Dermatology Update 2018 FALL



Understanding the drug discovery pathway of an oral therapy

The invention of apremilast as an orally active phosphodiesterase 4 (PDE4) inhibitor and anti-inflammatory agent began with the optimization of previously reported 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(3,4- dimethoxyphenyl) propionic acid PDE4 inhibitors, leading to a series of sulfone analogues. Evaluation of the structure-activity relationship of substitutions on the phthalimide group led to the synthesis of an S-isomer acetylamino analogue CC-10004 or apremilast.1 Drug discovery screening was initially focused on inhibition of tumor necrosis factor-α (TNF-α) production by peripheral blood mononuclear cells (PBMC) and whole blood, and was later expanded to include other cell types such as polymorphonuclear cells, T cells, Natural Killer cells, keratinocytes, chondrocytes, and synoviocytes.2-3

In vivo pharmacology models included systemic TNF-α production in the rat, and the psoriasiform dermatitis mouse model, wherein apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features, and reduced expression of TNF-α and other inflammation markers in the lesioned skin.2 While it was known that PDE4 acted as proinflammatory enzymes via degradation of cyclic adenosine monophosphate (cAMP), little was known on the expression pattern of PDE4 in psoriasis. PDE4B and PDE4D mRNA were found to be overexpressed in PBMC and lesional skin from psoriasis patients.4 While the PDE4 biochemical selectivity of apremilast is broad, inhibiting isoforms from all four PDE4 sub-families (A, B, C, and D), with IC50 values in the range of 10 to 100 nM, it is also very selective and does not significantly inhibit other PDEs, kinases, enzymes, or receptors.5 The effects of apremilast on innate immunity and tolerability were tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). In this model apremilast significantly inhibited lung neutrophilia at 1 mg/kg but did not induce significant emetic reflexes at doses <30 mg/kg. The pharmacological effects of apremilast demonstrate that it is a targeted PDE4 inhibitor, with selective effects on innate immune responses and a wide therapeutic index compared to its gastrointestinal side effects.5

Based upon its preclinical profile, apremilast was selected for clinical development for the potential oral treatment of inflammatory conditions, such as asthma and psoriasis. 6 Although the phase 2 asthma study failed to meet its clinical endpoint, in an open-label, single-arm pilot study in patients with severe plaque psoriasis in which 19 patients were treated with apremilast 20 mg QD for 29 days, the primary pharmacodynamic activity end point defined as a > 20% reduction in epidermal skin thickness was met in 8 out of 15 evaluable patients (53.3%), and a decrease in ex vivo whole blood TNF-α production was observed. These results confirmed that apremilast could engage its target and was pharmacologically active in patients at a dose that was safe and well-tolerated. 7 A subsequent phase 2 trial in psoriatic arthritis (PsA) demonstrated 43.5% of patients receiving apremilast 20 mg BID and 35.8% of those receiving 40 mg QD achieved an ACR20 response at week 12, and >40% of patients in each group achieved the ACR20 level of improvement by week 24. 8 Efficacy of the 30 mg BID dose in PsA was ultimately confirmed in the phase 3 clinical trials (PALACE 1-4). In PALACE 1, apremilast was found to significantly reduce TNF-α, IL-6, IL-8, MIP-1????, MCP-1, and ferritin at Week 24; among these cytokines only TNF-α was found to associate with the ACR20 response to apremilast at both dose levels tested.  At the later time point of Week 40, IL-17, IL-23, IL-6, and ferritin were significantly decreased, while IL-10 and IL-1RA were significantly increased in the apremilast-treated subjects. 9 The US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis in March 2014.

In the phase 3 clinical trial in patients with moderate to severe psoriasis (ESTEEM 2) and in a subsequent phase 2b psoriasis trial conducted in Japan, treatment with apremilast was associated with significant reductions in plasma levels of TNF-α, and to a much greater extent with reductions in interleukin (IL)-17A, IL-17F, IL-22, and compared with placebo. The rapid, substantial reduction in systemic IL-17 protein levels should be highlighted: In these two studies, the median reduction was approximately −43% to −44% for IL-17A and −50% to −57% for IL-17F at Week 4. The median reductions in systemic IL-22 and TNF-α protein levels were significant, although more modest (−27% to −36% for IL-22 and −3% to −9% for TNF-α at Week 4). Multivariate analyses demonstrated that while changes in IL-17F were the most important predictor of improvement in Psoriasis Area and Severity Index scores, apremilast exerted synergistic attenuating effects among this key group of cytokines involved in the pathology of psoriasis, and these effects correlated with improved skin symptoms. 10 The US FDA approved apremilast for treating patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy in September 2014.

Overall, the properties of apremilast including its selectivity, therapeutic index, and in vivo clinical pharmacodynamics demonstrate that the beneficial effects of apremilast on key inflammatory mediators including TNF-α, IL-17, and IL-22 are associated with its clinical efficacy. 11


Missing Event Data
Dr. Peter H. Schafer

Dr. Peter H. Schafer

An executive director at Celgene

Celgene - Dermatology Update Sponsor


  1. Man HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H, Blease K, Leisten J, Shirley MA, Tang Y, Babusis DM, Chen R, Stirling D, Muller GW. Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor. J Med Chem. 2009 Mar 26;52(6):1522-4.
  2. Schafer P, Parton A, Gandhi A, Capone L, Adams M, Wu L, Bartlett J, Loveland M, Gilhar A, Cheung YF, Baillie G, Houslay M, Man HW, Muller G, Stirling D. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010; 159(4):842-55.
  3. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochemical Pharmacology. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012; 83(12):1583-90.
  4. Schafer PH, Truzzi F, Parton A, Wu L, Kosek J, Zhang LH, Horan G, Saltari A, Quadri M, Lotti R, Marconi A, Pincelli C. Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal. 2016 Jul;28(7):753-63.
  5. Schafer PH, Parton A, Capone L, Cedzik D, Brady H, Evans JF, Man HW, Muller GW, Stirling DI, Chopra R. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014 Sep;26(9):2016-29.
  6. Braddock M, Murray C. 10th anniversary Inflammation and Immune Diseases Drug Discovery and Development Summit. 20-21 March 2006, New Brunswick, USA. Expert Opin Investig Drugs. 2006 Jun;15(6):721-7
  7. Gottlieb AB, Strober B, Krueger JG, Rohane P, Zeldis JB, Hu CC, Kipnis C 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 May;24(5):1529-38.
  8. Schett G, Wollenhaupt J, Papp K, Joos R, Rodrigues JF, Vessey AR, Hu C, Stevens R, de Vlam KL. Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2012 Oct;64(10):3156-67.
  9. Schafer P, Chen P, Fang L, Wang A, Chopra R. The Pharmacodynamic Impact of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, on Circulating Levels of Inflammatory Biomarkers in Patients with Psoriatic Arthritis: Substudy Results from a Phase III, Randomized, Placebo-Controlled Trial (PALACE 1). J Immunol Res. 2015, Article ID 906349.
  10. 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. 2018 Sep;142(3):1010-1013.
  11. Pincelli C, Schafer PH, French LE, Augustin M, Krueger JG. Mechanisms Underlying the Clinical Effects of Apremilast for Psoriasis. J Drugs Dermatol. 2018 Aug 1;17(8):835-840.