Small Molecules

An Overview of Emerging Therapeutic Options in the Treatment of Psoriasis

Melinda Gooderham, MD, MSc, FRCPC


Skin Therapy Letter. 2013;18(7) 

In This Article

Phosphodiesterase 4 (PDE4) Inhibitors

Cyclic adenosine monophosphate (cAMP) is the principal secondary messenger responsible for immune response regulation. PDE4 is the main cAMP degrading enzyme found in cells of the immune system and keratinocytes. Inhibitors of PDE4 can prolong or enhance effects of cAMP, resulting in suppression of both Th1 and Th2 immune responses (Figure 2).[14] Due to these immune modulating effects, PDE4 inhibitors are currently under investigation for a variety of conditions including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, and psoriatic arthritis.[14,15]

Figure 2.

Action of PDE4 inhibitors can prolong or enhance effects of cAMP and result in suppression of both Th1 and Th2 immune responses
G-protein coupled receptor = integral membrane proteins that respond to extracellular stimuli in a cAMP dependent fashion; AC = adenylate cyclase; PKA = protein kinase A


The PDE4 inhibitor, apremilast (CC-10004, Celgene Corporation), has been shown to inhibit production of the pro-inflammatory cytokines, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-12 and IL-23, which are major players in the pathogenesis of psoriasis. Apremilast was shown to have a range of anti-inflammatory effects on a variety of cell lines in vitro and reduce the psoriasiform response in a preclinical model of psoriasis in vivo,[15] as well as demonstrate biologic activity in a pilot study in humans.[16]

A Phase 2, randomized, placebo-controlled trial demonstrated efficacy of apremilast 20 mg BID for 12 weeks in 259 patients.[17] Apremilast at 20 mg BID achieved PASI 75 in 24.4% of patients compared to only 10.3% of patients in a placebo group. A doseresponsewas observed with a mean percent reduction in PASI from baseline of 17.4% for placebo, 30.3% for apremilast 20 mg OD, and 52.1% for apremilast 20 mg BID.[17] Papp et al. (2012) reported results from the Phase 2b double-blind, randomized, placebocontrolled crossover trial in 352 patients, which compared apremilast 10 mg, 20 mg, 30 mg or placebo BID for 16 weeks, at which point patients receiving placebo were then randomized to 20 mg or 30 mg BID for up to 24 weeks. The primary endpoint of PASI 75 at 16 weeks was 11% for 10 mg, 29% for 20 mg, and 41% for 30 mg BID vs. 6% of patients on placebo.[18]

Patients treated with apremilast also demonstrated significant improvement on patient-reported quality of life outcomes with particular benefit noted at the 30 mg BID dose.[19] Reported adverse effects were mild to moderate and included headache, nausea, urinary tract infection and diarrhea, but no significant changes in laboratory values were observed in any of the trials.

Phase 3 studies investigating the long-term safety and efficacy of the 30 mg BID dose are currently ongoing. The preliminary findings from ESTEEM-1, a Phase 3 trial including 844 patients receiving oral apremilast 30 mg BID, reported a PASI 75 response of 33% at week 16 compared to the placebo response of 5.3%.[20]

Topical PDE4 Inhibitors

The development of oral PDE4 inhibitors has been limited in some instances by systemic side effects, which prompted development of topical therapeutic options. This led to discovery of a novel boron-containing topical PDE4 inhibitor, AN2728 (Anacor Pharmaceuticals Inc.).[21] Phase 1 and 2 trials on AN2728 have already been completed for psoriasis and Phase 2 trials are ongoing for use in atopic dermatitis. AN2728 was found to be both efficacious and well-tolerated in psoriasis.[22] In a previously reported Phase 2b randomized, double-blind, vehicle-controlled 12-week bilateral comparison study on 145 adults who acted as their own controls, subjects were randomized to 2% or 0.5% ointment vs. vehicle ointment OD or BID. In patients with mild to moderate plaque psoriasis, AN2728 2% ointment BID provided most benefit and was well-tolerated with no safety concerns.[23] Phase 3 trials in psoriasis have received clearance by the FDA, but have not yet been registered as Anacor is currently focusing the development of AN2728 in atopic dermatitis ( accessed October 7, 2013).