Topical Roflumilast Cream for Plaque Psoriasis: Case Presentations to Primary Care

Melinda Gooderham MD MSc FRCPC^1-3

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.