Once-daily – including challenging lesions in tough-to-treat intertriginous areas – in a phase 2b, randomized, double-blind, vehicle-controlled clinical trial, Mark G. Lebwohl, MD, reported at the virtual annual meeting of the American Academy of Dermatology.
The clinical improvement occurred rapidly. And topical roflumilast’s side effect profile was essentially the same as in vehicle-treated controls, which suggests a potential major advantage for the novel drug in future clinical practice. After all, topical treatment is the mainstay of psoriasis therapy, but the current topical agents – high-potency corticosteroids, vitamin D derivatives, and retinoids – have long-term tolerability, efficacy, or side effect issues, especially in treating sensitive skin areas, including the face and intertriginous areas.
“Roflumilast cream could really be a game changer,” predicted Dr. Lebwohl, professor and chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
Phosphodiesterase-4 (PDE-4) activity is elevated in psoriatic skin. Indeed, inhibition of PDE-4 via oral apremilast (Otezla) is an established strategy for improving psoriasis through down-regulation of inflammatory cytokines including tumor necrosis factor–alpha, interleukins-17 and -23, and interferon-gamma. Notably, however, roflumilast is orders of magnitude more potent than any other PDE-4 inhibitor. An oral version marketed as Daliresp has been available for treatment of chronic obstructive pulmonary disease for nearly a decade.
The 12-week, multicenter, phase 2b study included 331 patients with chronic plaque psoriasis who were randomized to once-daily 0.3% roflumilast cream, 0.15% roflumilast cream, or vehicle. Three-quarters of participants had a baseline Investigator Global Assessment (IGA) score of 3, indicative of moderate disease.
The primary endpoint was achievement of an IGA score of 0 or 1 (clear or almost clear) at week 6. The observed improvement was dose related, although both doses of roflumilast were significantly more effective than vehicle. However, peak improvement occurred at week 8, not week 6, with subsequent plateauing of response through week 12. A week 8 IGA of 0 or 1 plus at least a 2-grade improvement from baseline occurred in 32% of the high-dose roflumilast group, 25% of those on the 0.15% formulation, and 10% of controls.
“The effect in improvement was very rapid, with a statistically significant improvement compared to vehicle for both concentrations as early as week 2,” Dr. Lebwohl said.
A key secondary endpoint focused on treatment response in intertriginous areas, since “those are the areas where we really don’t want to use steroids because of major irritation problems,” the dermatologist explained. At week 12, treatment success as defined by an intertriginous IGA score of 0 or 1 plus at least a 2-point improvement from baseline was seen in 86% of the 0.3% roflumilast cream group, 50% on low-dose therapy, and 29% of controls.
About 65% of subjects on high-dose roflumilast cream reported at least a 4-point reduction in the Worst Itch–Numerical Rating Scale by week 8, as did 58% of those on the low-dose version and 42% of controls. Another secondary endpoint – patient-reported burden of disease as captured in a Psoriasis Symptoms Diary – showed a significant divergence between both doses of roflumilast and vehicle as early as week 2.
“Adverse events were negligible,” Dr. Lebwohl said. “In fact, there was only one discontinuation in the 0.3% arm, compared to none with 0.15% and two with vehicle.”
The phase 3 program is now recruiting participants.
The phase 2b study was funded by Arcutis Biotherapeutics. Dr. Lebwohl reported receiving research funding from and serving as a consultant to that company and numerous others.