Effect of Roflumilast Cream vs Vehicle Cream on Chronic Plaque Psoriasis: The DERMIS-1 and DERMIS-2 Randomized Clinical Trials

Abstract

Importance: Once-daily roflumilast cream, 0.3%, a potent phosphodiesterase 4 inhibitor, demonstrated efficacy and was well tolerated in a phase 2b trial of patients with psoriasis.

Objective: To evaluate the efficacy of roflumilast cream, 0.3%, applied once daily for 8 weeks in 2 trials of patients with plaque psoriasis.

Design, setting, and participants: Two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]) were conducted at 40 centers (trial 1) and 39 centers (trial 2) in the US and Canada between December 9, 2019, and November 16, 2020, and between December 9, 2019, and November 23, 2020, respectively. Patients aged 2 years or older with plaque psoriasis involving 2% to 20% of body surface area were enrolled. The dates of final follow-up were November 20, 2020, and November 23, 2020, for trial 1 and trial 2, respectively.

Interventions: Patients were randomized 2:1 to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks.

Main outcomes and measures: The primary efficacy end point was Investigator Global Assessment (IGA) success (clear or almost clear status plus ≥2-grade improvement from baseline [score range, 0-4]) at week 8, analyzed using a Cochran-Mantel-Haenszel test stratified by site, baseline IGA score, and intertriginous involvement. There were 9 secondary outcomes, including intertriginous IGA success, 75% reduction in Psoriasis Area and Severity Index (PASI) score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving 4-point reduction (WI-NRS success) at week 8 (scale: 0 [no itch] to 10 [worst imaginable itch]; minimum clinically important difference, 4 points).

Results: Among 881 participants (mean age, 47.5 years; 320 [36.3%] female), mean IGA scores in trial 1 were 2.9 [SD, 0.52] for roflumilast and 2.9 [SD, 0.45] for vehicle and in trial 2 were 2.9 [SD, 0.48] for roflumilast and 2.9 [SD, 0.47]) for vehicle. Statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had IGA success at week 8 (trial 1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3%-46.9%]; trial 2: 37.5% vs 6.9%; difference, 28.9% [95% CI, 20.8%-36.9%]; P < .001 for both). Of 9 secondary end points, statistically significant differences favoring roflumilast vs vehicle were observed for 8 in trial 1 and 9 in trial 2, including intertriginous IGA success (71.2% vs 13.8%; difference, 66.5% [95% CI, 47.1%-85.8%] and 68.1% vs 18.5%; difference, 51.6% [95% CI, 29.3%-73.8%]; P < .001 for both), 75% reduction in PASI score (41.6% vs 7.6%; difference, 36.1% [95% CI, 28.5%-43.8%] and 39.0% vs 5.3%; difference, 32.4% [95% CI, 24.9%-39.8%]; P < .001 for both), WI-NRS success (67.5% vs 26.8%; difference, 42.6% [95% CI, 31.3%-53.8%] and 69.4% vs 35.6%; difference, 30.2% [95% CI, 18.2%-42.2%]; P < .001 for both). The incidence of treatment-emergent adverse events was 25.2% with roflumilast vs 23.5% with vehicle in trial 1 and 25.9% with roflumilast vs 18.4% with vehicle in trial 2. The incidence of serious adverse events was 0.7% with roflumilast vs 0.7% with vehicle in trial 1 and 0% with roflumilast vs 0.7% with vehicle in trial 2.

Conclusions and relevance: Among patients with chronic plaque psoriasis, treatment with roflumilast cream, 0.3%, compared with vehicle cream resulted in better clinical status at 8 weeks. Further research is needed to assess efficacy compared with other active treatments and to assess longer-term efficacy and safety.

Trial registration: ClinicalTrials.gov Identifiers: NCT04211363, NCT04211389.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lebwohl reported being an employee of the Icahn School of Medicine at Mount Sinai; receiving research funds from AbbVie, Amgen, Arcutis Biotherapeutics Inc, Avotres, Boehringer Ingelheim, Dermavant Sciences, Eli Lilly Incyte, Janssen Research and Development LLC, Ortho Dermatologics, Regeneron, and UCB Inc; and being a consultant for Aditum Bio, Almirall, AltruBio Inc, AnaptysBio, Arcutis Biotherapeutics Inc, Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr Reddy’s Laboratories, Evelo Biosciences, Evommune Inc, Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. Dr Kircik reported receiving investigator fees, speaker fees, clinical research grants, and/or honoraria from Abbott Laboratories, Ablynx, Acambis, Allergan Inc, Almirall, Amgen, AnaptysBio, Aqua, Arcutis Biotherapeutics Inc, Astellas Pharma US Inc, Asubio Pharmaceuticals Inc, Bayer Consumer Healthcare Pharmaceuticals, Beiersdorf Inc, Biogen, Biolife, Biopelle Inc, Boehringer Ingelheim, Botanix Pharmaceuticals, Breckinridge Pharma, Bristol Myers Squibb, Cassiopea SpA, Celgene, Cellceutix, Centocor Ortho Biotech Inc, ChemoCentryx, CollaGenex Pharmaceuticals Inc, ColBar LifeScience Ltd, Connetics Corp, Coria Laboratories, Dermavant Sciences Inc, Dermik Laboratories, Dow Pharmaceutical Sciences Inc, DUSA Pharmaceuticals Inc, Embil Pharmaceuticals Co Ltd, EOS, Ferndale Laboratories Inc, Galderma Laboratories LP, Genentech Inc, GlaxoSmithKline, Healthpoint Incyte Corp, Intendis Inc, Isdin, Johnson & Johnson Consumer Products Company, Laboratory Skin Care Inc, LEO Pharma, 3M Pharmaceuticals, MC2 Therapeutics, Medical International Technologies, Medicis Pharmaceutical Corp, Merck & Co Inc, Merck Serono, Merz Pharmaceuticals LLC, NanoBio Corp, Novartis Pharmaceuticals Corp, Nucryst, Obagi Medical Products, Ortho Dermatologics, Onset Dermatologics, Pfizer Inc, Pharmaderm, Promius Pharma LLC, PuraCap Pharmaceutical, QLT Inc, Sandoz, SkinMedica Inc, Stiefel, Sun Pharmaceutical Industries Ltd, Taro Pharm, TolerRx, Triax Pharmaceuticals LLC, Valeant Pharmaceuticals International, Warner Chilcott, Xenoport Inc, and Zalicus. Dr Moore reported receiving research funds and/or honoraria from AbbVie, Almirall, Arcutis Biotherapeutics Inc, Biofrontera, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Evolus, Galderma Incyte, Janssen, Mayne, Nimbus, Parexel, Pfizer, UCB, Verrica, and Vyne. Dr Stein Gold reported receiving investigator fees, speaker fees, and/or honoraria from AbbVie, Amgen, Arcutis Biotherapeutics Inc, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly, Galderma Incyte, Novartis, Pfizer, Sanofi, Regeneron, UCB, and Valeant/Bausch Health. Dr Draelos reported receiving a research grant from Arcutis Biotherapeutics Inc to contribute to the data presented in the article. Dr Gooderham reported receiving investigator fees, speaker fees, and/or honoraria from AbbVie, Akros, Amgen, Arcutis Biotherapeutics Inc, Aslan, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline Incyte, Janssen, Kyowa Kirin, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sun Pharma, UCB, and Valeant/Bausch Health. Dr Papp reported receiving investigator fees, speaker fees, clinical research grants, and/or honoraria from AbbVie, Akros, Amgen, Anacor, Arcutis Biotherapeutics Inc, Astellas, Avillion, Valeant/Bauch, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Can-Fite Biopharma, Celgene, Celltrion, Coherus, Dermavant, Dermira, Dice Pharmaceuticals, Dow Pharma, Eli Lilly, Evelo, Forbion, Galapagos, Galderma, Genentech, Gilead, GlaxoSmithKline Incyte, Janssen, Kyowa Hakko Kirin, LEO Pharma, MedImmune, Meiji Seika Pharma, Merck, Merck-Serono, Mitsubishi Pharma, Moberg Pharma, Novartis, Pfizer, PRCL Research, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sandoz, Sun Pharma, Takeda, UCB, vTv Therapeutics, and Xencor. Dr Bagel reported receiving research funds payable to the Psoriasis Treatment Center of New Jersey from AbbVie, Amgen, Arcutis Biotherapeutics Inc, Boehringer Ingelheim, Brickell Biotech Inc, Bristol Myers Squibb, Celgene, Corrona, Dermavant Sciences Ltd, Dermira, Eli Lilly, Janssen Biotech, Kadmon Corp, LEO Pharma, Menlo Therapeutics, Mindera, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, Sun Pharmaceutical Industries Ltd, Target Pharma, Taro Pharmaceutical Industries Ltd, UCB, and Valeant Pharmaceuticals; receiving consultant fees from AbbVie, Amgen, Arcutis Biotherapeutics Inc, Bristol Myers Squibb, Celgene, Dermavant Sciences Ltd, Eli Lilly, Janssen Biotech, Mindera, Novartis, Sun Pharmaceutical Industries Ltd, UCB, and Valeant Pharmaceuticals; and receiving fees for speaking from AbbVie, Celgene, Eli Lilly, and Janssen Biotech. Dr Bhatia reported being an advisor, consultant, and investigator for Arcutis Biotherapeutics Inc. Dr Del Rosso reported receiving investigator fees, speaker fees, clinical research grants, and/or honoraria from Aclaris Therapeutics Inc, Almirall, Amgen, AnaptysBio, Arcutis Biotherapeutics Inc, Athenix, Biofrontera, BioPharmX, Biorasi LLC, BlueCreek Dermatologics Inc, Botanix Pharmaceuticals, Brickell Biotech Inc, Bristol Myers Squibb, Cara Therapeutics, Cassiopea SpA, Dermata Therapeutics, Dermavant Sciences, Dermira, Encore Dermatology Inc, Evommune Inc, Ferndale Laboratories Inc, Foamix, Galderma Laboratories LP, Genentech Inc, Incyte Corp, JEM Health, La Roche-Posay Laboratorie Pharmaceutique, LEO Pharma, Lilly ICOS LLC, L’Oreal USA Inc, Mayne Pharma Group, Menlo Therapeutics, Novan, Ortho Dermatologics, Pfizer Inc, Promius Pharma LLC, Ralexar Therapeutics Inc, Regeneron Pharmaceuticals Inc, Sanofi Genzyme, Sebacia, Sente Labs Inc, Sol-Gel Technologies, Sonoma Pharmaceuticals, Sun Pharmaceutical Industries Ltd, Trevi Therapeutics, UCB, Unilever Home and Personal Care USA, Verrica Pharmaceuticals Inc, and Viamet Pharmaceuticals Inc and receiving salary as an employee of Regeneron Pharmaceuticals Inc. Dr Ferris reported receiving investigator or consulting fees from AbbVie, Amgen, Arcutis Biotherapeutics Inc, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermavant, Eli Lilly, Galderma, Janssen, Novartis, Pfizer, Regeneron, and UCB. Dr Green reported receiving investigator fees, speaker fees, and/or consulting fees from Amgen, AbbVie, Arcutis Biotherapeutics Inc, Bristol Myers Squibb, Dermavant, Eli Lilly, Nimbus, OrthoDerm, SunPharma, and UCB. Dr Hebert reported receiving research grants from Arcutis Biotherapeutics Inc, Pfizer, LEO Pharma, Galderma, Brickell, Eli Lilly, Ortho Dermatologics, and Mayne; receiving honoraria from Arcutis Biotherapeutics Inc, Pfizer, Galderma, Eli Lilly, Ortho Dermatologics, Bristol Myers Squibb, Janssen, Mayne, LEO Incyte, Almirall, Verrica, and Vyne; and serving on data and safety monitoring boards for Regeneron, Sanofi, GlaxoSmithKline, and Bausch Health. Dr Pariser reported receiving investigator fees, speaker fees, clinical research grants, and/or honoraria from Almirall, Amgen, AOBiome LLC, Asana Biosciences LLC, Bickel Biotechnology, Biofrontera AG, Bristol Myers Squibb, Celgene, Dermira, Eli Lilly, LEO Pharma, Menlo Therapeutics, Novartis Pharmaceuticals Corp, Novo Nordisk A/S, Ortho Dermatologics, Pfizer Inc, Regeneron, and Sanofi. Dr Yamauchi reported being an investigator, consultant, and speaker for Amgen, AbbVie, Janssen, Eli Lilly, EPI Health Incyte, Pfizer, Sun Pharma, UCB, Regeneron, and Sanofi; being an investigator and consultant for Arcutis Biotherapeutics Inc, Dermavant, Bristol Myers Squibb, Novartis, LEO Pharma, Ortho Dermatologics, Galderma, and Boehringer Ingelheim; and being an investigator for AstraZeneca, Abcentra, AnaptysBio, and Aurigene. Dr Zirwas reported receiving consulting fees, investigator fees, speaker fees, clinical research grants or sponsored research, and/or honoraria from AbbVie, All Free Clear/Sun, AnaptysBio, Arcutis Biotherapeutics Inc, Asana, AsepticMD, Avillion, Bausch Health, Cara, Concert, Dermavant, Edessa Biotech, EPI Health, Fitbit, Galderma, Genentech/Novartis Incyte, Janssen, L’Oreal, LEO Pharma, Level-Ex, Eli Lilly, LUUM, Oculus, Peloton, Pfizer, Regeneron/Sanofi, Sol-Gel, Trevi, UCB, and Vyne. Dr Albrecht reported receiving consulting fees, investigator fees, speaker fees, clinical research grants or sponsored research, and/or honoraria from AbbVie, Akros, Amgen, Arcutis Biotherapeutics Inc, Avillion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Cutanea, Dermavant, Dermira, Eli Lilly, Galderma, Glenmark, Hoffman-La Roche, Janssen, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Sanofi, UCB, and Valeant/Bausch Health. Dr Devani reported receiving investigator fees, speaker fees, and/or honoraria from AbbVie, Amgen, Arcutis Biotherapeutics Inc, Valeant/Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Galapagos, Galderma, GlaxoSmithKline Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sandoz, Sun Pharma, Takeda, and UCB. Dr Lomaga reported receiving investigator fees, speaker fees, and/or honoraria from AbbVie, Akros, Amgen, Arcutis Biotherapeutics Inc, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline Incyte, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sun Pharma, UCB, and Valeant/Bausch Health. Drs Feng, Snyder, Burnett, and Berk and Mr Higham are employees of Arcutis Biotherapeutics Inc. No other disclosures were reported.

Figures

Figure 1.. Patient Disposition in the DERMIS-1 and DERMIS-2 Trials

aExcluded participants could have ≥1 reasons for ineligibility/nonenrollment. bDescriptions of PHQ-8 and modified PHQ-A are in the Methods; descriptions of PASI and IGA are in Table 1 footnotes. cExcept fully treated basal cell carcinoma, cutaneous squamous cell carcinoma, or carcinoma in situ of the cervix. dRandomization was stratified by study site, baseline IGA score (2 vs ≥3), and intertriginous involvement at baseline (I-IGA score >2, yes vs no; I-IGA evaluated on a scale of 0 [clear] to 4 [severe]).

Figure 2.. Percentage of Patients Achieving IGA Success Over Time in DERMIS-1 and DERMIS-2

The primary end point for both studies was success on the Investigator Global Assessment (IGA) scale, defined as achievement of clear or almost clear status plus ≥2-grade improvement from baseline at 8 weeks.P < .001 for the difference at 8 weeks for both studies. Patients who completed the IGA at week 8 (±7 days) were considered completers. The percentage of patients who completed the 8-week study was 88.4% in DERMIS-1 and 89.4% in DERMIS-2. Observed percentages are presented. P values are based on analysis with imputation of missing data and stratification by pooled study sites, baseline IGA, and baseline intertriginous IGA. Whiskers represent 95% CIs.

Figure 3.. Representative Photos of Patients Treated With Roflumilast Cream, 0.3%, Over Time in DERMIS-1 and DERMIS-2

IGA indicates Investigator Global Assessment; I-IGA, intertriginous IGA. IGA was measured based on whole-body involvement using a 5-point scale ranging from none (0) to severe (4). See eTable 1 in Supplement 5 for details of the scale. Images show an area of the whole-body measurement.