Roflumilast Cream, 0.15%, for Atopic Dermatitis

Atopic dermatitis (AD) is a chronic, persistent inflammatory condition that significantly disrupts the quality of life of patients diagnosed with it. Moreover, AD presents challenges for clinicians when counseling patients on the management of their condition.¹ Application frequency, treatment formulations, and potential side effects (e.g. skin atrophy with steroids and burning upon application with some non-steroidal agents) highlight some of the issues patients and providers must navigate with the current therapeutic options for AD.¹ A topical phosphodiesterase-4 (PDE4) inhibitor, crisaborole, was approved in 2016 for AD and is currently approved for use down to 3 months of age. However, it has a recommended twice-daily application schedule and has been associated with higher rates of application site pain than seen in its clinical trials.² Topical roflumilast, studied here, appears to be better tolerated and only needs to be applied once-daily, thus potentially improving patient adherence and outcomes.³

Objective

To evaluate the efficacy and safety profile of once-a-day application of roflumilast cream, 0.15%, vs vehicle cream in patients with AD.¹

Methods

A total of 1,337 patients aged 6 years or older with mild to moderate AD (based on the Validated Global Assessment for Atopic Dermatitis (assessed on a 5-point scale ranging from 0 [clear] to 4 [severe]) from sites in the US, Canada, and Poland were split into two, identical, phase 3, randomized double-blind, vehicle controlled trials called Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis 1 and 2 [INTEGUMENT-1 and INTEGUMENT-2].¹ Patients were randomized 2:1 to receive roflumilast cream, 0.15%, or vehicle cream once-daily for 4 weeks.¹

Outcomes and Measures

The primary endpoint of this study was Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) success at week 4, which was defined as a score of 0 or 1 plus at least a 2-grade improvement from baseline.¹ The secondary endpoints included Eczema Area and Severity Index (EASI) reduced by at least 75% at week 4, and Worst Itch Numeric Rating Scale (WI-NRS) success defined as ≥4-point reduction on the 11-point WI-NRS scale, which ranges from 0 [no itch] to 10 [worst itch imaginable]. Safety, through adverse events and local tolerability, was also evaluated through patient and investigator ratings.¹

Results

Among INTEGUMENT-1 (654 patients), 32% of those treated with roflumilast and 15.2% of those treated with the vehicle reached the primary endpoint of vIGA-AD success at week 4 (P < .001).¹ Among INTEGUMENT-2 (683 patients), 28.9% of those treated with roflumilast and 12% of those treated with the vehicle reached the primary endpoint of vIGA-AD success at week 4 (P < .001).¹ More patients treated with roflumilast reached vIGA-AD success compared to those treated with the vehicle.1 Roflumilast-treated patients saw statistically significant more reductions of at least 75% in EASI at week 4 (INTEGUMENT-1: 43.2% vs 22.0%, respectively; P < .001; INTEGUMENT-2: 42.0% vs 19.7%, respectively; P < .001).¹ More patients treated with roflumilast at least a baseline score of 4 on the WI-NRS achieved at least a 4 point reduction on the scale than patients treated with the vehicle cream.¹ Roflumilast was well tolerated with more than 95% of its treated patients having no signs irritation as noted by the investigator, as well as 90% of patients reporting no or mild sensation upon application.¹

Key Takeaway

This study shows that once-daily roflumilast cream, 0.15% is effective, well tolerated, and has a favorable safety profile for use in pediatric (down to age 6 years) and adult patients with mild to moderate AD.¹ This drug offers more treatment options to patients who may be frustrated with the currently available treatments.¹

Limitations

This study could be improved by increasing the duration for which patients are in the trial for longer than 4 weeks to evaluate efficacy for chronic/long term use. Additionally, including patients under the age of 6 years and including an active comparative drug group would help validify these findings.¹ 

Conclusion and Future Directions

In two, phase 3 trials enrolling adults, adolescents, and children, once-daily roflumilast cream, 0.15%, improved AD relative to a vehicle cream, based on multiple endpoints to test its efficacy, safety, and tolerability.¹ This finding is significant for patients with AD as it expands therapeutic options for effective, safe, and well-tolerated treatments.¹

Disclosures: Brianna Green has no conflicts of interest. Dr. Lio reports research grants/funding from AbbVie, AOBiome; is on the speaker's bureau for AbbVie, Arcutis, Eli Lilly, Galderma, Hyphens Pharma, Incyte, La Roche-Posay/L’Oreal, MyOR Diagnostics, ParentMD, Pfizer, Pierre-Fabre Dermatologie, Regeneron/Sanofi Genzyme, Verrica; reports consulting/advisory boards for Alphyn, AbbVie, Almirall, Amyris, Arcutis, ASLAN, Boston Skin Science, Bristol-Myers Squibb, Burt's Bees, Castle Biosciences, Codex Labs, Concerto Biosci, Dermavant, Eli Lilly, Galderma, Janssen, Johnson & Johnson, Kimberly-Clark, LEO Pharma, Lipidor, L’Oreal, Merck, Micreos, MyOR Diagnostics, Regeneron/Sanofi Genzyme, Skinfix, Theraplex, UCB, Unilever, Verrica Yobee Care; stock options with Codex, Concerto Biosciences and Yobee Care. In addition, Dr. Lio has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member of the National Eczema Association.

Brianna A. Green, BS

David Geffen School of Medicine at UCLA, Los Angeles, CA

Peter Lio, MD

Northwestern University Feinberg School of Medicine, Chicago, IL

References

1. Simpson, E. L., Eichenfield, L. F., Alonso-Llamazares, J., Draelos, Z. D., Ferris, L. K., Forman, S. B., Gooderham, M., Gonzalez, M. E., Hebert, A. A., Kircik, L. H., Lomaga, M., Moore, A., Papp, K. A., Prajapati, V. H., Hanna, D., Snyder, S., Krupa, D., Burnett, P., Almaraz, E., … Berk, D. R. (2024). Roflumilast Cream, 0.15%, for Atopic Dermatitis in Adults and Children: INTEGUMENT-1 and INTEGUMENT-2 Randomized Clinical Trials. JAMA Dermatology, e243121. https://doi.org/10.1001/jamadermatol.2024.3121

2. Lin CP, Gordon S, Her MJ, Rosmarin D. A retrospective study: application site pain with the use of crisaborole, a topical phosphodiesterase 4 inhibitor. Journal of the American Academy of Dermatology. 2019 May 1;80(5):1451-3.

3. Blauvelt, A., Langley, R. G., Gordon, K. B., Silverberg, J. I., Eyerich, K., Sommer, M. O. A., Felding, J., & Warren, R. B. (2023). Next Generation PDE4 Inhibitors that Selectively Target PDE4B/D Subtypes: A Narrative Review. Dermatology and Therapy, 13(12), 3031–3042. https://doi.org/10.1007/s13555-023-01054-3