Mechanisms Underlying the Clinical Effects of Apremilast for Psoriasis

August 2018 | Volume 17 | Issue 8 | Original Article | 835 | Copyright © August 2018


Carlo Pincelli MD,a Peter H. Schafer PhD,b Lars E. French MD,c Matthias Augustin MD,d James G. Krueger MD PhDe

aLaboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy bDepartment of Translational Development, Celgene Corporation, Summit, NJ cDepartment of Dermatology, Zurich University Hospital, Zurich, Switzerland dInstitute and German Center for Health Services Research in Dermatology, University Medical Center of Hamburg, Hamburg, Germany eLaboratory of Investigative Dermatology, The Rockefeller University, New York, NY

Figure3clinical efficacy that was maintained with continued treatment for up to 52 weeks,27-29 and some patients enrolled in the ESTEEM trials will continue to receive apremilast therapy for up to 5 years. In the more recent Evaluating Apremilast in a Phase IV Trial of Efficacy and Safety in Patients With Moderate Plaque Psoriasis (UNVEIL) study, the efficacy of apremilast was demonstrated in systemic-naive, post-topical patients with moderate plaque psoriasis (ie, 5% to 10% body surface area involvement and static Physician’s Global Assessment score of 3 [moderate] on a 6-point scale) and was consistent with results from the ESTEEM trials in patients with moderate to severe plaque psoriasis.31

SUMMARY

Psoriasis involves chronic, systemic dysregulation of pro-inflammatory and anti-inflammatory cytokines that leads to the symptoms of psoriasis and underlying systemic inflammation. Apremilast is an oral PDE4 inhibitor that has demonstrated safety and efficacy in the treatment of moderate to severe plaque psoriasis and psoriatic arthritis. Apremilast exhibits pleiotropic, synergistic attenuating effects on a key group of cytokines involved in the pathology of psoriasis, most notably IL-17A/F, IL-22, and TNF-α, and these effects correlate with reduced skin manifestations.24 Newly available pharmacodynamic data from clinical study patients further clarify the link between clinical efficacy and the beneficial effects of apremilast on these known inflammatory mediators.

DISCLOSURES

Dr. Pincelli reports grants from Expascience, Lilly, and Mylan; nonfinancial support from Celgene Corporation; and personal fees from Sienna. Dr. Schafer is an employee of and has stocks/stock options in Celgene Corporation. Dr. French has received a grant from Celgene Corporation and has served as a consultant for Celgene Corporation. Dr. Augustin has served as a consultant to or paid speaker for clinical trials sponsored by companies that manufacture drugs for the treatment of psoriasis, including AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene Corporation, Centocor, Eli Lilly, GSK, Janssen-Cilag, LEO Pharma, Medac, Merck, MSD, Novartis, Pfizer, UCB, and XenoPort. Dr. Krueger reports grants paid to institution and/or personal fees from AbbVie, Acros, Allergan, Amgen, Asana, Aurigne, Biogen-Idec, BiogenMA, BMS, Boehringer Ingelheim, Escalier, Innovaderm, Janssen, Kineta, LEO Pharma, Lilly, Novan, Novartis, Paraxel, Pfizer, Regeneron, Roche, Vitae, Sienna, UCB, and Valeant.

ACKNOWLEDGMENTS

This work was sponsored by Celgene Corporation. The authors received editorial support in the preparation of this review from Amy Shaberman, PhD, of Peloton Advantage, LLC, funded by Celgene Corporation. The authors, however, directed and are fully responsible for all content and editorial decisions for this review.

REFERENCES

  1. Helmick CG, Lee-Han H, Hirsch SC, Baird TL, Bartlett CL. Prevalence of Psoriasis Among Adults in the U.S.: 2003-2006 and 2009-2010 National Health and Nutrition Examination Surveys. Am J Prev Med. 2014;47:37-45.
  2. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377-385.
  3. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014;70:512-516.
  4. Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the management of psoriasis: results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. J Am Acad Dermatol. 2014;70:871-881.
  5. Baliwag J, Barnes DH, Johnston A. Cytokines in psoriasis. Cytokine. 2015;73:342-350.
  6. Kim J, Krueger JG. The immunopathogenesis of psoriasis. Dermatol Clin. 2015;33:13-23.
  7. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496-509.
  8. Stelara [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2014.
  9. Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016.
  10. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
  11. Humira (adalimumab) [package insert]. North Chicago, IL: AbbVie Inc.; 2014.
  12. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83:1583-1590.
  13. Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007;76:481-511.
  14. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17-26.
  15. Otezla [package insert]. Summit, NJ: Celgene Corporation; June 2017.
  16. Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014;26:2016-2029.
  17. Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159:842-855.
  18. Schafer PH, Truzzi F, Parton A, et al. Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal. 2016;28:753-763.
  19. Cai Y, Fleming C, Yan J. New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol. 2012;9:302-309.
  20. Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K. The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. Arch Immunol Ther Exp (Warsz). 2015;63:435-449.
  21. Marconi A, Truzzi F, Saltari A, et al. CD271 regulates human keratinocyte functions through phosphodiesterase 4 binding [abstract 142]. J Invest Dermatol. 2016;136(9[suppl 2]):S184.
  22. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008;24:1529-1538.
  23. Gottlieb AB, Matheson RT, Menter A, et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol. 2013;12:888-897.
  24. Krueger JG, Ohtsuki M, Garcet S, et al. Apremilast reduces IL-17F, IL-17A, IL-22, and TNF-α plasma protein levels in patients with moderate to severe plaque psoriasis: similar pharmacodynamic and correlative results from a phase 3 study in North America and Europe and a phase 2b study in Japan [poster P2081]. Paper presented at: Congress of the European Academy of Dermatology and Venereology; September 28-October 2, 2016; Vienna, Austria.
  25. Garcet S, Nograles K, Correa da Rosa J, Schafer PH, Krueger JG. Synergistic cytokine effects as apremilast response predictors in patients with psoriasis. J Allergy Clin Immunol. In press.
  26. Garcet S, Nograles K, Correa da Rosa J, Schafer PH, Krueger JG. Exploring the synergistic effects of cytokines as predictors of response to apremilast in patients with moderate to severe plaque psoriasis [poster]. Paper presented at: Annual Meeting of the Society for Investigative Dermatology; May 11-14, 2016; Scottsdale, AZ.
  27. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM 1]). J Am Acad Dermatol. 2015;73:37-49.
  28. Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque psoriasis over 52 weeks: a phase III, randomized, controlled trial (ESTEEM 2). Br J Dermatol. 2015;173:1387-1399.
  29. Reich K, Gooderham M, Green L, et al. The efficacy and safety of apremilast, etanercept, and placebo, in patients with moderate to severe plaque psoriasis: 52-week results from a phase 3b, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol. 2017;31:507-517.
  30. Sobell JM, Foley P, Toth D, et al. Effects of apremilast on pruritus and skin discomfort/pain correlate with improvements in quality of life in patients with moderate to severe plaque psoriasis. Acta Derm Venereol. 2016;96:514-520.
  31. Strober B, Bagel J, Lebwohl M, et al. Efficacy and safety of apremilast in patients with moderate plaque psoriasis with lower BSA: week

AUTHOR CORRESPONDENCE

Peter H. Schafer PhD pschafer@celgene.com
Close Menu