¹SKiN Centre for Dermatology Peterborough, ON, Canada
²Probity Medical Research, Peterborough, ON, Canada
³Queen’s University, Kingston, ON, Canada

Conflict of interest: MG has been an investigator, speaker and advisory board member for Arcutis.

Adapted from O’Toole A, Gooderham M. Topical Roflumilast for Plaque Psoriasis. Skin Therapy Lett. 2023 Sep;28(5):1-4. PMID: 37734074. Copyright 2023 by the Skincareguide.com Limited. Reprinted with permission.

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Case Presentations

Case #1

A 62-year-old female postal carrier presents with a 15-year history of plaque psoriasis which involves her elbows, dorsal hands, under the breasts and on the forehead and around the ears, total body surface area (BSA) of 3.5%. She has used numerous topical agents over the years, but most recently was prescribed hydrocortisone valerate 0.2% cream and clotrimazole for under the breasts, off-label tacrolimus 0.1% ointment for the face and ears and betamethasone valerate/calcipotriol foam for the elbows and hands. She reports using the topicals ‘when needed’ and presents with ongoing plaques in all described areas. She does admit she should probably be more consistent, but she has a busy life. Her past medical history is significant for obesity and hypertension. Her work uniform is uncomfortable and does not cover the visible areas of psoriasis making her very self-conscious. She books an appointment to discuss other options.

Case #2

A 38-year-old mechanic has a 10-year history of moderate-to-severe plaque psoriasis which requires systemic therapy. He has tried and failed methotrexate and acitretin in the past, and more recently has had success with an interleukin (IL)-23 inhibiting biologic agent started by his dermatologist. His body psoriasis cleared with the biologic, but he continues to have fissured plaques on his hands which is painful and interferes with his ability to work. He has been prescribed potent topical corticosteroid products in the past, including combination products, but he reports they are greasy, and he’s concerned about using steroids long-term. You see him in follow up, and he asks you for any other solutions.

Introduction

Plaque psoriasis is a chronic inflammatory skin condition with an estimated prevalence of 3%¹ and is characterized by scaly plaques which can be red to violaceous depending on the background skin tone. Psoriasis most commonly presents on the extensor surfaces but can involve anywhere on the body, including the scalp, face, and intertriginous areas (groin, under breasts or pannus, axillae). Most cases of plaque psoriasis are mild to moderate in severity, where half of patients have a BSA ≤3%.¹ Psoriasis significantly impacts quality of life, with the majority of patients reporting a “large impact” on their everyday life, even in those with limited BSA involvement.² Impact on quality of life is greater with special site involvement (i.e., face, groin, palms/soles) compared to no special site involvement.³ Itch is considered the most bothersome symptom in plaque psoriasis by almost half of patients.^3,4

The mainstay of treatment is topical including steroids, vitamin D analogs, retinoids, and calcineurin inhibitors (used off label), whether used as monotherapy in mild to moderate disease or as concomitant therapy with systemic agents in moderate to severe disease. Current topical therapies have limitations, however, including messy or greasy texture, complex or timeconsuming application, local side effects, or perceived inefficacy, which can all lead to lack of adherence to treatment and poor outcomes.⁵

Pathophysiology of Psoriasis and Role of Phosphodiesterase-4

Psoriasis is a chronic inflammatory disease influenced by environmental, genetic, and immunologic factors, characterized by rapid keratinocyte proliferation. The enzyme phosphodiesterase-4 (PDE4) plays a crucial role in immune cell regulation, with elevated activity in psoriatic skin promoting inflammation.⁶ PDE4 inhibitors, such as oral apremilast for moderate to severe psoriasis and crisaborole ointment for mild to moderate atopic dermatitis, are approved for use. Roflumilast, a potent PDE4 inhibitor, increases cyclic AMP, thereby reducing pro-inflammatory mediators like IL-17, IL-23, IFN-gamma, and TNF-alpha, thus normalizing immune response and keratinocyte differentiation.⁷ Roflumilast has greater affinity for PDE4 than the other currently available PDE4 inhibitors; depending on the comparator and isoform analyzed, it is approximately 25-300 times more potent than apremilast and crisaborole.^7-9

Topical Roflumilast Cream

Topical roflumilast 0.3% cream (Zoryve^TM) was approved for the treatment of plaque psoriasis including intertriginous psoriasis in adolescents (aged ≥12 years) and adults by the FDA in July 2022 and by Health Canada in April 2023; In October 2023, the FDA approved the expanded indication to include children 6-11 years of age as well. It is uniquely formulated as an emollient water-based cream designed to deliver the roflumilast molecule throughout the epidermis without disrupting the skin’s barrier function. A unique and patented emulsifier blend (Crodafos^TM CES) maintains the integrity of the lipid bilayer while facilitating delivery of roflumilast. The formulation does not contain sensitizing or irritating ingredients such as propylene glycol or fragrance, resulting in improved tolerability (compared to some other topicals currently available). Topical roflumilast 0.3% cream is also found in higher concentrations in the skin compared to that expected with oral dosing, with levels 62- to 126-fold higher in the skin compared to plasma.¹⁰ Its lipophilic and protein-affinity properties allow it to form a reservoir in the stratum corneum, enabling prolonged release. With a long half-life of 4 days, it allows for once-daily dosing, ensuring high efficacy and improved tolerability.¹⁰

Clinical Trials: Efficacy and Safety of Roflumilast

Phase 1 and 2 trials

A Phase 1/2a randomized controlled trial (NCT03392168) tested roflumilast cream 0.5%, 0.15% vs. vehicle for 28 days in patients with ≤5% BSA.¹¹ The primary endpoint was met with significant improvement in the Target Plaque Severity Score (TPSS) x target plaque area (TPA) with roflumilast 0.5% (P = .0007) and 0.15% cream (P = .0011) vs. vehicle; 66%-67% improvement from baseline to week 4 was noted with roflumilast vs. 38% for vehicle.¹¹

In a Phase 2b randomized controlled trial (NCT03638258), 331 adult patients were randomized to receive roflumilast cream 0.3%, 0.15%, or vehicle once daily for 12 weeks. The primary endpoint at 6 weeks of an Investigator Global Assessment (IGA) score of clear or almost clear (0 or 1) was reached by 28% in the roflumilast 0.3% group (P < .001), 23% in the roflumilast 0.15% group (P = .004), and 8% in the vehicle group (Figure 1A). Important secondary endpoints included an intertriginous IGA (I-IGA) response (clear or almost clear and ≥2 grade improvement from baseline) in 73% of the roflumilast 0.3% group, 44% of the roflumilast 0.15% group, and 29% of the vehicle group in the subgroup of participants with at least mild IGA intertriginous involvement (~15% of trial population).¹² Itch and itch-related sleep loss were also improved in subjects receiving roflumilast. Subjects with a baseline worst itch numeric rating scale (WI-NRS) ≥6 treated with roflumilast 0.3% cream achieved ≥4-point improvement compared with vehicle, which was significant at all time points between week 2 and week 12 (all P < .05).¹³ The least squares mean improvement in itch-related sleep loss was statistically significant for both doses of roflumilast as early as week 6 and maintained through week 12.¹³

Phase 3 trials

Two identical pivotal Phase 3 trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389), enrolled patients older than 2 years of age, with 2% to 20% BSA and an IGA of at least 2 (mild).¹⁴ A total of 439 and 442 subjects were enrolled (DERMIS-1 and DERMIS-2, respectively) and randomized to receive roflumilast cream 0.3% or vehicle. The primary endpoint was achieving IGA success (clear or almost clear [0 or 1] with ≥2 grade improvement from baseline) at 8 weeks. IGA success was achieved by participants receiving roflumilast 0.3% cream vs. vehicle by 42.4% and 6.1% (DERMIS-1) and by 37.5% and 6.9% (DERMIS-2), respectively (P < .001 for both) as shown in Figure 1B. Important secondary endpoints included I-IGA success at week 8, 75% improvement in Psoriasis Area and Severity Index (PASI75) at week 8, and itch improvement as measured by WI-NRS at weeks 2, 4, and 8. In participants with an I-IGA score of at least 2 at baseline (approximately 20% of trial population), I-IGA success at week 8 was achieved by 71.2% vs. 13.8% (DERMIS-1) and 68.1% vs. 18.5% (DERMIS-2) in roflumilast 0.3% cream vs. vehicle, respectively.¹⁴ The majority of patients achieving I-IGA success also achieved an I-IGA score of clear (0) with 63.5% vs. 10.3% (DERMIS-1) and 57.4% vs. 7.4% (DERMIS-2) (P < .001) clearing intertriginous areas with roflumilast 0.3% vs. vehicle, respectively. PASI75 was reached with roflumilast 0.3% vs. vehicle in 41.6% vs. 7.6% (P <.001) and 39% vs. 5.3% (P < .001) in DERMIS-1 and DERMIS-2, respectively. Itch, the most bothersome symptom of psoriasis, also improved in patients with a baseline WI-NRS score of ≥4 at baseline. WI-NRS reduction of at least 4 points from baseline was achieved as early as week 2 in 34.9% vs. 22% (DERMIS-1, P = .12) and 41.9% vs. 21.1% (DERMIS-2, P = .003) and at week 8 in 67.5% vs. 26.8% (DERMIS-1, P < .001) and 69.4% vs. 35.6% (DERMIS-2, P < .001).¹⁴

Topical roflumilast was well tolerated with rates of treatment emergent adverse effects (TEAEs) similar in both groups: DERMIS-1 (roflumilast: 25.2% and vehicle: 23.5%) and DERMIS-2 (roflumilast: 25.9% and vehicle: 18.9%).¹⁴ Less than 1% of patients in any group experienced a serious adverse event. Rates of discontinuation due to TEAEs were low and similar between groups. The most commonly reported TEAEs were headache and diarrhea consistent with the effects of oral PDE4 inhibition, but present at much lower rates than seen with oral agents. Diarrhea was mild to moderate and reported in 3.5% and 2.8% of participants receiving roflumilast in DERMIS-1 and DERMIS-2, respectively, compared to none in the vehicle group. No patients interrupted therapy or discontinued due to diarrhea.¹⁴ Headache was reported in 1% and 3.8% in the roflumilast groups and 1.3% and 0.7% in the vehicle groups. The cream was well tolerated with low rates of application site pain: DERMIS-1 (roflumilast: 0.7% and vehicle: 0.7%) and DERMIS-2 (roflumilast: 1.4% and vehicle: 0%). Investigator-rated tolerability was consistent with patient-rated tolerability, with 98- 99% of roflumilast patients and 98% of vehicle patients showing no signs of irritation and 99% of patients reporting ‘no or mild’ sensation with application when assessed at both weeks 4 and 8.¹⁴

Long-term Use of Topical Roflumilast

Long-term use of roflumilast was investigated in a 52-week open-label extension (OLE) of the Phase 2b study.¹⁵ There were two cohorts in the OLE: cohort 1 (n=230) was comprised of patients who completed the initial 12-week phase of the Phase 2b study (for a total of 64 weeks of therapy), and cohort 2 (n=102) had naïve patients with a diagnosis of at least mild psoriasis for a minimum of 6 months. The completion rate after 52 weeks was 73.5%, with low rates of discontinuation due to TEAEs or inefficacy, and the majority of discontinuations were due to withdrawal or loss of follow-up considering these trials were conducted during the COVID pandemic. The proportion of patients achieving IGA success was consistent over time, with 34.8% of cohort 1 patients and 39.5% of cohort 2 patients achieving IGA success with 64 weeks and 52 weeks of as-needed therapy, respectively. I-IGA success was achieved by 60% at week 12 and maintained by 66.7% of cohort 2 patients by week 52 but was not recorded in cohort 1 patients. Of the patients who achieved clear or almost clear skin during the open label portion, the mean durability of maintaining their response was 10 months.¹⁶ Topical roflumilast was well tolerated in the OLE, with the majority of TEAEs rated mild or moderate, 97% considered unrelated to treatment, and ≥97% showed no signs of irritation on physician assessment.¹⁵

Discussion

PDE4 inhibition with topical roflumilast is a promising nonsteroidal option for patients with plaque psoriasis of varying severities. Key data from the pivotal trials, DERMIS-1 and DERMIS-2, report IGA success in approximately 40% of study participants with psoriasis ranging from mild to severe. Results are supported by earlier phase studies measured at earlier time points. IGA success was noted as early as week 4, and responses were maintained to week 64 with as-needed use, suggesting that once a response is obtained, it can likely be sustained over time. Itch, the most bothersome symptom of plaque psoriasis, improved by 2 weeks (the first assessed time point) in all studies and itch improvement maintained over time. Itch-related sleep loss also improved compared to vehicle. Early responses such as itch and sleep improvement can encourage adherence to therapy and improve outcomes.

Given the spectrum of obstacles in the treatment of plaque psoriasis, including patient adherence and tolerance with topical therapies, as well as the management of itch and special sites (e.g., face and intertriginous areas), topical roflumilast appears to address these challenges. Individuals with psoriasis are often prescribed multiple topical medications to treat different skin areas, which contributes to a complicated treatment regimen and patient non-adherence. Topical roflumilast addresses this significant unmet need with its once-daily, non-steroidal and carefully designed vehicle that is appropriate for use on most body areas, avoiding the need for multiple prescriptions and simplifying the treatment regimen. A foam formulation is also being developed for use on the body and scalp.

The PASI75 responses noted with topical roflumilast were also comparable with a recent trial of oral apremilast for patients with mild to moderate psoriasis (ADVANCE trial, NCT03721172).¹⁷ With similar baseline characteristics (PASI 6-7, BSA 6-7% and the majority of patients with IGA 3 or moderate severity) in DERMIS-1/ DERMIS-2 and the ADVANCE trial, the proportion of patients achieving PASI75 were similar or better with roflumilast compared to oral apremilast. The comparability of a topical therapy demonstrating efficacy that is similar to or better than an oral PDE4 agent such as apremilast, can be explained by the properties of topical roflumilast, which include the lipophilicity and reservoir in the stratum corneum combined with the higher affinity of roflumilast for PDE4. In patients with mild to moderate psoriasis, topical roflumilast may potentially delay or even avoid the need for oral therapy by providing similar efficacy. The limitation will be patients with higher BSA where the risk of TEAEs, such as diarrhea, may be higher or those with psoriatic arthritis where a systemic therapy may be preferred.

Case Follow Up

Case #1 continued

After further discussion of options, this 62-year-old woman does not wish to start a systemic medication and would like to continue with topical therapy. For more effective control, she requires a more simplified treatment regimen and more education on how to use topical therapies effectively. Reducing the number of prescriptions and applications per day can simplify her busy life, so topical roflumilast 0.3% cream is one product that she can use on all areas of psoriasis once a day, making this convenient and easy for her. Alternatively, she could reduce her current regimen and use off-label tacrolimus 0.1% ointment twice daily on the face, ears, and body folds and the betamethasone dipropionate/calcipotriol foam once daily on the hands and elbows. Education on optimal use of these products is required to inform that they need to be continued until the skin is clear and then used as needed.

Case #2 continued

The 38-year-old male is looking for optimization of his current biologic therapy to improve the residual psoriasis on his hands and his preference is to not use steroids. Current options include: adding a non-steroidal, non-greasy, once-daily topical, such as roflumilast 0.3% cream; adding back an oral systemic medication such as acitretin in addition to his biologic; or increasing the frequency of his biologic injection. His preference is to try a new topical agent to avoid taking more systemic medication. After 4 months of follow up of using roflumilast 0.3% cream, his fissures have healed and his hands are almost clear. Not only does he feel better at work, but he has been able to re-join his softball league this year.

Conclusion

Targeting PDE4 with a highly selective inhibitor such as roflumilast is a proven effective strategy for the treatment of plaque psoriasis. Topical roflumilast cream 0.3%, already approved by Health Canada and the FDA for use in adolescents and adults, has demonstrated efficacy and tolerability. It is nonsteroidal, administered once daily, and highly potent, yet delivered in a cosmetically elegant formulation that is well tolerated by patients. It can be used on most body areas, including the sensitive intertriginous regions and face, making one product suitable for treating all areas of involvement. Topical roflumilast will offer patients and their health care providers a simple, convenient, safe, effective, and durable therapeutic option for the management of psoriasis.

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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¹SKiN Centre for Dermatology, Peterborough, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Queen’s University, Kingston, ON, Canada

Conflict of interest: A. O’Toole has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis Biotherapeutics, ASLAN Pharmaceuticals, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Sun Pharma, UCB and Ventyx. M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Aristea, ASLAN Pharmaceuticals, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, UCB and Ventyx.
Funding: None.

Abstract:
Roflumilast is a highly selective phosphodiesterase-4 inhibitor for the treatment of plaque psoriasis. Topical roflumilast 0.3% cream, approved by the US FDA and Health Canada for use in adolescents and adults, has proven efficacy and tolerability. It is non-steroidal, administered once-daily, and highly potent, with a unique delivery formulation. It can be used on most body areas, including the sensitive intertriginous regions and face. Herein, we review the safety and efficacy of roflumilast 0.3% cream, as demonstrated in clinical trials.

Keywords: roflumilast, PDE4 inhibitor, topical therapy, plaque psoriasis, intertriginous psoriasis, inverse psoriasis

Introduction

Plaque psoriasis is a chronic inflammatory skin condition with an estimated prevalence of 3%¹ and is characterized by scaly plaques which can be red to violaceous depending on the background color of skin. Psoriasis most commonly presents on the extensor surfaces but can involve anywhere on the body, including the scalp, face, and intertriginous areas. Most cases of plaque psoriasis are mild to moderate in severity, where half of patients have a body surface area (BSA) ≤3% and three-quarters have a BSA ≤10%.¹ Psoriasis significantly impacts quality of life, with the majority of patients reporting a “large impact” on their everyday life, even in those with limited BSA involvement.² Impact on quality of life is greater with special site involvement (i.e., face, groin, palms/soles) compared to no special site involvement.³ Itch is considered the most bothersome symptom in plaque psoriasis by almost half of patients.^3,4

The mainstay of treatment is topical including steroids, vitamin D analogs, retinoids, and calcineurin inhibitors (used off label), whether used as monotherapy in mild to moderate disease or as concomitant therapy with systemic agents in moderate to severe disease. Current topical therapies have limitations, however, including messy or greasy texture, complex or time-consuming application, local side effects, or perceived inefficacy, which can all lead to lack of adherence to treatment and poor outcomes.⁵ Indeed, almost 80% of patients with a BSA of ≤10% were very dissatisfied with their treatment in one US survey.²

Pathophysiology of Psoriasis and Role of Phosphodiesterase-4

Environmental, genetic, and immunologic factors play a role in this complex, chronic, multifactorial inflammatory disease that involves hyperproliferation of the keratinocytes with an increase in epidermal cell turnover rate. Phosphodiesterase-4 (PDE4) is a key enzyme involved in immune cell homeostasis. Elevated PDE4 activity in psoriatic skin leads to an increase in pro-inflammatory pathogenic mediators underlying plaque psoriasis,⁶ making PDE4 a suitable target in disease management. PDE4 inhibitors have been approved for use in dermatology, including oral apremilast for moderate to severe plaque psoriasis (and psoriatic arthritis) and crisaborole ointment for mild to moderate atopic dermatitis. Roflumilast is a selective and highly potent inhibitor of PDE4,⁷ resulting in an increase in cyclic 3′,5′-adenosine monophosphate (cAMP) activity and subsequent decrease in the expression levels of key pro-inflammatory mediators of psoriasis including interleukin (IL)-17, IL-23, interferon‐gamma and tumor necrosis factor-alpha.⁶ Reducing pro-inflammatory mediators helps balance the immune response and normalizes keratinocyte differentiation.⁶ Roflumilast has greater affinity for PDE4 than the other currently available PDE4 inhibitors used to treat skin disease; depending on the comparator and isoform analyzed, it is approximately 25-300 times more potent than apremilast and crisaborole.^7-9

Topical Roflumilast

Topical roflumilast 0.3% cream (Zoryve^TM) was approved by the US FDA for the treatment of plaque psoriasis including intertriginous psoriasis in adolescents (aged ≥12 years) and adults in July 2022, with Health Canada approval gained in April 2023. It is uniquely formulated as an emollient water-based cream designed to deliver the roflumilast molecule throughout the epidermis without disrupting the skin’s barrier function or extracting lipids from the epidermis. A unique and patented emulsifier blend (Crodafos^TM CES) maintains the integrity of the lipid bilayer while facilitating delivery of roflumilast. The composition of Crodafos^TM CES includes cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate which allows roflumilast to diffuse through the epidermis by saturating the stratum corneum and subsequently entering the dermis via the intracellular space. The formulation does not contain ingredients such as propylene glycol or fragrance, resulting in improved tolerability (compared to some other topicals currently available). Topical roflumilast 0.3% cream is also found in higher concentrations in the skin compared to that expected with oral dosing, with levels 61.8- to 126-fold higher in the skin compared to plasma.¹⁰ The lipophilic, protein-affinity and water-insoluble properties of topical roflumilast leads to reservoir formation in the stratum corneum and prolonged release into the skin and systemic circulation. In fact, topical roflumilast has a long half-life of 4 days,¹⁰ affording the ability for once-daily dosing, high efficacy and improved tolerability. The tolerability and low rate of adverse effects are attributable to reduced bioavailability in the topical form compared to the oral form of roflumilast.¹⁰

Clinical Trials: Efficacy and Safety of Roflumilast

Topical roflumilast has proven efficacy and safety in multiple clinical trials. A Phase 1/2a randomized controlled trial (NCT03392168) tested roflumilast cream 0.5%, 0.15% vs. vehicle for 28 days in patients with ≤5% BSA.¹¹ The primary endpoint was met with significant improvement in the Target Plaque Severity Score (TPSS) x target plaque area (TPA) with roflumilast 0.5% (P = .0007) and 0.15% cream (P = .0011) vs. vehicle; 66%-67% improvement from baseline to week 4 was noted with roflumilast vs. 38% for vehicle.¹¹

In a Phase 2b randomized double-blinded controlled trial (NCT03638258), 331 adult patients were randomized 1:1:1 to receive roflumilast cream 0.3%, 0.15%, or vehicle once daily for 12 weeks. The primary endpoint at 6 weeks of an Investigator Global Assessment (IGA) score of clear or almost clear (0 or 1) was reached by 28% in the roflumilast 0.3% group (P < .001), 23% in the roflumilast 0.15% group (P = .004), and 8% in the vehicle group (Figure 1A). The mean change in Psoriasis Area and Severity Index (PASI) from baseline at week 6 was -50.0%, -49.0%, and -17.8%, in roflumilast 0.3%, roflumilast 0.15%, and vehicle, respectively. Important secondary endpoints included an intertriginous IGA (I-IGA) response (clear or almost clear and ≥2 grade improvement from baseline) in 73% of the roflumilast 0.3% group, 44% of the roflumilast 0.15% group, and 29% of the vehicle group in the subgroup of participants with at least mild IGA intertriginous involvement (~15% of trial population).¹² Itch and itch-related sleep loss were also improved in subjects receiving roflumilast. Subjects with a baseline worst itch numeric rating scale (WI-NRS) ≥6 treated with roflumilast 0.3% cream achieved ≥4-point improvement compared with vehicle, which was significant at all time points between week 2 and week 12 (all P < .05).¹³ The least squares mean improvement in itch-related sleep loss was statistically significant for both doses of roflumilast as early as week 6 and maintained through week 12.¹³

Two identical pivotal Phase 3 trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389), enrolled patients older than 2 years of age, with 2% to 20% BSA and an IGA of at least 2 (mild).¹⁴ A total of 439 and 442 subjects were enrolled (DERMIS-1 and DERMIS-2, respectively) and randomized 2:1 to receive roflumilast cream 0.3% or vehicle. The primary endpoint was achieving IGA success (clear or almost clear [0 or 1] with ≥2 grade improvement from baseline) at 8 weeks. IGA success was achieved by participants receiving roflumilast 0.3% cream vs. vehicle by 42.4% and 6.1% (DERMIS-1) and by 37.5% and 6.9% (DERMIS-2), respectively (P < .001 for both) as shown in Figure 1B. Important secondary endpoints included I-IGA success at week 8, 75% improvement in PASI (PASI75) at week 8, and itch improvement as measured by WI-NRS at weeks 2, 4, and 8. In participants with an I-IGA score of at least 2 at baseline (approximately 20% of trial population), I-IGA success at week 8 was achieved by 71.2% vs. 13.8% (DERMIS-1) and 68.1% vs. 18.5% (DERMIS-2) in roflumilast 0.3% cream vs. vehicle, respectively.¹⁴ The majority of patients achieving I-IGA success also achieved an I-IGA score of clear (0) with 63.5% vs. 10.3% (DERMIS-1) and 57.4% vs. 7.4% (DERMIS-2) (P < .001) clearing intertriginous areas with roflumilast 0.3% vs. vehicle, respectively. PASI75 was reached with roflumilast 0.3% vs. vehicle in 41.6% vs. 7.6% (P < .001) and 39% vs. 5.3% (P < .001) in DERMIS-1 and DERMIS-2, respectively. Itch, the most bothersome symptom of psoriasis, also improved in patients with a baseline WI-NRS score of ≥4 at baseline. WI-NRS reduction of at least 4 points from baseline was achieved as early as week 2 in 34.9% vs. 22% (DERMIS-1, P = .12) and 41.9% vs. 21.1% (DERMIS-2, P = .003) and at week 8 in 67.5% vs. 26.8% (DERMIS-1, P < .001) and 69.4% vs. 35.6% (DERMIS-2, P < .001).¹⁴

Topical roflumilast was well tolerated with rates of treatment emergent adverse effects (TEAEs) similar in both groups: DERMIS-1 (roflumilast: 25.2% and vehicle: 23.5%) and DERMIS-2 (roflumilast: 25.9% and vehicle: 18.9%).¹⁴ Less than 1% of patients in any group experienced a serious adverse event. Rates of discontinuation due to TEAEs were low and similar between groups. The most commonly reported TEAEs were headache and diarrhea consistent with the effects of oral PDE4 inhibition, but present at much lower rates than seen with oral agents. Diarrhea was mild to moderate and reported in 3.5% and 2.8% of participants receiving roflumilast in DERMIS-1 and DERMIS-2, respectively, compared to none in the vehicle group. No patients interrupted therapy or discontinued due to diarrhea.¹⁴ Headache was reported in 1% and 3.8% in the roflumilast group and 1.3% and 0.7% in the vehicle group. The cream was well tolerated with low rates of application site pain: DERMIS-1 (roflumilast: 0.7% and vehicle: 0.7%) and DERMIS-2 (roflumilast: 1.4% and vehicle: 0%). Investigator-rated tolerability was consistent with patient-rated tolerability, with 98- 99% of roflumilast patients and 98% of vehicle patients showing no signs of irritation and 99% of patients reporting ‘no or mild’ sensation with application when assessed at both weeks 4 and 8.¹⁴

Long-term Use of Topical Roflumilast

Long-term use of roflumilast was investigated in a 52-week openlabel extension (OLE) of the Phase 2b study.¹⁵ There were two cohorts in the OLE: cohort 1 (n=230) was comprised of patients who completed the initial 12-week phase of the Phase 2b study (for a total of 64 weeks of therapy), and cohort 2 (n=102) had naïve patients with a diagnosis of at least mild psoriasis for a minimum of 6 months. The completion rate after 52 weeks was 73.5%, with low rates of discontinuation due to TEAEs or inefficacy, and the majority of discontinuations were due to withdrawal or loss of follow-up. The proportion of patients achieving IGA success was consistent over time, with 34.8% of cohort 1 patients and 39.5% of cohort 2 patients achieving IGA success with 64 weeks and 52 weeks of as-needed therapy, respectively. I-IGA success was achieved by 60% at week 12 and maintained by 66.7% of cohort 2 patients by week 52 but was not recorded in cohort 1 patients. Of the patients who achieved clear or almost clear skin during the open label portion, the mean durability of maintaining their response was 10 months.¹⁶ Topical roflumilast was well tolerated in the OLE, with the majority of TEAEs rated mild or moderate, 97% considered unrelated to treatment, and ≥97% showed no signs of irritation on physician assessment.¹⁵

Discussion

PDE4 inhibition with topical roflumilast is a promising non-steroidal option for patients with plaque psoriasis of varying severities. Key data from the pivotal trials, DERMIS-1 and DERMIS-2, report IGA success in approximately 40% of study participants with psoriasis ranging from mild to severe. Results are supported by earlier phase studies measured at earlier time points. IGA success was noted as early as week 4, and responses were maintained to week 64 with as-needed use, suggesting that once a response is obtained, it can likely be sustained over time. Itch, the most bothersome symptom of plaque psoriasis, improved by 2 weeks (the first assessed time point) in all studies and itch improvement maintained over time. Itch-related sleep loss also improved compared to vehicle. Early responses such as itch and sleep improvement can encourage adherence to therapy and improve outcomes.

Given the spectrum of obstacles in the treatment of plaque psoriasis, including patient adherence and tolerance with topical therapies, as well as the management of itch and special sites (e.g., scalp and intertriginous areas), topical roflumilast appears to address these challenges. Individuals with psoriasis are often prescribed multiple topical medications to treat different skin areas, which contributes to a complicated treatment regimen and patient non-adherence. Topical roflumilast addresses this significant unmet need with its once-daily, non-steroidal and carefully designed vehicle that is appropriate for use on most body areas, avoiding the need for multiple prescriptions and simplifying the treatment regimen. A foam formulation is also being developed for use on the body and scalp.

The PASI75 responses noted with topical roflumilast were also comparable with a recent trial of oral apremilast for patients with mild to moderate psoriasis (ADVANCE trial, NCT03721172).17 With similar baseline characteristics (PASI 6-7, BSA 6-7% and the majority of patients with IGA 3 or moderate severity) in DERMIS-1/ DERMIS-2 and the ADVANCE trial, the proportion of patients achieving PASI75 were similar or better with roflumilast compared to oral apremilast. In ADVANCE, 21.6% of those receiving oral apremilast 30 mg twice daily achieved PASI75 compared to 4.1% receiving placebo at 16 weeks. In DERMIS-1 and DERMIS-2, after 8 weeks of therapy, 41.6% and 39% of roflumilast patients achieved PASI75 compared to 7.6% and 5.3% of vehicle patients, respectively. The comparability of a topical therapy demonstrating efficacy that is similar to or better than an oral PDE4 agent such as apremilast, can be explained by the properties of topical roflumilast, which include the lipophilicity and reservoir in the stratum corneum combined with the higher affinity of roflumilast for PDE4. In patients with mild to moderate psoriasis, topical roflumilast may potentially delay or even avoid the need for oral therapy by providing similar efficacy. The limitation will be patients with higher BSA where the risk of TEAEs, such as diarrhea, may be higher or those with psoriatic arthritis where a systemic therapy may be preferred.

Conclusion

Targeting PDE4 with a highly selective inhibitor such as roflumilast is a proven effective strategy for the treatment of plaque psoriasis. Topical roflumilast cream 0.3%, already approved by Health Canada and the FDA for use in adolescents and adults, has demonstrated efficacy and tolerability. It is non-steroidal, administered oncedaily, and highly potent, yet delivered in a cosmetically elegant formulation that is well tolerated by patients. It can be used on most body areas, including the sensitive intertriginous regions and face, making one product suitable for treating all areas of involvement. Topical roflumilast will offer patients and their health care providers a simple, convenient, safe, effective, and durable therapeutic option for the management of psoriasis.

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¹Beacon Dermatology, Calgary, AB, Canada
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Dermatologie Clinic, Drummondville, QC, Canada
⁴Bausch Health Canada Inc, Laval, QC, Canada
⁵SKiN Centre for Dermatology, Peterborough, ON, Canada
⁶Queen’s University, Kingston, ON, Canada

Conflict of interest: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:
Isabelle Delorme has been a member of advisory boards for AbbVie, Bausch Health, Eli-Lilly, Janssen, Novartis, Sanofi-Genzyme. She has been a part of clinical trials for AbbVie, Amgen, Anaptys Bio, Arcutis, Bausch Health, BMS, Celgene, Dermira, Devonian, Eli-Lilly, Galderma, Glenmark Pharmaceutical, Innovaderm Research, Janssen, Leo Pharma, Novartis, Regeneron. She has recieved honoraria from AbbVie, Amgen, Avene, Celgene, Eli-Lilly, Janssen, Novartis, UCB Pharma. She has been part of speaker’s bureaus for AbbVie, Celgene, Bausch Health, Eli-Lilly, Janssen, Medexus Inc., Novartis, Sanofi Genzyme. Melinda Gooderham has been an investigator, speaker and/or advisor for – AbbVie, Amgen, Akros, Arcutis, Aslan, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Andrei Metelitsa has been a consultant for Bausch Health, Galderma, Leo Pharma and Pfizer.
Daniel O’Sullivan, Rami Zeinab and Mark Legault are employees of Bausch Health Canada.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Dermatological diseases such as atopic dermatitis, acne, and psoriasis result in significant morbidity and decreased quality of life. The first line of treatment for such diseases is often topical medications. While topical delivery allows active drug to be delivered directly to the target site, the skin is a virtually impermeable barrier that impedes delivery of large molecules. Thus, the formulation and delivery system are integral elements of topical medications. Patients also have preferences for the properties of topical formulations and these preferences can positively or negatively impact adherence. Therefore, the choice of topical formulation is a key consideration. Recent developments in drug delivery systems have produced enhanced topical treatments that improve efficacy, safety, and patient acceptability. Awareness of the delivery system in which drugs are formulated is critical as this can have profound implications on treatment success. This paper provides an overview and clinical commentary on advances in topical delivery systems and their impact on dermatological practice.

Keywords: acne, corticosteroid, dermatitis, dermatology, halobetasol, psoriasis, retinoid, tazarotene, topical, vehicle, Duobrii, Arazlo, Bryhali

Introduction

Topical therapies are often the first line of treatment for common skin diseases such as atopic dermatitis (AD), acne vulgaris (AV), and psoriasis (PsO).¹ Prescribing effective therapy is crucial for optimal treatment outcomes.² However, the composition of topical treatments is complex and should be taken into consideration when choosing a topical treatment in terms of both “formulation” and “drug delivery system” wherein the formulation includes the active drug and vehicle while the delivery system refers to technologies affecting the therapeutic action of the drug (including potency, stability, dispersion, and penetration). Both formulation and delivery system should be considered for each patient on the basis of the potency of the active molecule, patient preference, skin type, skin condition, and affected site.³ Several recent reviews have discussed topical vehicles, ingredients, and their effects on the skin,^4-10 however, there is a gap in reviewing advanced delivery systems currently in clinical use. This paper provides an up-to-date review of advances in topical delivery systems with a focus on those in clinical use for the treatment of AD, AV, and PsO.

Atopic Dermatitis, Acne Vulgaris and Psoriasis

Skin conditions are a common cause of disease globally,¹¹ with AD, AV, and PsO amongst those with the highest disease burden on patients¹². These conditions disrupt the normal skin function,¹³ trigger abnormal inflammatory responses, alter skin microbiome, and increase susceptibility to irritants/allergens.^5-7 AD is a chronic, relapsing disease, presenting as inflamed skin with intense itching.^14,15 AV is due to inflammation of the sebaceous follicles, resulting in increased sebum production and a favorable environment for bacterial growth.¹⁶ PsO is a chronic disease that presents with characteristic scaling, redness, and thickening of the skin. All of these skin diseases can have important detrimental effects on short and long-term psychosocial and physical health, with substantial morbidity and reduced quality of life.^15,17,18 As such, early treatment with the most efficacious therapies available is critical.

Factors to Consider with Topical Drug Delivery Systems

Applying treatment topically provides several advantages for managing skin diseases. It enables delivery of drug directly to the target site, minimizing systemic exposure.¹⁹ The skin provides for a regulated, constant delivery rate and circumvents first-pass metabolism.²⁰ However, delivering drugs to targets beneath the epidermis can be challenging.²¹ The skin is a multi-layered defense barrier constructed to withstand the penetration of external compounds.²² The stratum corneum is very effective in performing this role and minimizes the ingress and egress of molecules/ chemicals.²³ As a result, the skin is impermeable to almost all compounds with a molecular weight greater than 500 Daltons.^22,23 As diffusion is the principal mechanism by which a drug penetrates the skin,²² formulations must be optimized to maintain solubility, stability, dispersion, and penetration of the active ingredient(s) while ensuring they are sustained at the target site for sufficient time, as well as limit systemic exposure³.

The effectiveness of a topical medication depends not only on pharmacodynamic factors but also on patient preferences, adherence, and the location of disease.^2,24 Patient preferences are related to the formulation and drug delivery system whose attributes include moisturization, absorption, greasiness, stickiness, as well as ease and frequency of use.²⁵ These attributes influence adherence to the therapeutic regimen which is a major determinant of treatment success.²⁵ Teixeira et al.²⁶ reported that adherence was impacted not only by patient preferences, but also the body area affected. For example, adherence was higher for patients using gel/cream vs. ointment formulations when the body area affected was large. However, this was reversed with smaller areas. As such, delivery systems are no longer only considered ‘carriers’ of active ingredients, but also integral to the formulation. Hence, drug delivery system research and development have been the main drivers of recent advancements in topical formulations.

Advanced Topical Drug Delivery Systems

Over the years, advanced drug delivery systems have been developed to enhance effectiveness, tolerability, safety, and patient acceptability of topical formulations. Some of these advanced delivery systems are integrated into approved products utilized in clinical practice in Canada (Figures 1 & 2). As such, it is important for healthcare providers to be aware of these systems and their profound implications on treatment outcomes. The following summary provides an overview of some recent advances in drug delivery systems and their clinical application (Table 1).

Table 1. Advanced topical drug delivery systems in clinical use

Microencapsulation

Description of Delivery System

Microencapsulation is a technique that involves entrapping active ingredient(s) in a microcapsule, creating a barrier between the ingredients and the skin.²⁷ Once applied, microcapsules allow controlled release of active ingredients over time.²⁸ This offers advantages for topical delivery of agents (Table 1) where active ingredients are protected against degradation and maintained at the target site for an extended time while limiting local adverse reactions.^28,29

Clinical Application Highlights

Encapsulation is the technology behind two topical treatments approved for treatment of moderate to severe AV in the US. The first formulation is a foam-based delivery system that optimizes the topical delivery of minocycline (minocycline topical foam 4%, Amzeeq®).³⁰ Minocycline was previously not available topically due to its instability and systemic side effects.³¹ Such limitations were mitigated with microencapsulation. In phase 2^32,33 and 3³⁴ clinical trials, microencapsulated minocycline significantly reduced AV lesions and severity compared to placebo; with minimal adverse effects. The second is a cream-based formulation combining tretinoin 0.1% and benzoyl peroxide (BPO) 3% (Twyneo®).³⁵ Tretinoin and BPO are individually entrapped within silica-based microcapsules preventing the degradation of tretinoin by BPO.²⁸ The active ingredients are released over time, providing a consistent drug concentration at the affected site.³⁶ Results from clinical trials show that patients who received this encapsulated combination therapy had improved treatment outcomes compared with patients who received vehicle only. The treatment was well tolerated.³⁶

Microsponges

Description of Delivery System

Microsponges are microscopic, uniform, spherical, porous delivery systems.³⁷ Some features of micropsonges are summarized in Table 1. Their large surface area allows a range of substances to be incorporated into gels, creams, liquids, or powders.³⁸ They can absorb skin secretions, therefore reducing the oiliness of the skin.^38,39 When applied, the release of drug is controlled through diffusion, rubbing, moisture, pH, friction, or ambient skin temperature, producing a controlled release and reducing side effects.⁴⁰ Microsponge polymers possess the ability to load a spectrum of active ingredients and provide the benefits of enhanced effectiveness, mildness, and tolerability to a wide range of skin therapies.⁴¹ The microsponge system is stable over a range of pH and temperatures, compatible with most vehicles and ingredients, self-sterilizing as average pore size prevents bacterial penetration, and has a higher payload⁴² (50-60%) vs. conventional topical drugs and microencapsulation. However, due to their size (5-300 μm), passage through the stratum corneum is limited.³⁹

Clinical Application Highlights

Early topical formulations of tretinoin had high concentrations of active ingredients in alcohol-based solutions leading to skin dryness and irritation.^43,44 The innovation of microsponges led to the first alcohol-free, topical retinoid delivery system (tretinoin gel, Retin-A Micro^®).⁴⁵ This microsponge gel contains tretinoin in concentrations of 0.04%, 0.06%, 0.08%, and 0.1%. Tretinoin is entrapped in patented methyl methacrylate/glycol dimethacrylate copolymer porous microspheres (Microsponges^® system), within a carbomer-based gel. In the vehicle-controlled clinical trials, tretinoin gel was significantly more effective than vehicle in reducing the severity of acne lesions; and significantly superior to vehicle in the investigator’s global evaluation of the clinical response.^46-48 Microsponge delivery of tretinoin has also been associated with decreased irritation compared to earlier alcoholbased cream (Retin-A® cream, 0.1%).⁴⁹

Polymeric Emulsion Technology

Description of Delivery System

In polymeric emulsion technology (PET), active ingredients are encapsulated within oil droplets, together with moisturizing/ hydrating ingredients (light mineral oil, diethyl sebacate).⁵⁰ The oil droplets are uniformly dispersed within an oil-in-water emulsion and separated by a three-dimensional mesh matrix.⁵¹ Recently, PET has been combined with optimized selection of excipients and emollients to produce a patented delivery system called Prismatrex™. This novel technology allows simultaneous and uniform dispersion of active ingredients onto the skin at lower doses than conventional formulations to achieve comparable therapeutic effect, while providing enhanced hydration and moisturization.⁵² Also, the technology allows many attributes of patient preferences to be met. By combining water-soluble moisturizing components within the matrix, a lotion can have a pleasant feel; the use of moisturizers over alcohol-based components creates a lowirritancy/ low-drying formulation; and the mesh network breaking down upon contact with the salts on the skin surface results in quick release and absorption, leaving behind minimal greasy or sticky residue.^50,51

Clinical Application Highlights

Prismatrex™ is used in recent formulations containing retinoids, corticosteroids, or combination of both. Topical corticosteroids are a mainstay in the treatment of AD and PsO. Due to the defective skin barrier in AD and PsO, formulations with moisturizing effects in a patient-preferred format offer additional therapeutic advantages over previous formulations.⁵³ Halobetasol propionate (HP) 0.01% lotion (Bryhali^®), formulated with Prismatrex™, provides several improvements compared to the older 0.05% cream formulation. For example, a reduced concentration of drug while maintaining comparable efficacy to the cream formulation, and a safety profile that allows extended use up to 8 weeks.⁵⁴ Furthermore, the formulation is non-greasy and aesthetically pleasing, providing a patient preferred treatment option.⁵⁵

Topical retinoids are a cornerstone in the treatment of AV. However, dryness, erythema, and peeling are important side effects that can impact treatment adherence.⁵⁶ Prismatrex™ has been used to formulate the third-generation retinoid, tazarotene (TAZ) 0.045% lotion (Arazlo®). The small particle size with this formulation allows better access to the pilosebaceous unit.⁵⁷ Also, this novel technology allows for uniform distribution of TAZ on the skin along with moisturizing ingredients and emollients, therefore, TAZ may be delivered at a lower and potentially less irritating concentration than the previous 0.1% cream formulation.⁵⁸ Two identical phase 3, vehicle-controlled studies demonstrated statistically superior efficacy for TAZ 0.045% lotion vs. placebo in once-daily treatment of moderate to severe AV.⁵⁹

A fixed-combination lotion containing both HP 0.01% and TAZ 0.045% (Duobrii®, HP/TAZ) is formulated using Prismatrex™ technology and indicated for PsO treatment. Higher tissue permeation efficiency of both HP (vs. HP 0.05% cream) and TAZ (vs. TAZ 0.1% cream, Tazorac®) has been achieved with the combination using Prismatrex™ technology.⁵⁰ The delivery of both active ingredients with anti-inflammatory and anti-proliferative properties into a lotion confers a synergistic effect.^50,52 Also, it has demonstrated improved efficacy, tolerability, and maintenance of therapeutic effect compared with monotherapy with either of the active ingredients.^50,52,60-62 HP/TAZ’s acute and long-term efficacy (including maintenance of efficacy after cessation of treatment), tolerability, and safety have been demonstrated in phase 2 and 3 vehicle-controlled trials and an open-label extension study.⁶³ Importantly, HP/TAZ is associated with low incidences of adverse events that may be of concern with corticosteroid and retinoid monotherapy.⁶⁴ Skin atrophy occurs in up to 5% of patients treated with topical corticosteroids.⁶⁴ In HP/TAZ clinical trials, incidences of skin atrophy were rare and generally resolved by the end of the study despite 8 weeks of daily application.^63-64 This may be because TAZ increases the number and activity of dermal fibroblasts and stimulates collagen and elastin production.⁶⁵ Irritation, pain, and retinoid dermatitis may be a challenge with retinoid monotherapy. Incidences of these AEs were lower with HP/TAZ, than with TAZ monotherapy, potentially due to the anti-inflammatory properties of HP.⁶⁴ Clinical trials have also shown that the majority of participants who achieve clear skin with HP/TAZ, experience prolonged maintenance of therapeutic effect after treatment cessation.⁶⁰ Taken together, HP/TAZ provides a treatment option for PsO that is efficacious, safe, combines the beneficial effects of corticosteroids and retinoids, delivers moisturizing and hydrating ingredients, yields longer remission, and is acceptable to patients.

Real World Clinical Commentary

A challenge frequently encountered by dermatologists when managing AD, AV, and PsO is balancing sustained disease suppression with the avoidance of local/systemic side effects. To address this concern, advanced drug delivery systems, such as Primsmatrex™, allow for more efficient delivery of lower doses of active ingredients without compromising efficacy. However, this must also be balanced with overall patient acceptance. Patients consistently cite the following preferences for treatment options: non-greasy applications, reduced skin irritation, spreadable and easily absorbed,³⁶ easily applied in certain body sites (e.g., scalp); easy to wash off with minimal residue, and fast skin responses.⁶⁶ Novel delivery systems often enhance utilization of existing ingredients making them more acceptable to patients, resulting in therapeutic advances. For example, in acne, the innovative drug delivery systems used in Retin-A Micro®, Arazlo® and Twyneo® have significantly improved tolerability of existing topical retinoid ingredients without sacrificing the overall efficacy of these molecules. While patients are advised to maintain a dosing schedule of every second day during the initial phases of treatment to avoid potential irritation, these agents are well tolerated given the nature of the formulations.

The microencapsulation of minocycline foam allows delivery in a topical formulation as opposed to an oral format, which significantly enhances the safety profile. In psoriasis, where availability of topical agents is quite limited, the Prismatrex™ technology in HP/TAZ provides an excellent new treatment option which combines two effective drugs and is a welcome addition to our therapeutic algorithm. In clinical practice, this formulation is effective, can be less irritating to the skin than TAZ alone and is less likely to induce steroid-induced atrophy as compared to HP alone. Another advantage to these advanced topicals is that they result in improved adherence and therefore better treatment outcomes in the long run. Overall, when choosing the optimal therapeutic agent for treatment of AD, AV, or PsO the dermatologist now has the option to select a formulation that uses an advanced drug delivery system to maximize the chances of achieving successful treatment outcomes. Research in advanced delivery systems is vast, with a wide range of technologies showing promise for future clinical use, such as nanoparticles⁶⁷, ethosomes⁶⁸, niosomes⁶⁹, and liposomes⁷⁰.

Conclusion

Topical treatment is a cornerstone in managing AD, AV, and PsO;¹⁹ however, the delivery of active drugs through the dermal barrier remains a challenge. Furthermore, patient acceptability is a major contributing factor to the effectiveness and adherence to topical treatments. Advances in topical drug formulations and delivery systems address many limitations seen with older formulations. These advances allow for efficient and uniform delivery of active ingredients to target sites, greater patient acceptability, and enhanced treatment outcomes.

Acknowledgements

Medical writing assistance for this manuscript was provided by KTP (Knowledge Translation Partners), Montreal, Canada, funded by Bausch Health Canada.

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Melinda J. Gooderham, MSc, MD, FRCPC^1,2; H. Chih-ho Hong, MD, FRCPC^2,3; Ivan V. Litvinov, MD, PhD, FRCPC⁴

¹Skin Centre for Dermatology, Peterborough, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada

Conflict of interest:
M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Arena Pharmaceuticals, Asana BioSciences, ASLAN Pharmaceuticals, Bausch Health/Valeant, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, and UCB. H. C. Hong has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli-Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Leo Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Roche, Sanofi-Genzyme, Sun Pharma, and UCB. I. Litvinov has received a grant or an honorarium from AbbVie, Actelion, Bausch Health, Bristol-Myers Squibb, Galderma, ICPDHM, Janssen, Johnson & Johnson, Merck, Novartis, Pfizer, and Sun Pharmaceuticals.

Funding for this manuscript was provided in the form of an educational grant from Bristol Myers Squibb Canada Co.

Abstract:
Moderate to severe chronic plaque psoriasis may be difficult to control using current therapies, which has led to development of a novel class of therapy, selective tyrosine kinase 2 (TYK2) inhibitors, to address this unmet need. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, which has shown efficacy in moderate to severe chronic plaque psoriasis from two phase III pivotal trials (POETYK PSO-1 and PSO-2), whereby response rates were significantly higher with deucravacitinib vs. placebo or apremilast for Psoriasis Area Severity Index (PASI) 75 and static Physician’s Global Assessment (sPGA) 0/1. Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast. Although deucravacitinib is a type of Janus kinase (JAK) inhibitor, it only blocks specific cytokine-driven responses, potentially reducing off-target effects more commonly associated with other JAK inhibitors on the market. Incidence rates of serious adverse events, such as serious infections, malignancies, thrombosis, cardiovascular events, creatinine kinase elevation, hematologic changes, and lipid profile abnormalities were absent or low.

Key Words:
plaque psoriasis, TYK2 inhibitor, deucravacitinib, apremilast, clinical trial, efficacy, safety, PASI, sPGA

Introduction

Psoriasis is a common, chronic, immune-mediated inflammatory disease, estimated to affect 1 million people in Canada.^1,2 The most common type is chronic plaque psoriasis, which affects 90% of this patient population.¹

Moderate chronic plaque psoriasis is typically defined as involving ≥3-10% body surface area (BSA), with severe disease involving more than 10% BSA.³ When inadequately treated, this can cause severe psychosocial impact and impair patients’ quality of life (QoL).³

Currently, various oral systemic agents, biologic agents, and phototherapy have Health Canada-approved indications for management of moderate to severe chronic plaque psoriasis. Despite numerous treatment options, unmet needs still exist. An emerging class of therapy in development are selective tyrosine kinase 2 (TYK2) inhibitors, which may meet those needs. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, recently US FDA approved and currently under review by Health Canada. Other oral selective TYK2 inhibitors for treatment of moderate to severe plaque psoriasis in various stages of development include GLPG3667 and NDI-034858.^4,5

Pathogenesis of Plaque Psoriasis

The pathogenesis of chronic plaque psoriasis starts with environmental, immunologic, and/or genetic triggers that can lead to release of cytokines from innate immune cells, activating myeloid dendritic cells.^6,7 Activated myeloid dendritic cells present antigens to T cells and release cytokines, including interleukin (IL)-23 and IL-12;^6-8 both IL-23 and IL-12 signal through TYK2-mediated pathways. IL-12 contributes to T helper (Th)1-cell differentiation and IL-23 activates keratinocytes via pro-inflammatory Th17 cells;⁶ both processes lead to tumor necrosis factor (TNF)-α and interferon (IFN)-γ production. Cytokines secreted by Th17 and Th1 cells activate keratinocytes;⁹ this is one of the first steps in the development of psoriatic lesions. A positive feedback loop recruits other immune cells, further potentiating the inflammatory process.⁶

Rationale for Targeting TYK2 in Plaque Psoriasis Treatment

TYK2 is a Janus kinase (JAK) enzyme that is coded by the TYK2 gene and constitutively expressed in immune cells.¹⁰ Mutations and polymorphisms in TYK2 impact IL-23, IFN-α/β, and IL-12 immune-mediated signalling, and are associated with an altered risk for psoriasis; for example, loss of function mutations in TYK2 have been found to be protective against autoimmunity, including psoriasis.¹⁰ Selective TYK2 inhibition blocks IL-23, IL-12, and type I IFN-driven responses, but not those driven by other JAKs (Figure 1).^11-13

Deucravacitinib: Mechanism of Action

Deucravacitinib is a specific, oral, intracellular TYK2 inhibitor that targets immune responses driven by type 1 IFN and IL-23 that contribute to psoriasis pathogenesis, including IL-17 production and Th1/Th17 polarization.^12-14 It binds with high specificity to the TYK2 regulatory domain, blocking kinase activity and conferring selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis (Figure 2).^12-14

Deucravacitinib uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range while reducing off-target effects.^11-13 In contrast, JAK 1–3 inhibitors bind to the active domain adenosine triphosphate (ATP) binding site common to all JAK molecules (including TYK2) to mediate both immune responses and broader systemic processes (e.g., myelopoiesis, granulopoiesis, lymphoid cell maturation and function, hematopoiesis, growth factor response, metabolic activity regulation, lipid metabolism, etc.), some of which are necessary for normal physiologic functioning, resulting in a narrower therapeutic range.¹³

Efficacy of Deucravacitinib: Key Evidence from Pivotal Phase III Clinical Trials

In a phase II trial of patients with psoriasis, deucravacitinib demonstrated superior efficacy vs. placebo based on ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) over 12 weeks.¹⁴ Efficacy results from two phase III pivotal trials of deucravacitinib were recently reported and confirmed results from the phase II trial.

In the 52-week, double-blinded, phase III POETYK PSO-1 trial, participants with moderate to severe chronic plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=332), placebo (n=166), or apremilast 30 mg twice daily (n=168).¹⁵ Similarly, participants in the 52-week, doubleblinded, phase III POETYK PSO-2 trial were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=511), placebo (n=255), or apremilast 30 mg twice daily (n=254).¹⁶

The coprimary endpoints of both trials were response rates for PASI 75 and static Physician’s Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib vs. placebo at week 16.^15,16 Key secondary endpoints included the scalp-specific Physician’s Global Assessment (ss-PGA) and patient-reported symptoms and signs of psoriasis (evaluated using the Psoriasis Symptoms and Signs Diary [PSSD]) and QoL (evaluated using the Dermatology Life Quality Index [DLQI]).¹⁵

In both PSO-1 and PSO-2 trials, PASI 75 response rates at week 16 were significantly higher with deucravacitinib (58.4% and 53.0%) vs. placebo (12.7% and 9.4%) or apremilast (35.1% and 39.8%). Response rates for sPGA 0/1 were also significantly higher with deucravacitinib (53.6% and 50.3%) vs. placebo (7.2% and 8.6%) or apremilast (32.1% and 34.3%) (Table 1).^15,16 Deucravacitinib responses improved beyond week 16 and were maintained through week 52.¹⁵ Furthermore, patients who switched from placebo to deucravacitinib at week 16 demonstrated PASI 75 and sPGA 0/1 responses at week 52 comparable to those observed in patients who received continuous deucravacitinib treatment from day 1.¹⁵

Regarding key secondary endpoints, significantly greater proportions of patients in the deucravacitinib vs. placebo and apremilast arms achieved ss-PGA 0/1 and DLQI 0/1 responses, as well as greater reduction from baseline in PSSD symptom scores at week 16 and week 24 (Table 1).^15,16

Table 1. POETYK PSO-1 and PSO-2 efficacy results

Pooled PSO-1 and PSO-2 data showed that significantly greater proportions of patients receiving deucravacitinib achieved absolute PASI ≤1, ≤2, and ≤5 vs. patients receiving placebo (week 16) or apremilast (weeks 16 and 24), and proportions of patients achieving different PASI thresholds with deucravacitinib increased from week 16 to week 24.¹⁷

In an analysis of PSO-1 and PSO-2 that compared efficacy of deucravacitinib vs. placebo and apremilast in individual scoring components (erythema, induration, desquamation) and body regions of PASI (head/neck, upper extremities, trunk, lower extremities), deucravacitinib was associated with numerically greater percent reductions from baseline in each PASI body region and component scores at week 16 than placebo and apremilast.¹⁸ Higher proportions of patients in the deucravacitinib vs. placebo and apremilast groups achieved ≥75% reduction at week 16 in each PASI body region and PASI scoring; differences in efficacy when compared to apremilast were maintained at week 24.¹⁸ For patients in the deucravacitinib group, improvements occurred as early as week 1 and increased over time on treatment.¹⁸

In a long-term extension study of PSO trials, investigators analyzed the efficacy of deucravacitinib in patients who did not respond adequately to treatment with apremilast by week 24. Patients initially randomized to apremilast who failed to achieve a PASI 50 in PSO-1 (n=54) or PASI 75 in PSO-2 (n=111) were switched to deucravacitinib through week 52. After switching from apremilast to deucravacitinib, 46.3% of PASI 50 nonresponders and 42.3% of PASI 75 non-responders achieved PASI 75 by week 52.¹⁹ Improvements were also seen for sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score.¹⁹

Two-year data from a long-term extension of both PSO trials showed that deucravacitinib had durable clinical efficacy, including mean response rates of 79.8% for PASI 75 and 60.7% for sPGA 0/1 at week 60, regardless of which treatment was initiated at week 16 (when patients in the placebo group could switch to deucravacitinib) or at week 24 (when apremilast nonresponders could switch to deucravacitinib) in the parent study.²⁰

Deucravacitinib: Safety and Tolerability Profile

During weeks 0–16 and weeks 0–52 assessment periods in both PSO trials, overall adverse event (AE) rates were similar across all 3 treatment groups (deucravacitinib, placebo, and apremilast).^15,16,21 The most frequent AEs in patients treated with deucravacitinib were nasopharyngitis (9.0%) and upper respiratory tract infection (5.5%). The most frequent AEs in apremilast-treated patients were diarrhea (11.8%), headache (10.7%), nausea (10.0%), and nasopharyngitis (8.8%); placebotreated patients most frequently experienced nasopharyngitis (8.6%) and diarrhea (6.0%).16,21 Incidence rates for AEs of interest, including skin events (e.g., acne and folliculitis), herpes zoster, serious infections, malignancies, thrombotic events, cardiovascular events, creatinine kinase elevation, changes in complete blood count, and changes in lipid profile were absent or low in the deucravacitinib group.¹⁵

The frequency of serious adverse events (SAEs) reported in weeks 0–16 were low across all groups (1.8% in deucravacitinib treated patients vs. 2.9% with placebo and 1.2% with apremilast).^16,21 Discontinuation rates due to AEs were lowest in the deucravacitinib group (2.4%) vs. placebo (3.8%) and apremilast (5.2%).^16,21

A pooled analysis of PSO-1 and PSO-2 trials confirmed that deucravacitinib was well tolerated for up to 52 weeks across patient subgroups based on baseline characteristics of age, sex, race, and body weight. The frequency and type of AEs and SAEs in each subgroup were consistent with the overall patient population, with similar trends for overall AEs and AE classes in the placebo and apremilast groups across subgroups.²¹

In the long-term extension trial, safety results were consistent with those reported in PSO-1 and PSO-2 trials. SAEs remained low, including those that led to discontinuation. There were no new safety signals or clinically meaningful changes in laboratory values.²⁰ The most common AEs included nasopharyngitis (16.8% at 1 year; 17.8% at 2 years), upper respiratory tract infection (9.1% at 1 year; 9.9% at 2 years), headache (5.9% at 1 year; 6.5% at 2 years), diarrhea (5.1% at 1 year; 5.5% at 2 years), and arthralgia (4.0% at 1 year; 5.6% at 2 years).²⁰ An increase in serious infections was observed, which the authors concluded was attributable to COVID-19 infections due to the ongoing pandemic (studies were conducted during the pandemic through the cut-off date of October 1, 2021, prior to widespread availability of vaccines).

These safety results have not as of yet uncovered treatmentemergent SAEs that are more commonly associated with JAK inhibitors, such as herpes zoster, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities.^20-24

Discussion

Selective TYK2 inhibition is a promising novel target for the treatment of moderate to severe chronic plaque psoriasis. Molecules that confer selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis, without involvement of other JAKs, can lead to a broad therapeutic range while reducing off-target effects such as serious infections, malignancies, thrombosis, and MACE.

Key data from the pivotal phase III POETYK PSO-1 and PSO-2 clinical trials showed that patients with moderate to severe chronic plaque psoriasis treated with the first-in-class, oral, selective TYK2 inhibitor deucravacitinib achieved statistically significant PASI 75 and sPGA 0/1 outcomes that were superior to placebo and apremilast at week 16.^15,16 Additionally, significantly greater proportions of patients achieved absolute PASI ≤1, ≤2, and ≤5 with deucravacitinib vs. placebo or apremilast.¹⁷ Body region-specific data showed that deucravacitinib had numerically larger percentage improvements at weeks 16 and 24 from baseline vs. apremilast and placebo, across all components of scoring and with onset of action as early as week 1.¹⁸

Deucravacitinib was efficacious at week 52 in patients who had inadequate responses to apremilast at week 24 and subsequently switched to deucravacitinib, which was demonstrated in physician-assessed endpoints (PASI 75/90, percentage change from baseline in PASI, and sPGA 0/1) and in patient-reported outcomes (DLQI 0/1 and change from baseline in PSSD symptom score).¹⁹

Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast, with overall AE rates similar across all 3 treatment groups.^15,21 The most common AEs in patients treated with deucravacitinib were nasopharyngitis and upper respiratory tract infection, while incidence rates of SAEs and AEs of interest were low.^15,21

1. What are the off-target serious adverse effects associated with JAK inhibitors?
2. In the PSO-1 and PSO-2 clinical trials, what were the outcomes of apremilast non-responders who were switched to deucravacitinib at week 24?

Conclusion

Selective TYK2 inhibition is a novel target in the treatment of moderate to severe plaque psoriasis. The first-in-class oral TYK2 inhibitor deucravacitinib, already approved by the FDA in the US, has been shown to be efficacious, safe, and tolerable for up to 2 years of use. It is expected that deucravacitinib, and potentially other oral TYK2 inhibitors in development, will offer dermatologists and their patients with a convenient, effective, and safe alternative to other currently available oral systemic agents biologic agents, and phototherapy for the management of moderate to severe chronic plaque psoriasis.

Acknowledgements

The authors wish to thank Teri Morrison and Athena Kalyvas from the International Centre for Professional Development in Health and Medicine (ICPDHM) for editorial support.

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IL-23s: Psoriasis therapy overview

People with moderate-to-severe psoriasis can benefit from tildrakizumab (Ilumya), a biologic treatment that belongs to a class of drugs called interleukin-23 (IL-23) inhibitors. Biologics are protein-based medications that target specific parts of the immune system. IL-23 inhibitor specifically targets a type of cytokine called IL-23 and blocks cellular activity, which results in reduced inflammation that causes psoriasis.

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Selecting from IL-23s

Tildrakizumab (Ilumya) is a brand-name biologic medication that’s used to treat moderate to severe plaque psoriasis. This drug is an interleukin (IL-23) inhibitor that’s very effective and works long-term to control the symptoms of psoriasis. Tildrakizumab can help a wide range of psoriasis patients (even those with inflammatory bowel disease, IBD), including those with other health complications. A dermatologist can prescribe the medication, which is injected under your skin (subcutaneous injection) once every 12 weeks.

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Tildrakizumab candidates

Tildrakizumab (Ilumya), an Interleukin-23 (IL-23) inhibitor, can provide long-term improvement, even in higher-risk psoriasis patients. Tildrakizumab is a type of drug called a monoclonal antibody. It is a protein that specifically treats certain parts of your immune system. Unlike many other psoriasis treatments, tildrakizumab can be used in higher-risk populations, such as in the elderly or those with psoriasis in addition to other health conditions like inflammatory bowel disease (IBD) or psoriatic arthritis.

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Tildrakizumab effectiveness related to trial results

After 12 weeks of treatment with tildrakizumab (Ilumya), over 50 percent of patients can be cleared of their psoriasis. This biologic drug was approved in Canada in October 2021. In clinical dermatology experience, after one month of therapy with this interleukin-23 (IL-23) medication, a high majority of psoriasis patients experienced improvement in their symptoms. In research and real-life settings, tildrakizumab has been shown to be safe and offer long-term effectiveness.

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Tildrakizumab effectiveness

After 12 weeks of treatment with the interleukin-23 (IL-23) inhibitor, tildrakizumab (Ilumya), the majority of psoriasis patients can be clear or almost clear of their skin symptoms. People with psoriasis are frequently frustrated over treatments that are ineffective for them, such as tumor necrosis factor biologics, phototherapy, or systemic drugs (such as methotrexate). IL-23 inhibitors, like tildrakizumab, can be an important and effective therapeutic option when patients do not respond to other treatments.

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Tildrakizumab long-term effectiveness