Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast

BioDrugs (2015) 29:327–339 DOI 10.1007/s40259-015-0144-3 REVIEW ARTICLE Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast Melinda Gooderham1,3 • Kim Papp2,3 Published online: 19 October 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Phosphodiesterase (PDE) 4 participates in regulating the inflammatory response by degrading cyclic adenosine 30 ,50 -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-c, tumor necrosis factor-a, 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, & Kim Papp 1 Skin Centre for Dermatology, Peterborough, ON, Canada 2 K. Papp Clinical Research, Waterloo, ON, Canada 3 Probity Medical Research, 135 Union Street East, Waterloo, ON N2J 1C4, Canada and there was no requirement for laboratory test monitoring. These results make apremilast an attractive therapeutic option for plaque psoriasis. Key Points Apremilast, a selective phosphodiesterase 4 inhibitor, has been shown to reduce the production of pro-inflammatory cytokines and promote the production of anti-inflammatory cytokines. Apremilast has proven efficacy and safety in the treatment of psoriasis and psoriatic arthritis in phase II and III studies. Apremilast treatment is generally well tolerated and is a promising new treatment for psoriatic disease. 1 Introduction Phosphodiesterase (PDE) 4 is involved in regulating the inflammatory response by degrading cyclic adenosine 30 ,50 monophosphate (cAMP), a key second messenger [1, 2]. Degradation of cAMP to adenosine monophosphate (AMP) reduces protein kinase A activity, leading to production of pro-inflammatory mediators (e.g., tumor necrosis factor [TNF]-a and interleukin [IL]-23) and inhibition of anti-inflammatory cytokines (e.g., IL-10) [1, 2]. Selective expression of PDE4 in cells of the immune system leads to their activation and upregulation in chronic plaque psoriasis and other inflammatory conditions [2]. In 328 addition to its expression in immune cells, PDE4 is also expressed in structural cell types, such as keratinocytes, vascular endothelium, and synovium [2]. Psoriasis is a complex disease, manifested in the skin, joints, and possibly the bowel. Each of these manifestations is expressed through an inflammatory, immune-mediated process [3]. PDE4 inhibitors block the cAMP-degrading action of PDE4 by competitive binding to the cAMP catalytic site, which results in a reduction in T helper (Th) 1, Th2, and Th17 immune responses [4]. As a result of PDE4 inhibition, there is an increase in the intracellular cAMP level, which leads to a reduction in inflammatory mediators and increase in anti-inflammatory mediators [1, 5]. The immune-modulating effects of PDE4 inhibitors have been investigated in a number of inflammatory conditions, such as asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, Behçet’s disease, psoriasis, and psoriatic arthritis (PsA) [1, 2, 4, 6]. Apremilast (CC-10004, OtezlaTM; Celgene Corporation) is a selective PDE4 inhibitor, which has been shown to block the production of the pro-inflammatory cytokines interferon (IFN)-c, TNF-a, IL-12, IL-17, and IL-23—all major players in the pathogenesis of psoriasis. Apremilast was shown, through early-phase trials, to result in (1) a range of anti-inflammatory effects on a variety of cell lines in vitro; (2) a reduction in the psoriasiform response in a preclinical model of psoriasis in vivo; [7] and (3) a reduction of biologic activity in a pilot study in humans [8]. Apremilast binds to the catalytic site of the PDE4 enzyme and blocks degradation of cAMP [9]. Elevating intracellular cAMP, apremilast induces phosphorylation of the protein kinase A substrates cAMP responsive element binding protein (CREB), activates activating transcription factor (ATF)-1, and inhibits the transcriptional activity of nuclear factor (NF)-jB. Activation of ATF-1 and inhibition of NF-kB result in up- and downregulation of several different genes induced via toll-like receptor (TLR) 4 in monocytes and T cells [2, 10]. Apremilast has been evaluated in the treatment of psoriasis and PsA. The efficacy and safety of apremilast in the treatment of psoriasis have been demonstrated in phase II [11–14] and phase III clinical trials (ESTEEM [Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis] 1 and 2 [15, 16] and LIBERATE [Evaluation in a Placebo-Controlled Study of Oral Apremilast and Etanercept in Plaque Psoriasis]) [17]. In addition to psoriasis, the efficacy and safety of apremilast were also evaluated in the phase III PALACE (Psoriatic Arthritis Long-Term Assessment of Clinical Efficacy) clinical trial program in patients with PsA, which is discussed briefly in this review [18–22]. M. Gooderham, K. Papp 2 Apremilast in Plaque Psoriasis: Phase II Trials The efficacy of apremilast has been evaluated in phase II, double-blind, randomized, placebo-controlled clinical trials [11–14]. In a 12-week trial (n = 259), the Psoriasis Area and Severity Index (PASI) was reduced by 75 % (PASI-75) in 24.4 % of patients treated with apremilast 20 mg twice daily (BID) versus 10.3 % of patients treated with placebo. A dose–response relationship was observed, with mean percentage PASI reductions from baseline of 52.1 % with apremilast 20 mg BID, 30.3 % with apremilast 20 mg once daily (OD), and 17.4 % with placebo [11]. In a phase IIb crossover trial (n = 352), Papp et al. [12] compared apremilast 10 mg BID, apremilast 20 mg BID, apremilast 30 mg BID, and placebo BID for 16 weeks. After 16 weeks, patients randomized to receive placebo were assigned to receive apremilast 20 mg BID or 30 mg BID up to 24 weeks. At 16 weeks, the prim (...truncated)