Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast

Abstract

Phosphodiesterase (PDE) 4 participates in regulating the inflammatory response by degrading cyclic adenosine 3'5'-monophosphate (cAMP), a key second messenger. Inhibition of PDE4 increases the intracellular cAMP level, which in turn results in a reduction in inflammatory mediators and an increase in anti-inflammatory mediators. Immune-modulating effects of PDE4 inhibitors have been investigated in a number of inflammatory conditions, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, Behçet’s disease, psoriasis, and psoriatic arthritis. Apremilast, a selective PDE4 inhibitor, has been shown to block the production of pro-inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin [IL]-12, IL-17, and IL-23), which are the key players in the pathogenesis of psoriasis. Increased intracellular cAMP levels result in a range of anti-inflammatory effects on numerous cell lines. A decrease in proinflammatory activity has been shown to result in a reduced psoriasiform response in preclinical in vivo models of psoriasis, and reduction of biologic activity in a pilot study in humans. The efficacy and safety of apremilast in the treatment of psoriasis have been demonstrated in phase II and III clinical trials. Apremilast demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis. Treatment with apremilast was well tolerated, with generally mild gastrointestinal complaints, which occurred early in the course of the treatment and resolved over time, and there was no requirement for laboratory test monitoring. These results make apremilast an attractive therapeutic option for plaque psoriasis.

Figures

Fig. 1

ESTEEM [Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis] 1 and 2 study design [15, 16]. aDoses of apremilast were titrated during the first week of administration. bA responder was defined as a patient achieving a ≥75 % reduction from their baseline Psoriasis Area and Severity Index (PASI) score (≥PASI-75) in ESTEEM 1 or ≥PASI-50 in ESTEEM 2 at week 32. cIn ESTEEM 1, patients were switched to apremilast at the time of loss of PASI-75, but no later than week 52. In ESTEEM 2, patients were switched to apremilast at the time of loss of effect (defined as the time of loss of 50 % of the PASI improvement obtained at week 32 compared with baseline) but no later than week 52. dAt week 32, patients had the option of adding topical therapy and/or ultraviolet B (UVB) phototherapy (T/P). The decision could made only at week 32 but did not need to be initiated at that visit. 30 apremilast 30 mg BID, BID twice daily, P placebo

Fig. 2

ESTEEM [Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis] 1 and 2: patients achieving a 75 % reduction from their baseline Psoriasis Area and Severity Index score (PASI-75; the primary end point), PASI-50, and Static Physician’s Global Assessment (sPGA) response (a score of clear [0] or almost clear [1] with at least a 2‐point reduction from baseline) with apremilast 30 mg twice daily (BID) versus placebo at week 16 [15, 16]. Full analysis set, last observation carried forward: n = 844 in ESTEEM 1 and n = 411 in ESTEEM 2

Fig. 3

LIBERATE [Evaluation in a Placebo-Controlled Study of Oral Apremilast and Etanercept in Plaque Psoriasis] study design [17]. *Starting at week 32, all non-responders (patients achieving a †Patients were stratified according to their calculated body mass index (BMI) categories at screening (BMI ≥30 kg/m2 or BMI 30 kg/m2). LOCF last observation carried forward, BID twice daily, QW once weekly

Fig. 4

LIBERATE [Evaluation in a Placebo-Controlled Study of Oral Apremilast and Etanercept in Plaque Psoriasis]: percentages of patients achieving a 75 % reduction from their baseline Psoriasis Area and Severity Index score (PASI-75) response at weeks 16 and 32 [17]. Modified intent-to-treat population, last observation carried forward. BID twice daily, QW once weekly

Fig. 5

LIBERATE [Evaluation in a Placebo-Controlled Study of Oral Apremilast and Etanercept in Plaque Psoriasis]: percentages of patients with a Static Physician’s Global Assessment (sPGA) score ≥3 (moderate to very severe) at baseline who achieved a score of 0–1 at weeks 16 and 32 [17]. Modified intent-to-treat population, last observation carried forward. BID twice daily, QW once weekly