Investigational topical shows strong results for intertriginous psoriatic areas

In phase 2b testing, potentially the first topical phosphodiesterase (PDE)-4 inhibitor for psoriasis (roflumilast cream, Arcutis) has demonstrated improvements on par with topical corticosteroids. A small subset of patients with intertriginous psoriasis fared particularly well, investigators add.

Nonsteroidal topical treatments approved for psoriasis include vitamin D analogues and retinoids. Both can be irritating, says Mark Lebwohl, M.D., principal study investigator.

“We know the side effects of corticosteroids. Specifically, we are worried about using corticosteroids or non-steroids in facial and intertriginous areas because of irritation and other side effects like formation of stretch marks,” he says. Dr. Lebwohl is Waldman Professor and Chairman, Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York.

The PDE-4 enzyme maintains intracellular levels of cyclic adenosine monophosphate and mediates biologic responses to extracellular stimuli in various cell types including immune cells.

“PDE-4 activity is elevated psoriatic skin,” Dr. Lebwohl adds.

Inhibiting PDE-4 leads to downregulation of tumor necrosis factor α, interferon y, interleukin (IL)-17 and IL-23. Roflumilast cream is a selective PDE-4 inhibitor that is 25- to 300-fold more potent than currently available PDE-4 inhibitors, he says.

The study was published July 16 in the New England Journal of Medicine.1 Investigators randomized 331 patients with mild-to-severe psoriasis to roflumilast 0.3% cream (109 patients) roflumilast 0.15% cream (113) or vehicle cream (109). All treatment groups were similar in terms of age, gender and disease severity (mean Psoriasis Area and Severity Index/PASI scores: 7.6-8.0).

“One exception is that in intertriginous areas, the 0.3% cohort had a little bit more severe involvement than the 0.15% group, but it was comparable in severity to the vehicle group,” he says.

The combined percentages of patients in these groups with moderate and severe IGA scores were 56%, 23% and 59%, respectively.

“At the primary endpoint — percentage of patients who were clear or almost clear with at least a two-grade improvement over baseline at week six — both doses of roflumilast cream were significantly more effective than the vehicle. And there was a dose-related improvement,” Dr. Lebwohl says.

The proportions of patients who achieved Investigator Global Assessment (IGA) success with the 0.3% and 0.15% creams were 28% (95% confidence interval/CI 20-37) and 23% (95% CI 16-31%), respectively, versus 8% (95% CI 4-15) for placebo.

Roflumilast took effect quickly, with both concentrations delivering statistically significant IGA improvements over vehicle by week two. Peak improvement for the 0.3% concentration occurred at week eight, with approximately 32% of patients achieving IGA success, versus 24% for the lower concentration and 10% for vehicle (P<0.001 and P=0.005 for vehicle comparisons, respectively).

The IGA success of roflumilast 0.3% at week eight parallels results historically reported for topical glucocorticoids, Lebwohl et al write. Due to differences in trial design, however, no clinical conclusions can be drawn in this regard.

Somewhat similarly, in pivotal trials of the oral PDE-4 inhibitor apremilast, approximately 30% of patients with moderate-to-severe plaque psoriasis reached PASI 75 at week 16. In roflumilast phase 2b, 31% of patients reached PASI 75 at week eight, although again, direct comparisons between disparate trials cannot be made.

“We now have a topical PDE-4 inhibitor that improves psoriasis. Roflumilast once-daily cream resulted in significant improvement in psoriasis signs and symptoms. It also improved itch and dramatically improved intertriginous psoriasis, with most patients in this group being clear at week eight,” says Dr. Lebwohl.

Regarding intertriginous-area IGA scores, patients on both concentrations continued to improve through week 12. The 0.3% dose peaked at this point, with more than 90% of patients achieving intertriginous-area IGA scores of zero or one.

Subject-reported worst itch numeric rating scale (WI-NRS) scores improved significantly with the higher concentration as early as week two. These improvements grew through week 8, when 65% of patients had at least four-point reductions. WI-NRS scores for the lower concentration improved through week 12, with 70% of patients achieving at least four-point reductions.

“The adverse events (AEs) seen with roflumilast cream were negligible,” Dr. Lebwohl says.

Only one roflumilast-treated patient (who was in the 0.3% group) discontinued treatment due to AEs, versus two in the vehicle cohort. The most common AEs overall (impacting at least 3% of patients in any group) included upper respiratory tract infection, nasopharyngitis and viral upper respiratory tract infection. Among treatment-related AEs reported in more than 1% of any group, application-site pain impacted two patients (1.8%) in the 0.3% group, one patient (0.9%) in the 0.15 % group, and three patients (2.8%) in the vehicle group.

“This is a very well-tolerated cream, with no local pain different than placebo,” he says.

Limitations included the trial’s relatively short duration and small intertriginous psoriasis subgroup (approximately 15% of patients). Additionally, investigators could not draw clinical conclusions regarding several secondary outcomes because the trial lacked a plan for adjustment of the 95% CI for multiple comparisons with these outcomes. Arcutis expects topline phase 3 data in the first half of 2021.

DISCLOSURES:

Dr. Lebwohl reports receiving grant support from AbbVie, Amgen, Eli Lilly, Incyte, Janssen, Ortho Dermatologics and UCB; grant support and consulting fees from Arcutis Biotherapeutics, Boehringer Ingelheim, Dermavant Sciences, LEO Pharma and Pfizer; and consulting fees from Aditum Bio, Allergan, Almirall, Avotres Therapeutics, BirchBioMed, BMD Skincare, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, EMD Serono, Evelo Biosciences, Inozyme Pharma, Kyowa Kirin, Meiji Seika Pharma, Menlo Therapeutics, Mitsubishi Pharma, NeuroDerm, Promius Pharma/Dr. Reddy’s Laboratories, Theravance Biopharma and Verrica Pharmaceuticals. All grants and fees are paid to Dr. Lebwohl’s institution.

REFERENCE:

Lebwohl MG, Papp KA, Stein Gold L, et al. Trial of roflumilast cream for chronic plaque psoriasis. N Engl J Med. 2020;383(3):229-239. doi:10.1056/NEJMoa2000073.