Topical PDE4 Inhibitor ZORYVE® (Roflumilast) Cream for the Treatment of Atopic Dermatitis

Atopic dermatitis (AD) is a complex skin disease characterized by dysfunction of the skin barrier and dysregulation of the innate and adaptive immune systems that involves multiple proinflammatory cytokines.1,2Multiple conventional treatment options, such as topical corticosteroids and topical calcineurin inhibitors, are available for AD; however, management remains suboptimal, and more than 80% of children with AD continue to have symptoms into adulthood.1-3 Inhibition of PDE4 has shown promise as a steroid-free mechanism for long-term treatment of AD.4 PDE4 inhibitors, such as ZORYVE® (roflumilast) cream 0.15% (Arcutis Biotherapeutics), aim to provide effective treatment for AD with minimal AEs and favorable characteristics to promote patient adherence, such as once-daily dosing, cream formulation (as opposed to ointment), and greater selectivity for PDE4 that increases the absorption rate and further reduces the already-low risk for application-site reactions.5,6

Indication and Mechanism of Action

ZORYVE is indicated for once-daily treatment of patients 6 years or older with mild to moderate AD.6 Because ZORYVE more closely resembles cAMP compared with other PDE4 inhibitors, it has a higher affinity for PDE4 and greater potency than does crisaborole in vitro.2,7 Additionally, this topical therapy uses an emollient, water-based, moisturizing vehicle cream that does not have sensitizers or penetration enhancers, which helps protect the skin barrier function that is often disrupted in AD.2

Clinical Efficacy

The INTEGUMENT-1 and INTEGUMENT-2 trials (NCT04773587 and NCT04773600, respectively) were identical, parallel-group, double-blind, vehicle-controlled, randomized clinical trials carried out in the US, Canada, and Poland. Patients aged 6 years with mild or moderate AD were randomly assigned 2:1 to receive ZORYVE cream, 0.15%, or vehicle cream. The primary efficacy end point in both trials was a validated IGA for AD (vIGA-AD) of 0 (clear) or 1 (almost clear) plus an improvement of 2 grades or more from baseline at 4 weeks. Secondary end points included vIGA-AD success at 4 weeks in patients with a vIGA-AD score of 3 points at randomization; Worst Itch Numeric Rating Scale (WI-NRS) success (≥ 4-point reduction on the WI-NRS scale in patients with a baseline WI-NRS score ≥ 4 points) at 1, 2, and 4 weeks; at least 75% reduction in Eczema Area and Severity Index (EASI-75) at 4 weeks; vIGA-AD score of 0 or 1 point at 1, 2, and 4 weeks; and vIGA-AD success at 1 and 2 weeks.2

A greater proportion of patients in the ZORYVE group reached the primary end point of vIGA-AD success at week 4 (INTEGUMENT-1, 32.0% vs 15.2% [percent difference, 17.4%; P < .001]; INTEGUMENT-2, 28.9% vs 12.0% [percent difference, 16.5%; P < .001]). The vIGA-AD success rates at 1, 2, and 4 weeks were higher in ZORYVE-treated patients than in patients given vehicle, and a greater proportion of ZORYVE-treated patients in both trials reached EASI-75 and vIGA-AD of 0 or 1 point at 1, 2, and 4 weeks. Additionally, a greater proportion of ZORYVE-treated patients with a WI-NRS score of 4 points or higher at baseline had a 4-point or greater reduction in WI-NRS at 1, 2, and 4 weeks compared with those treated with vehicle.2

Safety and Tolerability

ZORYVE had an acceptable safety profile, with relatively low rates of TEAEs and treatment-related TEAEs in both ZORYVE and vehicle treatment groups. Most TEAEs were mild or moderate in severity. Less than 1% of patients treated with ZORYVE in each trial had serious TEAEs; of these 8 events, 2 occurrences (1 case each of general physical health deterioration and rapid progression of AD) presumably were related to the treatment. Rates of application-site pain with ZORYVE were low in both trials (0.9%-2.1%), and none of the patients who experienced stinging or burning with crisaborole ointment before trial enrollment had application-site pain with ZORYVE. Rates of TEAEs leading to discontinuation were also low across treatment groups and trials (0.9%-1.8%). ZORYVE’s favorable safety profile, once-daily application, and cream formulation (as opposed to greasier ointments) may also have improved treatment adherence.2

Pediatric Population

The findings from the phase 3, parallel-group, double-blind INTEGUMENT-PED trial (NCT04845620) suggested that although ZORYVE cream, 0.05%, is not yet approved for children younger than 6 years, it could be an effective, safe treatment option for children aged 2 to 5 years with mild to moderate AD—further supporting treatment of AD early in the disease course. Study participants were randomly assigned 2:1 to receive once-daily ZORYVE cream, 0.05%, or vehicle cream for 4 weeks. The lower concentration of ZORYVE was chosen because children aged 2 to 5 years have a greater BSA to body mass ratio and greater AD BSA involvement compared with older patients. This lower concentration was anticipated to yield similar pharmacokinetic, efficacy, and safety profiles compared with the 0.15% concentration in older patients. The primary end point was the proportion of patients who had vIGA-AD success at 4 weeks. Secondary end points included the proportion of patients with vIGA-AD success at 1 and 2 weeks; vIGA-AD success at 4 weeks in patients with moderate vIGA-AD before randomization; vIGA-AD of 0 or 1 point at 1, 2, and 4 weeks; EASI-75 at 4 weeks; and WI-NRS success at 4 weeks in patients with a WI-NRS of 4 points or greater at baseline.8

The proportion of patients who had vIGA-AD success at 4 weeks was significantly greater among the ZORYVE group compared with the vehicle group (25.4% vs 10.7%; P < .0001).Significant differences were also seen at week 1, highlighting the rapid onset of effect with ZORYVE. The proportions of patients with vIGA-AD of 0 or 1 at 4 weeks were also greater in the ZORYVE group than the vehicle group (35.4% vs 14.6%) and EASI-75 (39.4% vs 20.6%). A greater proportion of patients with moderate vIGA-AD at baseline had vIGA-AD success at 4 weeks with ZORYVE than with vehicle (27.7% vs 11.0%; P < .0001). Of those with a WI-NRS of at least 4 at baseline, a greater proportion of those who received ZORYVE achieved WI-NRS success at 4 weeks (35.3% vs 18.0%; nominal P = .0002), with reductions in pruritus reported within 24 hours of the first application.8

Rates of application-site TEAEs, treatment-related TEAEs, and TEAEs leading to discontinuation were relatively low among both groups. The rates of application-site TEAEs (5.3% vs 6.0%), application-site pain (1.6% vs 1.9%), and stinging or burning that caused discomfort within 15 minutes of application (0.7% vs 3.6%) were numerically lower with ZORYVE cream. The authors concluded that the risk-benefit and local safety profiles were beneficial and similar to those observed in the trials of ZORYVE cream, 0.15%, in patients 6 years and older.8

Long-term and Maintenance Use

To assess whether ZORYVE is safe and effective with long-term and/or twice-weekly maintenance use, the ongoing INTEGUMENT-OLE trial (NCT04804605) is evaluating safety and effectiveness through an additional 52 weeks for patients 2 years and older with AD who participated in the INTEGUMENT-01, INTEGUMENT-02, or INTEGUMENT-PED trials. In this open-label extension trial (OLE), all patients (including those who received vehicle cream in the phase 3 trial) applied ZORYVE cream daily for 4 weeks. After 4 weeks, patients who achieved a vIGA-AD of 0 could shift from daily dosing to proactive biweekly application; these patients applied ZORYVE twice weekly on nonconsecutive days to areas commonly or recently affected by AD. If patients had worsening signs or symptoms of AD for 1 week with biweekly application, they contacted the trial site and went back to daily application.9

In an analysis of patients from the INTEGUMENT-01 and INTEGUMENT-02 trials (data collection is ongoing for the OLE patients from the INTEGUMENT-PED trial), safety and tolerability appeared to be maintained through the additional 52-week period, with less than 2% of patients exhibiting signs of irritation at the application site with investigator assessment at any OLE visit. Application-site pain was reported in 0.5% of patients, and all cases were mild or moderate in severity. Patient-rated stinging or burning was reported by 0.4% to 2.1% of patients at any OLE visit. The proportion of patients who achieved a vIGA-AD of 0 or 1 increased over the 52-week period to 56.6% among patients who received ZORYVE continuously and 53.8% among those who received vehicle in the initial trial followed by ZORYVE in the OLE trial. Similar trends were observed with all secondary end points. Of patients who switched to biweekly dosing, 57.7% maintained disease control through the final visit, highlighting the potential for using ZORYVE prophylactically over a long-term period as a maintenance therapy to prevent flares. The authors also noted that this proactive approach could decrease the need for a reactive approach to treatment using TCS or TCI.9

Conclusion

In conclusion, targeting PDE4 with inhibitors such as ZORYVE provides a steroid-free mechanism that addresses many mechanisms of immune system dysregulation seen with AD.4,6 Additional research will be important to ensure the long-term safety and efficacy of PDE4 inhibition and its usefulness in proactively preventing disease flares during maintenance treatment.9

References

1. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.e4. doi:10.1016/j.jaad.2016.05.046
2. Simpson EL, Eichenfield LF, Alonso-Llamazares J, et al. ZORYVE cream, 0.15%, for atopic dermatitis in adults and children: INTEGUMENT-1 and INTEGUMENT-2 randomized clinical trials. JAMA Dermatol. 2024;160(11):1161-1170. doi:10.1001/jamadermatol.2024.3121
3. Huang A, Cho C, Leung DYM, Brar K. Atopic dermatitis: early treatment in children. Curr Treat Options Allergy. 2017;4(3):355-369. doi:10.1007/s40521-017-0140-6
4. Guttman-Yassky E, Hanifin JM, Boguniewicz M, et al. The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition. Exp Dermatol. 2019;28(1):3-10. doi:10.1111/exd.13808
5. Freitas E, Torres T. Difamilast for the treatment of atopic dermatitis. J Int Med Res. 2023;51(6):3000605231169445. doi:10.1177/03000605231169445
6. Zoryve. Prescribing information. Arcutis Biotherapeutics; 2024. https://www.arcutis.com/wp-content/uploads/USPI-ZORYVE-cream.pdf
7. Dong C, Virtucio C, Zemska O, et al. Treatment of skin inflammation with benzoxaborole phosphodiesterase inhibitors: selectivity, cellular activity, and effect on cytokines associated with skin inflammation and skin architecture changes. J Pharmacol Exp Ther. 2016;358(3):413-422. doi:10.1124/jpet.116.232819
8. Eichenfield LF, Serrao R, Prajapati VH, et al. Efficacy and safety of once-daily ZORYVE cream 0.05% in pediatric patients aged 2-5 years with mild-to-moderate atopic dermatitis (INTEGUMENT-PED): a phase 3 randomized controlled trial. Pediatr Dermatol. 2025;42(2):296-304. doi:10.1111/pde.15840
9. Simpson EL, Eichenfield LF, Papp KA, et al. Long-term safety and efficacy with ZORYVE cream 0.15% in patients aged ≥6 years with atopic dermatitis: a phase 3 open-label extension trial. Dermatitis. Published online January 10, 2025. doi:10.1089/derm.2024.0418

IMPORTANT SAFETY INFORMATION

ZORYVE is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C).

Flammability: The propellants in ZORYVE foam are flammable. Avoid fire, flame, and smoking during and immediately following application.

The most common adverse reactions (≥1%) for ZORYVE cream 0.3% for plaque psoriasis include diarrhea (3.1%), headache (2.4%), insomnia (1.4%), nausea (1.2%), application site pain (1.0%), upper respiratory tract infection (1.0%), and urinary tract infection (1.0%).

The most common adverse reactions (≥1%) for ZORYVE cream 0.15% for atopic dermatitis include headache (2.9%), nausea (1.9%), application site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

The most common adverse reactions (≥1%) for ZORYVE foam 0.3% for seborrheic dermatitis include nasopharyngitis (1.5%), nausea (1.3%), and headache (1.1%).

Please see full Prescribing Information for ZORYVE cream and full Prescribing Information for ZORYVE foam.

INDICATIONS

ZORYVE cream, 0.3%, is indicated for topical treatment of plaque psoriasis, including intertriginous areas, in adult and pediatric patients 6 years of age and older.

ZORYVE cream, 0.15%, is indicated for topical treatment of mild to moderate atopic dermatitis in adult and pediatric patients 6 years of age and older.

ZORYVE foam, 0.3%, is indicated for the treatment of seborrheic dermatitis in adult and pediatric patients 9 years of age and older.

Pivotal Study Designs

Atopic Dermatitis: Two Phase 3 multicenter, randomized, double-blind, vehicle-controlled studies (INTEGUMENT 1 & 2) evaluated 1337 participants with mild to moderate atopic dermatitis treated with ZORYVE or vehicle once daily for 4 weeks. ZORYVE cream = 884, vehicle = 453. Primary endpoint was vIGA-AD Success at Week 4. WI-NRS Success at Week 4 was a key secondary endpoint.1

Seborrheic Dermatitis: Two multicenter, randomized, double-blind, vehicle-controlled studies (STRATUM and Trial 203) evaluated 683 participants with moderate to severe seborrheic dermatitis treated with ZORYVE or vehicle once daily for 8 weeks. STRATUM: ZORYVE foam = 304, vehicle = 153. Trial 203: ZORYVE foam = 154, vehicle = 72. Primary endpoint was IGA Success at Week 8.2

Plaque Psoriasis: Two Phase 3 randomized, parallel, double-blind, vehicle-controlled, multicenter studies (DERMIS-1 and DERMIS-2) evaluated 881 participants with plaque psoriasis treated with ZORYVE or vehicle once daily for 8 weeks. ZORYVE = 576, vehicle = 305. Primary endpoint was IGA Success at Week 8.1

IGA = Investigator Global Assessment. IGA Success/vIGA-AD Success = Achievement of Clear (0)/ Almost Clear (1) and a ≥2-grade improvement from baseline. vIGA-AD = Validated Investigator Global Assessment-Atopic Dermatitis. WI-NRS = Worst Itch Numeric Rating Scale. WI-NRS Success = ≥4-point improvement for patients with a baseline score ≥4. WI-NRS: 0 (no itch) to 10 (worst imaginable itch).

References: 1. ZORYVE® cream. Prescribing information. Arcutis Biotherapeutics, Inc; 2024. 2. ZORYVE® foam. Prescribing information. Arcutis Biotherapeutics, Inc; 2023. 3. Stein Gold L, Bagel J, Del Rosso J, et al. Pooled efficacy and safety results from the DERMIS-1 and DERMIS-2 Phase 3 trials of once-daily roflumilast cream 0.3% by baseline body surface area. Poster presented at: American Academy of Dermatology Annual Meeting; March 25-29, 2022; Boston, MA. 4. Ferris LK, Armstrong A, Del Rosso J, et al. Efficacy and tolerability of roflumilast cream 0.3% in patients with chronic plaque psoriasis involvement on the face, intertriginous, or genital areas: Pooled results from Phase 3 trials (DERMIS-1 and DERMIS-2). Poster presented at: European Academy of Dermatology and Venereology Congress; September 7-11, 2022; Milan, Italy. 5. Bunick CG, Bhatia N, Del Rosso J, et al. Investigator and patient-rated local tolerability in Phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis. Poster presented at: Fall Clinical Dermatology Conference; October 19-22, 2023; Las Vegas, NV. 6. Lebwohl M, Stein Gold L, Gooderham MJ, et al. Durability of efficacy and safety of roflumilast cream 0.3% in adults with chronic plaque psoriasis from a 52-week, Phase 2 open-label safety trial. Poster presented at: Winter Clinical Dermatology Conference; January 13-18, 2023; Kohala Coast, HI. 7. Alexis AF, Zirwas M, Bukhalo M, et al. Long-term safety and efficacy of roflumilast foam 0.3% in patients with seborrheic dermatitis in a 24–52-week, open-label Phase 2 trial. Poster presented at: The European Academy of Dermatology and Venereology Congress; September 7-11, 2022; Milan, Italy. 8. Simpson EL, Eichenfield LF, Papp KA, et al. Long-term safety and efficacy of roflumilast cream 0.15% in adults and children aged ≥6 years with mild to moderate atopic dermatitis: A 52-week, Phase 3, open-label safety trial. Poster presented at: Revolutionizing Alopecia Areata, Vitiligo, and Eczema (RAVE) Conference; June 8-10, 2024; Chicago, IL. 9. Data on File. Arcutis Biotherapeutics, Inc. 10. Simpson E, Boguniewicz M, Eichenfield L, et al. Pooled efficacy, patient-reported outcomes, and safety of roflumilast cream 0.15% from the INTEGUMENT-1 and INTEGUMENT-2 Phase 3 clinical trials of adults and children with atopic dermatitis. Poster presented at: American Academy of Dermatology Annual Meeting; March 8-12, 2024; San Diego, CA. 11. Lebwohl M, Gooderham MJ, Guenthner ST, et al. Pooled efficacy and safety results from the DERMIS-1 and DERMIS-2 Phase 3 trials of once-daily roflumilast cream 0.3% for the treatment of plaque psoriasis. Poster presented at: American Academy of Dermatology Annual Meeting; March 25-29, 2022; Boston, MA. 12. Osborne DW, Musakhanian J. Skin penetration and permeation properties of Transcutol®- neat or diluted mixtures. AAPS PharmSciTech. 2018;19(8):3512-3533. 13. Osborne DW. Diethylene glycol monoethyl ether: an emerging solvent in topical dermatology products. J Cosmet Dermatol. 2011;10:325-329. 14. Berk D, Osborne DW. Krafft temperature of surfactants in vehicles for roflumilast and pimecrolimus cream and effects on skin tolerability. Poster presented at: The Society for Investigative Dermatology Annual Meeting; May 18-22, 2022; Portland, OR. 15. Björklund S, Pham QD, Jensen LB, et al. The effects of polar excipients transcutol and dexpanthenol on molecular mobility, permeability, and electrical impedance of the skin barrier. J Colloid Interface Sci. 2016;479:207-220. 16. CMS.gov. 2024 ICD-10-CM. Centers for Medicare & Medicaid Services. Updated February 1, 2024. Accessed April 20, 2024. https://www.cms.gov/medicare/coding-billing/icd-10-codes/2024-icd-10-cm 17. Sidbury R, Alikhan A, Bercovitch L, et al. Guidelines of care for the management of atopic dermatitis in adults with topical therapies. J Am Acad Dermatol. 2023; 89(1):e1-e20. 18. Clark GW, Pope SM, Jaboori KA. Diagnosis and treatment of seborrheic dermatitis. Am Fam Physician. 2015;91(3):185-190. 19. Elmets CA, Korman NJ, Prater EF, et al. Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures. J Am Acad Dermatol. 2021;84(2):432-470.