Mark G Lebwohl1, Leon H Kircik1,2,3,4, Angela Y Moore5,6, Linda Stein Gold7, Zoe D Draelos8, Melinda J Gooderham9,10,11, Kim A Papp12,13, Jerry Bagel14, Neal Bhatia15, James Q Del Rosso16,17, Laura K Ferris18, Lawrence J Green19, Adelaide A Hebert20, Terry Jones21, Steven E Kempers22, David M Pariser23,24, Paul S Yamauchi25,26, Matthew Zirwas27,28,29, Lorne Albrecht30,31, Alim R Devani32,33, Mark Lomaga34,35, Amy Feng36, Scott Snyder36, Patrick Burnett36, Robert C Higham36, David R Berk36. 1. Icahn School of Medicine at Mount Sinai, New York, New York. 2. Indiana Medical Center, Indianapolis. 3. Physicians Skin Care PLLC, Louisville, Kentucky. 4. Skin Sciences PLLC, Louisville, Kentucky. 5. Arlington Research Center, Arlington, Texas. 6. Baylor University Medical Center, Dallas, Texas. 7. Henry Ford Medical Center, Detroit, Michigan. 8. Dermatology Consulting Services, High Point, North Carolina. 9. SkiN Centre for Dermatology, Peterborough, Ontario, Canada. 10. Probity Medical Research, Peterborough, Ontario, Canada. 11. Queen's University, Peterborough, Ontario, Canada. 12. Probity Medical Research, Waterloo, Ontario, Canada. 13. K Papp Clinical Research, Waterloo, Ontario, Canada. 14. Psoriasis Treatment Center of Central New Jersey, East Windsor. 15. Therapeutics Clinical Research, San Diego, California. 16. JDR Dermatology Research Center LLC, Las Vegas, Nevada. 17. Advanced Dermatology and Cosmetic Surgery, Maitland, Florida. 18. University of Pittsburgh Clinical and Translational Science Institute, Pittsburgh, Pennsylvania. 19. George Washington University School of Medicine, Rockville, Maryland. 20. UT Health McGovern Medical School, Houston, Texas. 21. US Dermatology Partners Bryan, Bryan, Texas. 22. Minnesota Clinical Study Center, Fridley. 23. Eastern Virginia Medical School, Norfolk. 24. Virginia Clinical Research Inc, Norfolk. 25. David Geffen School of Medicine at UCLA, Los Angeles, California. 26. Dermatology Institute and Skin Care Center Inc, Santa Monica, California. 27. Dermatologists of the Central States, Bexley, Ohio. 28. Probity Medical Research, Bexley, Ohio. 29. Ohio University, Bexley, Ohio. 30. Enverus Medical Research, Surrey, British Columbia, Canada. 31. Probity Medical Research, Surrey, British Columbia, Canada. 32. Dermatology Research Institute, Calgary, Alberta, Canada. 33. Probity Medical Research, Calgary, Alberta, Canada. 34. DermEdge Research, Mississauga, Ontario, Canada. 35. Probity Medical Research, Mississauga, Ontario, Canada. 36. Arcutis Biotherapeutics Inc, Westlake Village, California.
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.
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.
Authors: Mark G Lebwohl; Kim A Papp; Linda Stein Gold; Melinda J Gooderham; Leon H Kircik; Zoe D Draelos; Steven E Kempers; Mathew Zirwas; Kathleen Smith; David W Osborne; Marie-Louise Trotman; Lynn Navale; Charlotte Merritt; David R Berk; Howard Welgus Journal: N Engl J Med Date: 2020-07-16 Impact factor: 91.245
Authors: April N Naegeli; Emuella Flood; Jennifer Tucker; Jennifer Devlen; Emily Edson-Heredia Journal: Int J Dermatol Date: 2014-12-16 Impact factor: 2.736
Authors: Bruce E Strober; Judit Nyirady; Usha G Mallya; Achim Guettner; Charis Papavassilis; Alice B Gottlieb; Boni E Elewski; Diane M Turner-Bowker; Alan L Shields; Chad J Gwaltney; Mark Lebwohl Journal: Value Health Date: 2013 Sep-Oct Impact factor: 5.725
Authors: B Elewski; A F Alexis; M Lebwohl; L Stein Gold; D Pariser; J Del Rosso; G Yosipovitch Journal: J Eur Acad Dermatol Venereol Date: 2019-05-10 Impact factor: 6.166
Authors: Kim A Papp; Melinda Gooderham; Michael Droege; Charlotte Merritt; David W Osborne; David R Berk; Archie W Thurston; Valerie H Smith; Howard Welgus Journal: J Drugs Dermatol Date: 2020-08-01 Impact factor: 2.114