therapy

Introduction

Acne vulgaris is a common skin condition that impacts 85% of adolescents and young adults.^1,2 Acne prevalence decreases with age, yet many patients are burdened by acne throughout adulthood leading to known psychosocial impact and associated morbidity, including anxiety, depression, and low self-esteem.^3,4 The pathogenesis of acne is multifactorial and influenced by androgen stimulation, host microbiome, immune responses, genetics, and diet.^5-7 Androgens and other sebogenic hormones stimulate sebum production within the pilosebaceous unit, which enhances the proliferation and dysbiosis of Cutibacterium acnes (C. acnes) leading to inflammation and follicular hyperkeratinization⁸ (Figure 1). Acne onset is typically observed at adrenarche, and is rare in the prepubertal period when levels of sebogenic hormones are low.⁹ Associations also exist between acne and conditions with known androgen excess, such as polycystic ovarian syndrome (PCOS), congenital adrenal hyperplasia, and adrenal or ovarian tumors.^10-12

Common first-line acne therapies include topical retinoids, benzoyl peroxide, and topical or oral antibiotics.¹³ Combined oral contraceptives (containing estrogen and progesterone) and spironolactone effectively target the hormonal pathogenesis of acne.¹⁴ However, their use is limited to the female population and carries the potential risk of systemic adverse effects, such as thromboembolism or hyperkalemia.^15,16 Notably, there are no existing topical acne therapies that target hormonal factors involved in acne.

Novel Therapy for Acne Vulgaris

In August 2020, the US FDA approved clascoterone 1% cream as a novel therapy for the treatment of acne vulgaris in individuals aged 12 or older. Two identical randomized phase 3 trials (n=708 and n=732) demonstrated that clascoterone 1% cream showed favorable efficacy compared to vehicle cream at achieving treatment success for acne vulgaris with minimal side effects.¹⁷

Mechanism of Action

Clascoterone (cortexolone 17a-propionate) is a novel topical androgen receptor inhibitor. Clascoterone competitively binds to the androgen receptor with high affinity, competing with the endogenous ligand dihydrotestosterone (DHT) at the site of application¹⁸ (Figure 1). In vitro studies revealed that clascoterone decreases the downstream signaling events from androgen receptors, thereby reducing the transcription of androgenregulated genes and downstream lipid and proinflammatory cytokine production.¹⁸ Ultimately, this decreases sebum production and inflammation of the pilosebaceous unit.¹⁸ Esterases present in the skin and plasma hydrolyze clascoterone into its inactive parent form (cortexolone), resulting in a localized effect of clascoterone to the site of topical application and minimizing systemic antiandrogenic effects.¹⁹ Small dosefinding phase 2a studies showed that steady-state plasma concentrations of clascoterone were achieved by day 5 at 4.5 ng/mL, which was an approximate two-fold increase compared with the first dose.²⁰ Plasma concentrations of cortexolone (the inactive metabolite of clascoterone) were undetectable (<0.5 ng/mL).

Clinical Trials

Initial pilot studies demonstrated that 1% topical clascoterone cream was more effective than placebo cream at reducing the total number of acne lesions, inflammatory lesions and acne severity.²¹ The small pilot study also suggested that clascoterone was similar or more clinically effective than its comparator, 0.05% tretinoin cream.²¹ Phase 2 studies revealed that clascoterone 0.1%, 0.5% and 1% cream were safe and welltolerated in male and female adolescent and adult populations, with application of clascoterone 1% twice daily showing the most favorable clinical results.^20,22

The efficacy and safety of clascoterone 1% cream was further assessed in two identical randomized placebo-controlled double-blind phase 3 studies in patients over the age of 9 with moderate to severe facial acne (ClinicalTrials.gov Identifiers: NCT02608450 and NCT02608476).¹⁷ Subjects enrolled in the study had between 30-75 inflammatory acne lesions and 30-100 non-inflammatory acne lesions. Subjects were excluded if they expressed 2 or more facial nodules on assessment.

Severity of patient acne was scored using the 5-point category Investigator’s Global Assessment (IGA) scale (0=clear, 1=trace, 2=mild, 3=moderate, 4=severe). Composite treatment success was defined as a ≥2 point reduction in IGA score from baseline, and a score of 0 (clear) or 1 (almost clear) at 12 weeks. Three coprimary efficacy endpoints assessed during the trial included: (1) proportion of subjects that achieved treatment success at 12 weeks, and absolute change in number of (2) non-inflammatory and (3) inflammatory acne lesions at week 12 of the study. Secondary endpoints addressed changes in total lesion count, including percentage and absolute changes in lesion number from baseline at 12 weeks.

A total of 1440 subjects were randomized 1:1 to receive clascoterone 1% cream (n=722) or vehicle (n=718) in two identical multicentre trials (n=708, n=732). Approximately 1 gram of clascoterone or vehicle cream was applied to the whole face twice daily for 12 weeks. The subjects included male and non-pregnant female patients, with a median age of 18 years (range 9-58 years) and a slight female predominance (60.6%-65.9% female across all groups). The main phototypes were Fitzpatrick types II, III, and IV, with the majority of subjects being White (>83%) with lesser representation of Black, Asian or other races.

At 12 weeks, subjects assigned to the clascoterone groups achieved significantly more treatment success compared to vehicle controls. In the clascoterone groups, 18.4% (trial 1) and 20.3% (trial 2) obtained treatment success at week 12, compared to only 9.0% (trial 1) and 6.5% (trial 2) of vehicle groups (p<0.001 for both trials). There was also a significant reduction in the absolute number of inflammatory (trial 1, p=0.003; trial 2, p<0.001) and non-inflammatory acne lesions (p<0.001 for both trials) in the clascoterone group compared to vehicle at week 12. As a result, both phase 3 trials met the three coprimary efficacy endpoints. Secondary endpoints, including percentage change in total, inflammatory and non-inflammatory lesion counts from baseline, also favored clascoterone treatment over vehicle in both trials (percentage change in total lesion count: trial 1 p=0.001, trial 2 p<0.001; inflammatory lesion count: trial 1 p=0.005, trial 2 p<0.001; non-inflammatory lesion count: trial 1 p=0.009, trial 2 p<0.001).

Safety Profile

In the phase 3 trials, clascoterone was well-tolerated and maintained a safety profile similar to vehicle.¹⁷ The most common local skin reactions were erythema (11.3%-13.1% clascoterone, 14.8%-15.7% vehicle), xerosis (8.8%-12.2% clascoterone, 7.6%-13% vehicle), and local pruritus (5.1%-5.4% clascoterone, 5.2%-6.0% vehicle); while the most common treatment emergent adverse events included nasopharyngitis (1.4% clascoterone, 2.7% vehicle), oropharyngeal pain (0.06% clascoterone, 0.04% vehicle) and headache (0.08% clascoterone, 0.06% vehicle). No electrocardiogram changes or systemic adverse effects were observed in the phase 3 trials. Most reported adverse events were mild in severity, and 76.8% had resolved by conclusion of the study.²² Notably, topical clascoterone did not demonstrate side effects associated with systemic spironolactone use, such as hyperkalemia, abnormal uterine bleeding, hypotension, and renal disturbance.²³ In the phase 2a dose-finding study, 7% of subjects (3/42) exhibited an abnormal hypothalamic-pituitary-adrenal (HPA) axis response with elevated serum cortisol levels on day 14 of the study (range 14.9-17.7 μg/dL).²⁰ Follow-up 4 weeks after study conclusion revealed normal cortisol concentrations without evidence of adrenal suppression. In the phase 3 studies, no symptoms of adrenal suppression were observed.¹⁷ It should be noted that no studies were performed to assess the long-term safety of clascoterone use, or the safety of clascoterone use in combination with other existing anti-acne therapies (topical or systemic).

Conclusion

Clascoterone 1% cream represents a novel and promising therapeutic agent in the management of acne vulgaris for individuals ≥12 years of age. Evidence surrounding its use demonstrates that clascoterone is an efficacious treatment with a reassuring safety profile, where the most common side effects include erythema, xerosis, and pruritus.¹⁷ Notably, this topical agent was not observed to have significant systemic effects seen with systemic anti-androgenic agents. No evidence exists regarding the safety of clascoterone use during pregnancy or lactation, or its efficacy in combination with or compared to existing topical and systemic acne therapies. Indeed, a previous small study (n=77) indicated that clascoterone 1% cream had similar, if not better, efficacy than its comparator tretinoin 0.05% cream,²¹ yet these findings remain to be substantiated in larger scale trials. Further studies on the long-term safety and efficacy of clascoterone in combination with other therapies are warranted, and subgroup analyses may help guide the clinical utility of clascoterone in specific patient populations.

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¹Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
²Division of Dermatology, University of Alberta, Edmonton, AB, Canada

Conflict of interest:
The authors have no conflicts to declare for this work.

Abstract
Atopic dermatitis is a common cutaneous disease with significant morbidity affecting children and adults. The mainstay of atopic dermatitis therapy has typically included emollients, topical corticosteroids, and topical calcineurin inhibitors. Among the newer advances recently introduced is crisaborole (Eucrisa™), a phosphodiesterase type-4 inhibitor (PDE-4) for the treatment of mild moderate atopic dermatitis. Evidence from phase 3 trials demonstrates crisaborole as an efficacious topical agent with a favorable safety profile and limited systemic exposure. While the efficacy of crisaborole compared to existing therapies remains unknown, crisaborole is a promising candidate in the treatment of atopic dermatitis.

Key Words:
atopic dermatitis, crisaborole, eczema, Eucrisa, phosphodiesterase-4 inhibitor, topical treatment

Introduction

Atopic dermatitis (AD) is a chronic inflammatory cutaneous condition associated with significant morbidity and stigma in affected patients.¹ AD is characterized by the sudden onset of a recurrent, pruritic, erythematous and fissured dermatoses. It is estimated to affect up to 15-30% of children and up to 10% of adults living in industrialized countries.² In the United States alone, AD imposes a considerable economic burden, with an estimated cost of up to $3.8 billion annually.^1,3 Clinical features differ with age. The flexural surfaces of upper and lower extremities and face are most often affected during childhood, whereas hands and feet are more commonly involved in adult patients.⁴ AD can be associated with serious comorbidities including allergic rhinitis, asthma, hay fever, urticaria and asthma.^3,5 Patients with genodermatoses, such as Wiskott-Aldrich syndrome, may show an AD like skin condition.⁶ Individuals with AD are more prone to cutaneous secondary infections by pathogens including Staphylococcus aureus, which is also a leading cause of soft-tissue infections. Moreover, secondary skin infection can lead to exacerbation of AD disease severity.⁷

As the frequency of AD continues to rise, renewed focused on treatment and management is increasingly important.¹ As no curative options exist, therapy centers on controlling disease progression, reducing flares and providing relief from symptoms, including pain and pruritus.^8,9 The mainstays of such therapies include the use of emollients, cosmeceuticals, topical and systemic corticosteroids, as well as topical calcineurin inhibitors (TCIs).² Treatment options are predicated on age and AD severity. For instance, mild to moderate AD may be treated with TCIs or corticosteroids such as desonide 0.05% or fluocinolone 0.01%.⁸ In patients with moderate to severe AD who are recalcitrant to topical therapy, systemic treatment may include dupilumab administered at 300 mg subcutaneously once weekly or every other week for adults.^10,11 Proactive therapy with tacrolimus 0.1% ointment or pimecrolimus 2% twice daily⁹ may be employed to prevent relapses and extend periods without recurrence in patients who experience frequent exacerbations. TCIs have been issued a black box warning based on theoretical concerns that their use may be linked to lymphoma,¹² however, long-term surveillance has not substantiated this risk. Moreover, prolonged use of topical corticosteroids has been associated with cutaneous atrophy, telangiectasia, and striae formation.⁸ This has led to the development of new therapies, particularly aimed at the pediatric population. Crisaborole (formerly known as AN2728) is a novel, boron-based phosphodiesterase-4 (PDE-4) inhibitor developed to treat this populace.^8,13

A Novel Treatment for Mild-Moderate AD

Crisaborole (Eucrisa™) 2% ointment is indicated as a topical treatment for patients aged ≥2 years with mild to moderate AD. Early phase 1 and 2 studies provided evidence that showed the potential for crisaborole to be an efficacious and noncarcinogenic treatment option with a positive safety profile.^14-16 Approved in December of 2016 by the US FDA and June 2018 by Health Canada, it is the first topical PDE-4 inhibitor to be indicated for AD.

Mechanism of Action

In patients with AD, elevation of PDE-4 is associated with increased inflammatory mediators leading to a chronic inflammatory state.¹⁷ PDE-4 facilitates this inflammatory process through the degradation of 3’5’-cyclic adenosine monophosphate (cAMP). Crisaborole works through the selective inhibition of PDE-4, preventing the breakdown of cAMP, leading to an accumulation of cellular cAMP, suppression of pro-inflammatory cytokines, and reduction in inflammatory pathways.^8,17,18 Specifically, elevated levels of cAMP result in further activation of protein kinase A and inhibition of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) signaling pathways. Crisaborole targets the underlying mechanism of the disease through suppression of pro-inflammatory cytokines, including interleukin (IL)-2, IL-5, interferon-γ, and tumor necrosis factor-α.^17-19 Of note, this mechanism of cytokine-production inhibition by crisaborole is distinct from that of corticosteroids.¹⁷

Phase 3 Clinical Trials

The efficacy and safety of crisaborole was evaluated through two randomized, double-blind controlled phase 3 clinical trials, which included a total of 1522 patients ≥2 years of age with mild to moderate AD.²⁰ Although both pediatric and adult patients were represented in the study population, the mean age of the crisaborole ointment treatment groups was 12 and 12.6 in both studies. Adult patients (≥18 years of age) constituted 12.9% and 15% of the crisaborole treatment groups. The efficacy of crisaborole within these studies was determined by the clearance or almost clearance of AD with a 2-grade or more improvement from baseline using the Investigator’s Static Global Assessment (ISGA). In both studies, more crisaborole-treated patients showed improvement in the ISGA score at day 29 (32.8%, 31.4%) as compared against vehicle-treated patients (25.4%, 18%), respectively. Furthermore, patients in the crisaboroletreated group achieved success in the ISGA score earlier than the control. Pooled data between the two studies demonstrated an improvement in disease severity, as measured by the reduction in signs and symptoms, including erythema, exudation, excoriations, induration/papulation and lichenification. Improvement and sustained relief of pruritus was achieved earlier in crisaboroletreated patients (1.37 vs. 1.7 days, p=0.001).²⁰ A secondary analysis of the phase 3 trials performed by Yosipovitch et al.21 confirmed the early improvement in pruritus for the treatment cohort compared to control (56.6% vs. 39.5%; p<0.001).

Safety and Long-term Complications

Unlike topical corticosteroids and calcineurin inhibitors, which have potential adverse side effects with continued use, crisaborole demonstrates a promising safety profile. Crisaborole effectively penetrates through the skin due to its low molecular weight (251 Da) and lipophilic properties,¹⁷ with only trace amounts reaching the systemic circulation.²² Steady-state levels of crisaborole and its metabolites were reached in a pharmacokinetic 8-day trial under maximal-use conditions.²² In this study, the mean maximum plasma concentration of crisaborole remained stable with a mean maximum concentration of 127 ng/mL seen on day 8. Once in the bloodstream, the drug is quickly metabolized into inactive metabolites, limiting the systemic impact of crisaborole to the site of application.^17,22 Whereas nausea, emesis, and/or diarrhea are side effects associated with oral PDE-4 inhibitors, similar symptoms are uncommonly observed with topical use.^20,23,24 The majority of adverse events include burning or stinging at the site of application.²⁰ Of these adverse events, 77.6% of patients experienced resolution within 1 day of onset. No serious adverse events were recorded. Lastly, the low discontinuation rates (1.2%, pooled data) that were observed in phase 3 trials may indicate the potential for higher treatment compliance.

After completion of a 28-day phase 3 pivotal study, a longitudinal multicenter, open-label trial was conducted that followed 517 patients over 48 weeks to assess the long-term safety of crisaborole.²⁴ Only 10.3% of patients experienced treatmentrelated adverse events. Of these, the vast majority of adverse events were considered mild (51.2%) or moderate (44.6%). The most common events reported were atopic dermatitis (3.1%), application-site pain (2.3%) and application-site infection (1.2%). No change in the frequency of adverse events was observed throughout the study. Rescue therapy with a topical corticosteroid or TCI was required in 22.2% of patients, with the majority (79%) resuming crisaborole after the end of rescue therapy.

Conclusion

Crisaborole represents a novel and efficacious therapeutic approach for the treatment of mild to moderate AD. Through the inhibition of PDE-4 and reduction of local inflammation, crisaborole has been shown to provide a significant improvement in the management of AD.^14-16,20,22 Furthermore, crisaborole demonstrates early and continued decrease in pruritus, which improves quality of life and reduces the potential risk of infection and scarring.^24,25 The small size of the crisaborole molecule allows for effective skin penetration, while its quick metabolism in the bloodstream limits systemic exposure, which is associated with the long-term use of topical corticosteroids and TCIs.²² Further studies comparing crisaborole against topical corticosteroids or TCIs are warranted to establish it role in the treatment paradigm for mild to moderate AD, as well as its utility in children <2 years of age.

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