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NEW ORLEANS -- A novel lower-concentration topical formulation of the PDE4 inhibitor roflumilast produced rapid improvement in mild to moderate atopic dermatitis (AD) in children and adults, two randomized, vehicle-controlled trials showed.

About 30% of patients met criteria for treatment success at 4 weeks, and more than 40% had at least 75% improvement in the Eczema Area and Severity Index (EASI-75). A similar proportion of patients in the two trials had clinically meaningful and statistically significant improvement in itch after 1 month of once-daily treatment.

The 0.15% cream was well tolerated, with 5-6% of patients having any type of treatment-emergent adverse events (TEAEs), reported Eric Simpson, MD, of Oregon Health & Science University in Portland, at the American Academy of Dermatology meeting.

"We observed significant improvement based on EASI-75 as early as 1 week after treatment initiation," said Simpson. "A reduction in pruritus was observed at 24 hours following the first application. No adverse event occurred in more than 3.5% of patients, with low rates of application-site pain in both the roflumilast- and vehicle-treated patients."

Various concentrations of topical roflumilast are being evaluated in clinical trials of psoriasis and seborrheic dermatitis, as well as AD. The 0.3% formulation (Zoryve) received FDA approval in 2022 for once-daily treatment of mild, moderate, or severe plaque psoriasis.

Topical roflumilast has a water-based cream vehicle that is free of ethanol, propylene glycol, and fragrances and contains a novel emulsifier that does not extract epidermal lipids, Simpson noted in his introduction to the study. Roflumilast has greater affinity for PDE4 as compared with apremilast (Otezla) or crisaborole (Eucrisa), which has translated into greater in vitro potency.

The 0.15% formulation was evaluated in two large, randomized phase III trials ( and ) in patients age 6 years or older with mild or moderate AD, defined as an AD-validated Investigator Global Assessment (vIGA) of 2 or 3, body surface area ≥3%, and an Eczema Area and Severity Index (EASI) score ≥5.

The studies involved a combined total of 1,337 patients who had a mean age of 26-28. About a third of the patients identified as a minority race. Almost half of the patients were ages 6-17.

Investigators in both trials randomized patients 2:1 to topical roflumilast or vehicle, and the primary endpoint was the proportion of patients who achieved success at 4 weeks as indicated by a vIGA score of 0/1 and at least 2-point improvement from baseline. The primary analysis showed that more than twice as many patients allocated to roflumilast met the endpoint (32.0% vs 15.2% in INTEGUMENT 1 and 28.9% vs 12.0% in INTEGUMENT 2, P<0.0001). Response rates differed significantly within 1-2 weeks (P<0.0001).

All secondary endpoints favored roflumilast at 4 weeks in INTEGUMENT 1 and 2, respectively:

• vIGA 0/1: 41.5% vs 25.2% and 39.0% vs 16.9% (P<0.0001)
• EASI-75: 43.2% vs 22.0% and 42.0% vs 19.7% (P<0.0001)
• 4-point improvement in worst itch: 33.6% vs 20.7% (P=0.0089) and 302% vs 12.4% (P=0.0014)

Consistent with the primary endpoint, secondary endpoints showed a significant advantage for roflumilast within 1-2 weeks.

The most common TEAEs in the roflumilast groups were headache, nausea, and application-site pain. The proportion of patients who discontinued because of TEAEs was 1.4% to 1.8% with roflumilast and 0.9% to 1.4% with vehicle. Physicians and patients gave favorable ratings to roflumilast's local tolerability.

Pediatric dermatologist Lawrence Eichenfield, MD, of the University of California San Diego, said the data added to existing evidence of topical roflumilast's rapid onset of activity, safety and tolerability.

"Additionally, these pivotal phase III data show that roflumilast cream drove a significant and rapid reduction in itch as early as the first 24 hours, which could be a helpful early indication to children and adults that the treatment is working," said Eichenfield, a co-investigator in the trials, in a statement from study sponsor, Arcutis Biotherapeutics.

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