Apremilast for the treatment of psoriatic arthritis.

Drug Profile

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Apremilast for the treatment of psoriatic arthritis Expert Rev. Clin. Pharmacol. 7(3), 239–250 (2014)

Sowmya Varada‡, Suzanne J Tintle*‡ and Alice B Gottlieb Department of Dermatology, Tufts Medical Center, 800 Washington Street, Box #114, Boston, MA 02111, USA *Author for correspondence: [email protected] ‡

Authors contributed equally

Psoriatic arthritis occurs in about one-third of patients with psoriasis, and is a severely disabling, progressive inflammatory spondyloarthropathy typically treated with non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, TNF-a inhibitors and ustekinumab. These medications moderately improve the arthritis, dactylitis, and enthesitis that characterize psoriatic arthritis, however, they are associated with serious long-term adverse effects, issues with safety and tolerability, and high cost. Moreover, many patients do not respond or have resistant or recurrent manifestations to these agents. Apremilast is an orally available phosphodiesterase type 4 inhibitor that may block the pathogenic inflammatory Th17 and Th1 pathways upstream of current biologics, which target extracellular molecules of the immunological response. KEYWORDS: apremilast • biologic • phosphodiesterase inhibitor • psoriasis • psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic, immunemediated, seronegative inflammatory arthropathy that affects about 11% of patients with all types of psoriasis, although rates of up to 30% have been reported, differences attributable to disparate diagnostic criteria and study populations [1]. PsA is characterized by progressive damage to peripheral, axial and entheseal structures, associated with disability and reduced life expectancy [2–4]. Quality of life is significantly impaired in patients with PsA [5]. In addition to symptoms due to cutaneous psoriatic disease (intractable pruritus, physical irritation), patients with PsA have severe, debilitating pain and soreness that affect essential, basic tasks, such as using one’s hands and walking. Studies have found that patients with psoriasis and with PsA have an increased incidence of anxiety, depression and poor self-image [6]. Assessment of PsA has historically been based upon criteria used for rheumatoid arthritis (RA), although criteria specific for PsA are being developed [4]. The measures used in most studies are ACR20 (20% improvement in American College of Rheumatology [ACR] criteria), health assessment questionnairedisability index (HAQ-DI) and disease activity score in 28 joints. Apart from symptomatic control with nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs informahealthcare.com

10.1586/17512433.2014.904200

(DMARDs), therapy of moderate-to-severe PsA has been enhanced by biologics targeting the key proinflammatory cytokines that induce maturation of the Th1 and Th17 subsets; current biologics inhibit IL-12, IL-23, IL-17, IL-22 and TNF-a [7–9]. Additional research and drug development has focused on disrupting production of these cytokines and other proinflammatory molecules before they trigger tissue-specific damage by inhibiting intracellular molecules controlling gene expression, for example, by inhibiting the JAK and phosphodiesterases (PDE). Systemic therapies for PsA can be compromised by loss of efficacy over time, adverse events (AEs), safety and tolerability issues and subcutaneous or intravenous administration [10]. Apremilast, a novel, orally available inhibitor of PDE type 4 (PDE4), may represent an effective, well-tolerated, safe and easilyadministered alternative in the treatment of this progressively disabling disease. Current therapies for PsA

The chronic and progressive nature of PsA requires long-term treatment, and destructive joint disease warrants aggressive management [11]. Therapy of PsA often begins with NSAIDs, intra-articular corticosteroid injections and/or DMARDs, such as methotrexate or cyclosporine. Patients with moderate-tosevere disease, contraindication or failure of

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Drug Profile

Varada, Tintle & Gottlieb


Table 1. Currently available biological agents for psoriatic arthritis. Recommended dose

Mechanism of action

Efficacy

Adverse effects

Ref.

Etanercept

PsA: 25 mg sc. twice weekly Ps: 50 mg sc. twice weekly for 3 months; 50 mg once weekly thereafter

Fusion protein (TNF-a receptor bound to Fc portion of IgG) that binds TNF-a

PASI-75 achieved in 49% of Ps and 26% of PsA patients† ACR20 achieved in 59% of PsA patients†

Pruritus Headache Increased risk of infection Injection-site reaction

[4,32]

Adalimumab

PsA: 40 mg sc. every 2 weeks Ps: 80 mg sc. at week 0; 40 mg sc. every 2 weeks thereafter

Recombinant human IgG1 monoclonal antibody that binds TNF-a

PASI-75 achieved in 71% of Ps and 59% of PsA patients† ACR20 achieved in 58%†

Increased risk of infection

Infliximab

PsA: 5 mg/kg iv. at weeks 0, 2 and 6, and every 8 weeks thereafter Ps: same as above

Chimeric (mouse-human) monoclonal antibody that binds TNF-a


Lupus-like symptoms Infusion reactions

Golimumab

PsA: 50 mg sc. every 4 weeks

Human monoclonal antibody that binds TNF-a


Headache Nasopharyngitis

Certolizumab pegol

Ps: 200 mg every 2 weeks

Human monoclonal antibody that binds TNF-a

ACR20 achieved in 58.0%

Headache Nasopharyngitis

[94]

Ustekinumab

Ps: 45 or 90 mg sc. every 12 weeks

Monoclonal antibody that binds and inhibits IL-12 and IL-23

PASI-75 achieved in 67%† ACR20 achieved in 42%†

Increased risk of infection

[32,33]

† US FDA-approved dose. ACR20: At least a 20% improvement in American College of Rheumatology criteria; iv.: Intravenously; PASI-75: Improvement of at least 75% in psoriasis and area severity index; Ps: Psoriasis; PsA: Psoriatic arthritis; sc.: Subcutaneously; URI: Upper respiratory infections.

adequate response to these agents are often placed on a biologic, most commonly, a TNF-a inhibitor or ustekinumab (Stelara). NSAIDs are commonly employed for PsA and alleviate tender and swollen joint counts and pain scores in peripheral and axial disease [12]. Controlled studies on NSAIDs in psoriasis and PsA showed that NSAIDs do not affect erythrocyte sedimentation rates, do not have disease-modifying effects and do not improve cutaneous psoriatic disease [12]. While there are anecdotal reports of worsening of psoriasis upon initiation of both non-specific and COX-2 specific NSAIDs, larger, controlled trials have found psoriasis flare with NSAID therapy is uncommon [13]. Selective COX-2 inhibitors are not proven to be more efficacious than non-selective NSAIDs [12]. Periodic intra-articular corticosteroid injections are of utility in managing patients with dactylitis or oligoarticular peripheral arthritis, though their use becomes less practical when many joints are involved. Like NSAIDs, intra-articular corticosteroids provide symptomatic relief but fail to inhibit progression of structural joint damage. The use of systemic corticosteroids is discouraged due to the risk of inducing flares of psoriasis, particularly pustular psoriasis, upon withdrawal [14]. DMARDs, such as methotrexate, leflunomide, sulfasalazine and cyclosporine, are employed for moderate-to-severe PsA or mild PsA refractory to NSAIDs and corticosteroid injections [15]. 240

These broad immunosuppressive drugs are labeled as ‘diseasemodifying’ for their ability to halt joint destruction in patients with RA, but specific evidence of their efficacy in PsA has not been clearly demonstrated in clinical trials [14]. Moreover, none of the DMARDs has been shown to significantly influence dactylitis, enthesitis or axial joint disease. Although DMARDs are orally available and relatively inexpensive, these drugs are associated with serious organ toxicities and adverse effects (e.g., hepatic toxicity with methotrexate and nephrotoxicity with cyclosporine), prohibiting their use in patients with certain comorbidities, preventing their safe longterm use in otherwise healthy patients, and requiring frequent clinical (including laboratory) monitoring. The TNF-a inhibitors revolutionized treatment of moderate-to-severe psoriasis and PsA. Five are currently US FDAapproved in the USA: etanercept, adalimumab, infliximab, golimumab and certolizumab (TABLE 1). TNF-a is released by both the Th1 and Th17 inflammatory pathways and plays a crucial role in mediating joint damage and other pathology seen in psoriasis and PsA. Indeed, the presence of elevated levels of TNF-a in the synovium and synovial fluid of patients with PsA has been known for more than 15 years [16]. In addition to their efficacy in RA and other immune-mediated arthritides, anti-TNF-a agents have demonstrated considerable success in clinical trials for PsA. ACR20 was achieved by 51–59% of Expert Rev. Clin. Pharmacol. 7(3), (2014)


Apremilast for the treatment of PsA

patients on adalimumab, etanercept, golimumab or infliximab [17], average rates that are higher than those seen with DMARDs (36% of patients on leflunomide and 41% of patients on methotrexate have been reported to achieve ACR20) [18–20]. Addition of a DMARD such as methotrexate to biologic treatment is often superior to TNF-a inhibitor monotherapy [21,22]. Induction or exacerbation of cutaneous psoriasis is well documented, although uncommon in patients receiving TNF-a inhibitors for most immune-mediated inflammatory disorders for which they are approved for treatment. A 2009 literature review reported that approximately 0.6–5.3% of patients treated with TNF-a blockers develop worsened or de novo psoriasis [23]. Cases of PsA flares with TNF-a blockers were not found in our review of the English medical literature, although cases of cutaneous psoriatic flare in patients with PsA treated with TNF-a inhibitors have been reported [24,25]. Ustekinumab is approved for use in chronic moderate-tosevere plaque psoriasis and PsA (TABLE 1). It is a fully human monoclonal antibody that binds the common p40 subunit of IL-12 and IL-23, which are increased in synovial fluid of patients with PsA [26]. Single nucleotide polymorphisms in the IL-23 receptor and IL-12b genes have been found to increase susceptibility to psoriasis as well as PsA [27]. Further, inhibition of IL-12 dramatically attenuates the clinical and histopathological severity of collagen-induced arthritis in mice, with correspondent reductions of synovial tissue levels of TNF-a and (IFN-g) [28]. IL-23, a potent promoter of the Th17 pathway and IL-17 production, was recently shown to enhance osteoclastogenesis and bone resorption in the mouse model of collagen-induced arthritis [29,30]. Ustekinumab prevents these cytokines from binding the IL-12Rb1 receptor on antigenpresenting cells and naı¨ve T cells, and inducing their differentiation into Th1 and Th17 cells [31]. Ustekinumab is the first biologic to achieve 75% improvement in the psoriasis area and severity index (PASI-75) response rates in chronic plaque psoriasis comparable with those of TNF-a inhibitors. In a comparison of these agents, alefacept and ustekinumab in patients with psoriasis for 12 weeks at FDA-approved levels, ustekinumab ranked third, with 66.9% of patients reaching behind infliximab (78.6%) and adalimumab (70.5%) and ahead of etanercept (48.1%) and alefacept (21.0%) reaching PASI-75 [32]. However, in this comparison, trials for the TNF-a inhibitors included greater proportions of patients on concomitant methotrexate and/or NSAIDs than did trials of ustekinumab [33]. The impressive efficacy of ustekinumab in plaque psoriasis led to its study in PsA. With encouraging results of initial studies, described below, ustekinumab was approved for PsA treatment by the FDA in 2013. The recently completed Phase III PSUMMIT trials randomized patients with PsA (‡5 tender and ‡5 swollen joints; Creactive protein [CRP] ‡3.0 mg/l) to subcutaneous ustekinumab 45 mg, 90 mg or placebo at weeks 0, 4 and 12, respectively. In PSUMMIT-1, which included 615 PsA patients naı¨ve to biologics, 49.5 and 42.4% of patients receiving ustekinumab 90 and 45 mg, respectively, achieved a 20% or greater informahealthcare.com

Drug Profile

improvement in ACR20 criteria at week 24 versus 22.8% of those receiving placebo (p < 0.0001 for both comparisons) [34]. Of note, these response rates were maintained at week 52. Patients receiving ustekinumab had significantly greater improvement in Dermatology Life Quality Index (DLQI) compared with placebo (p < 0.0001) [34]. Of note, ustekinumab use in PsA has led to improvements in dactylitis and enthesitis, an effect which has otherwise been shown only with the TNF-a inhibitors [33,35]. PSUMMIT-2 studied 312 patients with PsA who had previously received anti-TNF-a inhibitors, and found similar results: 43.8 and 43.7%, respectively, of patients receiving ustekinumab 90 and 45 mg reached an ACR20 response, compared with only 20.2% of those receiving placebo [15]. AEs with ustekinumab were consistent with those in the placebo-treated groups, the most common being nasopharyngitis, upper respiratory infection (URI) and headache. In both PSUMMIT-1 and PSUMMIT-2, no cases of tuberculosis, opportunistic infection or death occurred. In combined data from PSUMMIT-1 and PSUMMIT-2, there were three cases of major adverse cardiovascular events (MACEs) and one case of squamous cell carcinoma in situ in ustekinumab-treated patients. Flares of PsA and previously unknown or subclinical joint disease have been observed with ustekinumab treatment, although neither was reported in Phase II or Phase III trials. Stamell et al. reported two patients with psoriasis who received ustekinumab monotherapy in whom disabling flares of PsA were observed, which returned to baseline following discontinuation of ustekinumab and treatment with TNF-a blockers [36]. Stevenson and Markowitz reported a similar experience with three patients with psoriasis and PsA who experienced flares of PsA after switching to ustekinumab treatment from TNFblockers [37]. These reports of flares and lack of efficacy present the possibility that ustekinumab, at doses recommended for plaque psoriasis, may not be sufficient to control joint disease in patients with PsA. It is also plausible that IL-12/23p40 plays a lesser role in the pathogenesis of joint disease as compared with cutaneous psoriasis lesions, and its blockade may predispose patients to flare of joint disease and even unmasking of previously unknown joint disease. In addition to risks of infection and malignancy, there has been particular concern regarding cardiovascular risks associated with anti-IL-12/23 agents, leading to the withdrawal of briakinumab from the market [38]. Patients with psoriasis have an elevated cardiovascular risk independent of traditional risk factors and it is unclear if IL-12/23 agents are associated with additional risk; an underlying mechanism for added cardiovascular risk is unknown [38–40]. Two meta-analyses seeking to evaluate the risk of MACEs with IL-12/23 agents found disparate results, albeit using different statistical methods: Ryan et al. found no statistically significant increased risk of MACEs with the use of anti-IL-12/23 agents (Mantel-Haenszel risk difference of 0.012 events/person-year) (95% CI: -0.001 to 0.026; p = 0.12), while Tzellos et al. found a statistically significant increased odds ratio of 4.23 (95% CI: 1.07–16.75; p = 0.04) 241

Drug Profile



Table 2. Biological agents in development for potential use in psoriatic arthritis. Route of administration

Mechanism of action

Efficacy

Adverse effects

Stage of development

Ref.

Brodalumab

sc.

Humanized antiIL-17-receptor monoclonal antibody

Baseline PASI improvement in 45.0, 85.9, 86.3, 76.0 and 16% (70, 140 or 210 mg every 2 weeks, 280 mg every 4 weeks, placebo) ACR20: not available

Nasopharyngitis URI Injection-site erythema Neutropenia

Phase III

[47]

Ixekizumab

sc.

Human antiIL-17 monoclonal antibody

PASI-75 in 76.7, 82.8, 82.1 and 7.7% (25 mg, 75 mg, 150 mg, placebo) ACR20: not available

Nasopharyngitis URI Injection-site reaction Headache

Phase III

[48]

Secukinumab

sc.

Human antiIL-17 monoclonal antibody

PASI-75 in 82, 52 and 9% (450 mg, 225 mg, placebo) ACR20 in 29 and 23% (secukinumab, placebo)

Nasopharyngitis URI Headache

Phase III

[21,95]

Tildrakizumab

sc.

Monoclonal antibody that binds the p19 subunit of IL-23

PASI-75 in 33, 64, 66, 74 and 4% (5 mg, 25 mg, 100 mg, 200 mg, placebo) ACR20: not available

None published

Phase II completed

Abatacept

iv.

Fusion protein (CTLA-4 and IgG1) that binds CD80+ and CD86+ T cells, inhibiting their activation

ACR20 in 48%† (19% placebo)

Dizziness Headache Hypertension Increased risk of infections

Phase II completed

Tofacitinib

Oral

Inhibits JAK

PASI-75 in 25, 40.8, 66.7 and 2% (2 mg, 5 mg, 15 mg, placebo) ACR20: not available

URI Nasopharyngitis Headache

Phase III

[49]

[58]

† US FDA-approved dose. ACR20: At least a 20% improvement in American College of Rheumatology criteria; CTLA-4: Cytotoxic T-lymphocyte antigen-4; iv.: Intravenously; PASI-75: Improvement of at least 75% in psoriasis and area severity index; Ps: Psoriasis; PsA: Psoriatic arthritis; sc.: Subcutaneously; URI: Upper respiratory infections.

with the use of ustekinumab, although this included a very wide CI [41,42]. Importantly, a recently published large postmarketing study of ustekinumab used for up to 5 years in patients with psoriasis did not find an increased risk of MACEs with ustekinumab [43]. Unmet needs of currently available therapies

Current biologics are the only proven medications to impede joint destruction in PsA [14]. However, the expense and inconvenience of biologics are major drawbacks, and many patients with PsA do not respond to typical therapies, including biologics, or do not maintain a clinical response with available medications [31]. The progressive debilitating nature of joint disease as well as the high proportion of PsA patients with polyarthritis [44] highlights the need for an affordable, disease-modifying treatment with long-term, sustained efficacy. Therapies in development for PsA

Several experimental biologics have shown encouraging results in initial studies of PsA, including ustekinumab, IL-17 inhibitors 242

(secukinumab, ixekizumab and brodalumab), IL-23p19 inhibitors, JAK inhibitors and abatacept (TABLE 2). Long-term efficacy and safety information is not yet available for these agents. Anti-IL-17 agents

IL-17 is a proinflammatory cytokine secreted by Th17 lymphocytes that trigger pathogenesis of psoriasis and PsA. Recent evidence of upregulation of IL-17 receptors in the synovial tissue of PsA, and IL-17 expression is higher in synovial fluid of patients with PsA compared with patients with osteoarthritis [9,45]. Three anti-IL-17 agents are currently under Phase III investigation: ixekizumab, secukinumab and brodalumab (TABLE 2) [46]. Secukinumab (Novartis AG, Basel, Switzerland), a fully human, high-affinity anti-IL-17A antibody, has been evaluated extensively for psoriasis and is the only anti-IL-17 agent currently being studied for PsA. In a Phase II proof-of-concept study, 42 patients with PsA were randomized to intravenous secukinumab 10 mg/kg or placebo on days 1 and 22. Improvements were seen at higher rates in the secukinumab group and were Expert Rev. Clin. Pharmacol. 7(3), (2014)



maintained throughout week 24, but the study was not powered to reach statistical significance. At weeks 6, 12 and 24, ACR20 was achieved by 39, 39 and 43% of those receiving secukinumab compared with 23% (p = 0.27), 15% (p = 0.13) and 18% (p = 0.14) of those receiving placebo [21]. Significant reductions in CRP (p = 0.039) and erythrocyte sedimentation rate (p = 0.038) were observed at week 6 in the secukinumab treatment group versus placebo. The secukinumab group scored significantly higher than placebo in percent change from baseline of HAQ-DI at all weeks. The most common AEs were nasopharyngitis, headache, nausea and dizziness; AEs were distributed equally in both treatment arms. Six serious AEs were reported in the secukinumab group and one in the placebo group, although none was determined to be a consequence of the study treatment. Phase III trials of secukinumab in PsA have begun. Brodalumab (Amgen, Thousand Oaks, CA, USA) is a monoclonal antibody that binds and blocks the IL-17A receptor, thus inhibiting multiple cytokines: IL-17A, IL-17F, IL-17A/F and IL-25. Brodalumab recently completed a Phase II trial for psoriasis and has not yet been studied in PsA. In 198 patients with chronic moderate-to-severe psoriasis randomized to placebo, 70, 140 or 210 mg brodalumab every 2 weeks or brodalumab 280 mg once every 4 weeks, 16.0, 45.0, 85.9, 86.3, and 76.0%, respectively, achieved improvement of baseline PASI [47]. AEs included nasopharyngitis, URI, injection-site erythema and two cases of neutropenia. Long-term efficacy and safety of brodalumab is currently being investigated in Phase III trials, including a comparator study with ustekinumab. Ixekizumab (Eli Lilly, Indianapolis, IN, USA) is a fully human IgG4 monoclonal antibody to IL-17A that has shown promising efficacy in chronic moderate-to-severe plaque psoriasis. In a double-blinded, multicenter, randomized Phase II study, 142 patients were randomized to placebo, 10, 25, 75 or 150 mg ixekizumab every 4 weeks. At 12 weeks, the percentage of patients who achieved PASI-75 was significantly greater with ixekizumab (150 mg [82.1%], 75 mg [82.8%] and 25 mg [76.7%]) than with placebo (7.7%; p < 0.001 for each comparison) [48]. Among patients with PsA, significant reductions in joint pain from baseline as assessed by the joint-pain visual analog scale (VAS) were observed in the 150 mg ixekizumab treatment group, a response that was sustained through week 20 [48]. DLQI scores improved significantly in the ixekizumab 150, 75 and 25 mg groups compared with placebo at 8 weeks, with many of these patients achieving a DLQI score of 0 by 16 weeks. The most frequently reported AEs were nasopharyngitis, URI, injection-site reaction and headache; no serious AEs were reported. Phase III trials of ixekizumab in plaque psoriasis are underway, including a comparator study of the drug with etanercept. Anti-IL-23 p19 agents

Tildrakizumab (MK-3222) (Merck, Whitehouse Station, NJ, USA), guselkumab (CNTO1959) (Janssen, Inc., Beerse, Belgium) and BI 655066 (Boehringer Ingelheim Pharmaceuticals, Germany) are three investigational monoclonal antibodies administered subcutaneously that bind to the p19 subunit of informahealthcare.com

Drug Profile

IL-23 (TABLE 2). In a Phase II randomized controlled trial, 339 patients with moderate-to-severe chronic plaque psoriasis were given varying doses of tildrakizumab (MK-3222) (5, 25, 100 and 200 mg) [49]. A dose–response effect was observed; doses of 5, 25, 100 and 200 mg MK-3222 and placebo led to PASI-75 response in 33, 64, 66, 74 and 4% of patients, respectively. Incidence of AEs was uniform across treatment groups. Four serious AEs were reported, including a case of septic arthritis possibly related to the treatment [49]. Two Phase III trials on tildrakizumab 100 and 200 mg in moderate-to-severe plaque psoriasis are ongoing at the time of this publication [49]. Guselkumab, a fully human IL-23p19 antibody, has just completed Phase I studies in patients with psoriasis (with and without PsA), palmoplantar psoriasis and RA [50]; and BI 655066 is still undergoing Phase I investigation [51]. Anti-IL-22 agents

IL-22, a member of the IL-10 cytokine superfamily, is a cytokine secreted by Th17, Th22 and natural killer cells. IL-22, with IL-20, is directly responsible for the final pathological alterations of keratinocytes that occur in psoriasis [52]. It acts primarily by activating the STAT3 transcription factor, upregulating expression of several proinflammatory proteins, thereby leading to inhibited keratinocyte differentiation with resultant epidermal hyperplasia and acanthosis [53,52]. In psoriasis, serum IL-22 levels have been found to correlate with disease severity [52], and the cytokine has been linked to the pathophysiology of several other autoimmune inflammatory diseases as well, including atopic dermatitis, inflammatory bowel disease and RA [54,55]. Fezakinumab (ILV-094, Pfizer Inc., NY, USA) is the first monoclonal antibody that targets IL-22. It has completed several Phase I trials both in healthy subjects and those with psoriasis. Phase II investigation has been completed in RA and is underway in atopic dermatitis and psoriasis, with unpublished results. JAK inhibitors

The aforementioned biologics will present many of the same practical drawbacks as do TNF-a inhibitors, including costliness, subcutaneous delivery and frequent safety analyses. Consequently, there is growing interest in the orally available JAK inhibitors. JAK is a tyrosine kinase that, through the JAK-STAT signaling pathway, triggers production of several proinflammatory molecules (IFN-g, ILs and growth factors) that induce expression of IL-2, IL-6, IL-7, IL-9, IL-15 and IL-21 [56]. Tofacitinib (CP-690,550, Pfizer Inc.) is a JAK-inhibitor selective for enzymes JAK1 and JAK3 available as an oral medication and as a topical ointment, which has been well tolerated and have shown moderate efficacy in chronic plaque psoriasis [57,58]. Oral tofacitinib is approved by the FDA for treatment of RA and is being assessed for PsA. In a Phase IIb study, patients with moderate-to-severe chronic plaque psoriasis randomized to tofacitinib 2, 5 and 15 mg, and placebo achieved PASI-75 at rates of 25, 40.8, 66.7 and 2%, respectively [58]. The most common AEs were defined as mild by investigators and included URI, nasopharyngitis and headache. Phase III 243

Drug Profile


O O N

O O S


NH

O

O

O

Figure 1. Chemical structure of (S)-N-(2-[1-(3-ethoxy4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo2,3-dihydro-1H-isoindol-4-yl)acetamide.

studies in PsA, including one in patients who have inadequately responded to TNF-blockers [59] and a comparator study with adalimumab, are underway [60]. Baricitinib (Eli Lilly) is a similar drug that inhibits JAK1 and JAK2, and ASP015K inhibits JAK3 inhibitor; both are being studied in Phase II trials [61]. Although safety data on tofacitinib and the other JAK inhibitors in psoriasis have not been published, there is concern these medications will be too broadly immunosuppressive, and little is known about their long-term safety. Tofacitinib has failed to achieve approval in Europe due to concerns over AEs, including an increase in serious infection rates compared with controls, particularly herpes zoster infections, cases of tuberculosis and non-tuberculosis opportunistic infections, lymphocytopenia and anemia [62,63]. Moreover, the cost of tofacitinib is comparable with that of injectable biologics: In the USA, the annual cost is currently about US$25,000 [62]. Introduction to apremilast

Biologics target extracellular receptors or proteins, and so are dependent upon specific cell types, cell-to-cell interactions and immune signaling. Thus, there is much interest in developing PsA therapies to target intracellular signaling pathways that control gene expression specific to disease pathology and do not depend on variable, complex antigen receptor-specific immunoregulatory mechanisms. cAMP is a ubiquitous second messenger key in regulation of gene expression. The concentration of intracellular cAMP is modulated through its activation by adenylylcyclases and inactivation by PDEs. PDEs represent the major enzyme group responsible for hydrolysis of cAMP and control of production or inhibition of several both pro- and anti-inflammatory mediators. Within the PDE superfamily of 11 tissue-specific isoenzymes, PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells [64]. Cells controlled by PDE4 include dendritic cells, T cells, macrophages and monocytes, as well as keratinocytes, synoviocytes and chondrocytes, thus PDE4 control is particularly relevant in psoriasis and PsA [65]. PDE4 inhibition leads to accumulation of intracellular cAMP and downstream modulation of gene transcription of many proinflammatory cytokines, notably TNF-a. 244

The high expression of PDE4 in inflammatory cells makes it a desirable target in several chronic inflammatory and autoimmune conditions, although the first PDE4 inhibitors developed showed limited and inconsistent efficacy and a high incidence of side effects, slowing their clinical use. The prototypic selective PDE4 inhibitor, rolipram, had potent anti-inflammatory effects in vitro, but clinical trials found unacceptably high rates of nausea and vomiting, associated with the drug [66,67]. Only one PDE4 inhibitor, roflumilast (Daliresp) has had a sufficient efficacy and tolerability ratio to reach the market. Roflumilast is FDA-approved for prevention of chronic obstructive pulmonary disease exacerbations [68]. The most common side effects are nausea, weight loss, decreased appetite, insomnia, diarrhea, headache and psychiatric complaints [68]. Apremilast (Celgene, Summit, NJ, USA) is a novel, orally available small molecule inhibitor of PDE4, and has been shown to decrease production of several proinflammatory mediators critical in psoriatic pathology: TNF-a, IFN-g, IL-12p70, IL-23A, CXCL9 and CXCL10 [69,70]. An oral medication, apremilast does not present the attendant inconvenience of currently available biologics, which all require subcutaneous or intravenous administration. Its expression within cell types such as keratinocytes, synoviocytes and chondrocytes allows its direct influence on target tissues in PsA. Chemistry

Apremilast is derived from 3-(1,3-dioxo-1,3-dihydroisoindol2-yl)-3-(3,4-dimethoxyphenyl)propionic acid derivatives (FIGURE 1) [71,70]. The active compound of apremilast, (S)-N-(2-[1-(3-ethoxy4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3dihydro-1H-isoindol-4-yl)acetamide (FIGURE 1), is approximately 90% protein-bound [70]. Enzymatic activity assays of apremilast in lysates from U937 human cells indicated competitive binding with an IC50 of 74 nm and an affinity constant (Ki) of 68 nm, with its inhibition fully reversible by dilution [69]. There is no marked selectivity of apremilast among the activity of the individual PDE4 isoenzymes, PDE4A–D and apremilast does not show any significant inhibition of the other PDE families other than PDE4 [69]. Pharmacodynamics

Neutrophils, T lymphocytes, monocytes, macrophages and eosinophils, all rely on PDE4 activation for gene transcription of several proinflammatory molecules [72–74]. Early studies of apremilast showed significant TNF-a inhibitory activity via increased NF-kB signaling in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells and human whole blood [71]. Apremilast was later found to inhibit TNF-a production by natural killer cells, keratinocytes, synoviocytes and chondrocytes [69]. In vitro, apremilast inhibits several additional critical chemokines and cytokines implicated in the pathogenesis of psoriasis and PsA: IFN-g, IL-2, IL-12 and IL-23, the chemokines CXCL9 and CXCL10, macrophage inflammatory protein-1a and granulocyte macrophage-colony stimulating factor [69]. Expert Rev. Clin. Pharmacol. 7(3), (2014)



Apremilast’s effects are not limited to control proinflammatory mediators alone: the drug also enhances production of proregulatory cytokines IL-10 and IL-6 [69]. Although a mouse model of PsA combining cutaneous psoriatic lesions and spondyloarthropathy has not yet been described, apremilast has been studied in animal models of psoriasis and collagen-induced arthritis. In animal models of psoriasis, results of apremilast use were encouraging; the drug demonstrated significant anti-inflammatory activity of apremilast with inhibition of systemic TNF-a production, neutrophilic infiltration of lesions and arthrogenic edema [75]. In vivo clinically relevant, downstream effects of apremilast on the characteristic histopathology found in psoriasis and PsA have also been shown, with significantly reduced acanthosis and epidermal hyperproliferation; in an open-label study of 30 patients with recalcitrant plaque psoriasis who received apremilast 30 mg twice daily had a 34% median reduction in epidermal thickness at week 12 (p = 0.083) [76]. Ten of 20 patients with evaluable skin biopsies demonstrated decreased keratin 16 [76]. This open-label study also found significantly reduced markers of inflammatory cell infiltration in lesional psoriasis, with reduction of epidermal and dermal CD11c+ cells (myeloid dendritic cells) and dermal CD3+ cells [76]. Of note, mRNA expression of key pathological cytokines IL-22, IL-12/ IL-23p40, IL-23p19, IL-8 and IL-17A were also significantly decreased in lesional skin biopsies after 12 weeks of apremilast treatment (p < 0.05) [76]. Reductions of IL-17A and keratin 16 significantly correlated with reductions in PASI [76]. Evidence of improvements in inflammatory arthritis has also recently been shown, although clinical evaluation of radiographic progression with PsA has not been studied. A 2013 study of apremilast 30 mg in patients with ankylosing spondylitis, which shares genetic and clinical similarities with PsA [17], found significant decreases in serum levels of osteoporosis biomarkers, including RANKL and sclerostin, which are associated with bone erosion and decreased bone mineral density [77,78]. Pharmacokinetics & metabolism

In an open-label pilot study, 19 patients with severe plaque psoriasis received apremilast 20 mg orally for 29 days. Steadystate exposure of apremilast on day 29 showed a maximum concentration of 207.07 ng/ml (450 nM) and area under the curve of 24 h (AUC24) of 1799 ng•h/ml [79]. At this dose, apremilast inhibited approximately 70% of TNF-a production by LPS-stimulated peripheral blood mononuclear cells in vitro [10]. In the pilot study in which six patients with psoriasis had pharmacodynamic data was available, there was no correlation between percent inhibition of LPS-stimulated TNF-a production and apremilast exposure. Thus, in comparison with the TNF-a inhibitors, apremilast causes an incomplete, lesser degree, of TNF-a inhibition, but also suppresses multiple other proinflammatory mediators implicated in the pathogenesis of psoriasis and PsA, as discussed above. informahealthcare.com

Drug Profile

In humans, studies have revealed that oral apremilast has a half-life of approximately 8.2 h and reaches a maximum plasma concentration at a median of 2 h [10,79]. Oral apremilast’s mean apparent volume of distribution (CL/F) is 128 l [79,80]. Apremilast is extensively metabolized, primarily through hydrolysis of the imide bond, demethylation and conjugation with glucuronic acid [10,69]. In the human liver, metabolism primarily occurs through catalysis via cytochrome 3A4, although clearance of apremilast occurs extensively via multiple routes, including non-cytochrome-mediated hydrolytic metabolism. Apremilast-related material was excreted principally in the urine (58% of the radioactive orally administered dose in pharmacokinetic studies), with 39% excreted in the feces [80]. Efficacy

Use of apremilast in PsA has shown promising though not marked results. While significant, patient response rates have been lower than those seen with the FDA-approved TNF-a blockers, with which 51–59% of PsA patients have achieved ACR20 over 12–14 weeks of therapy [17]. The first Phase II trial evaluating apremilast in the disease was conducted by Schett and colleagues and published in 2012 [81]. Schett et al. studied 204 subjects with PsA (‡3 swollen joints, ‡3 tender joints and absent serum rheumatoid factor) in a multicenter, randomized, double-blinded, placebo-controlled trial [81]. Subjects were allowed to continue stable doses of methotrexate and oral corticosteroids during the study, but discontinued all other PsA therapies with a washout period of at least 4 weeks prior to study initiation. Subjects were randomized to apremilast 20 mg twice daily, apremilast 40 mg once daily or placebo for a 12-week treatment phase, at which time patients initially randomized to placebo were rerandomized to either apremilast group. Among the 165 of the 204 subjects who completed the initial 12-week treatment phase, use of apremilast showed promising results: ACR20 was achieved by 43.5% of the apremilast 20 mg treatment group (p < 0.001), 35.8% of the apremilast 40 mg group (p = 0.002) and 11.8% of placebo group with a median response time of 4 weeks. Moreover, response to apremilast was sustained in both treatment groups: 42.5 and 43.5% of patients receiving 20 mg twice daily and 40 mg once daily, respectively, had achieved ACR20 at week 24. Higher ACR20 response rates were achieved in patients who entered the study with CRP >8 mg/l (defined upper limit of normal): apremilast 20 mg group, 48.0%; apremilast 40 mg group, 46.4% and placebo, 8.3%. Apremilast was not associated with an overall reduction in CRP levels over 12 weeks of treatment, although patients who entered the study with CRP >8 mg/l and received apremilast had greater reductions of CRP than those who received placebo (CRP change from baseline in 20 mg apremilast group, -49.6%; 40 mg apremilast group, -33.8% and placebo group, -18.8%). The Phase III PsA long-term assessment of clinical efficacy (PALACE) program consists of four independent, Phase III trials with treatment periods of 12 weeks followed by an extension 245


Drug Profile


period of 52 weeks. PALACE-1, 2 and 3 are active at the time of this publication and evaluate the efficacy and safety of apremilast 20 and 30 mg twice daily in 1500 biologic-naı¨ve and biologicexperienced PsA patients. Patients taking concurrent DMARDs were allowed to continue stable doses (methotrexate, sulfasalazine, leflunomide or a combination). Preliminary reports reveal apremilast to be significantly superior to placebo. At week 16, significantly more apremilast 20 mg twice daily 31.3% (p = 0.014) and apremilast 30 mg twice daily 40.0% (p < 0.0001) achieved ACR20, compared with placebo [82]. Similarly, in PALACE-2, at week 52, a significantly greater proportion of patients randomized to both apremilast 20 and 30 mg twice daily dosages achieved an ACR20 response versus placebo (52.9 and 52.6%, respectively; placebo, 19.5%) [83]. In PALACE-3, the efficacy of apremilast 20 and 30 mg twicedaily doses was assessed in 505 patients with active PsA and at least one psoriatic lesion (‡2 cm) despite prior DMARDs and/or biologics. Patients were allowed to continue stable doses of concurrent DMARDs (methotrexate, sulfasalazine, leflunomide or a combination). Responses were universally greater in patients receiving the higher dose of apremilast. At week 16, significantly more patients receiving apremilast achieved ACR20 versus placebo (apremilast 20 mg group: 29.4%; p = 0.0235; apremilast 30 mg group: 42.8%; p < 0.0001; placebo: 18.9%) [84]. Improvements were maintained or increased over the 52-week treatment extension period for multiple end points, including ACR20, HAQ-DI and PASI-75. In the apremilast 30 mg group, ACR20 at week 52 was achieved by 63%, the mean change of HAQ-DI from baseline was -0.350 (0.505) (meeting the minimal clinically important difference score of 0.30). PASI-75 was achieved by 39.1% and PASI-50 by 54.7% [84]. Results in groups with and without concurrent DMARD use have not yet been reported. In PALACE-1, 2 and 3, swollen and tender joint counts were significantly reduced with apremilast, with higher percent reductions in the apremilast 30 mg groups: median percent reduction of swollen joint counts in PALACE-1, 2 and 3 were -50% (p < 0.0001), -53.9% (p = 0.0009) and -50.0% (p = 0.0014), respectively. Tender joint counts were reduced by -42.9% (p < 0.0001), -33.3% (p = 0.0015) and -43.7% (p < 0.0001), respectively. These percentages were sustained at week 52 [85]. The severity of dactylitis and enthesitis were also significantly improved over the 52-week study periods as well. Median change in Maastricht ankylosing spondylitis enthesitis score was -66.7% with apremilast 20 and 30 mg, respectively, with a Maastricht ankylosing spondylitis enthesitis score of 0 (no pain at any enthuses assessed) achieved by 41.4 and 37.4%, respectively [83]. Reductions in dactylitis counts were seen, but only approached statistical significance: at week 24 median changes were -66.7%, -75.0% (p = 0.2158) and 79.3% (p = 0.0609) in patients receiving placebo, apremilast 20 and 30 mg, respectively. At week 52, both doses resulted in a median 100% decrease in dactylitis count [86]. In all three trials, treatment with 30 mg apremilast twice daily was associated with significant improvements in quality of 246

life and physical functioning (HAQ-DI; p £ 0.03) and the SF-36 Physical Functioning domain (p £ 0.05) versus placebo at week 24 [87]. Apremilast displayed a lower efficiency of the drug in patients who had received biological agents in the past: in the apremilast 30 mg group in PALACE-1, 43% of biologic-naı¨ve versus 28% of biologic-experienced patients achieved ACR20 responses at week 16 [88]. PALACE-4 found consistent rates of response among patients naı¨ve to DMARD therapy. The study included 501 patients with a history of psoriasis and active PsA (mean swollen joint counts, 11.2; mean tender joint counts, 20.1; mean HAQ-DI, 1.068; enthesitis present in 65% and dactylitis in 50%); 73% of patients were using NSAIDs at baseline. At week 16, a significantly greater proportion of patients treated with apremilast achieved ACR20 (apremilast 20 mg group: 29.2%; p = 0.0076; apremilast 30 mg group: 32.3%; p = 0.0011) versus placebo (16.9%) [89]. Safety

Pooled safety and tolerability analyses from PALACE-1, 2 and 3 have been reported. Most AEs reported with apremilast usage were mild or moderate in severity [90]; the most common were diarrhea (14%), nausea (13%), headache (10%) and URI (10%) [90]. Discontinuations due to AEs were low and occurred primarily in the first 24 weeks of treatment (apremilast 20 mg twice daily, 5.6%; apremilast 30 mg twice daily, 7.2%; placebo, placebo 4.2%). At week 52, 7.5% in the apremilast 20 mg daily group and 8.3% in apremilast 30 mg daily group discontinued treatment. Nausea and diarrhea, the most common AEs that led to apremilast discontinuation, occurred with reduced incidence after the first 2 weeks of dosing. Most cases resolved within 30 days despite continued therapy [90]. There is no specific management recommended at this time for management of gastrointestinal side effects, which are fully reversible with discontinuation of the drug. No apparent safety concerns were raised based on clinical laboratory assessments such as serum chemistry, hepatic or renal function tests or electrocardiogram in the PALACE Phase III trials, in the Phase II study by Schett et al. or in the psoriasis study by Papp et al. [10,81,90]. In pooled analysis of PALACE-1, 2 and 3, serious AEs occurred 3.4, 3.8 and 3.8% of patients at week 24 (apremilast 20 group, apremilast 30 group and placebo, respectively). At week 52, serious AEs occurred in 6.8 and 7.2% of patients receiving apremilast 20 and 30 mg daily, respectively. No significant difference among exposure-adjusted incidence rates of serious AEs, major adverse cardiac events, serious infections including systemic opportunistic infections or malignancies in apremilast-treated and placebo groups was observed, and neither de novo nor reactivation cases of tuberculosis was reported [84]. This is consistent with the finding that the phthalide moiety does not bind to cereblon, the molecular target of thalidomide responsible for its teratogenicity [91,92]. Worsening of psoriatic arthropathy was observed in 14 patients during the Phase II study by Schett et al., in 6 patients receiving placebo, 3 patients in the 20 mg daily apremilast group and in Expert Rev. Clin. Pharmacol. 7(3), (2014)


4 patients receiving apremilast 40 mg daily. Three of these events were suspected of being related to the study drug. Of patients receiving apremilast, flares of cutaneous psoriasis were observed in two patients (both of whom were receiving the 20 mg dose). Cases of psoriatic cutaneous or arthritic flares during the PALACE-1, 2 and 3 trials have not been reported.


Expert commentary & five-year view

As of December 2013, five Phase III studies and one Phase II study of apremilast treatment are underway or completed in PsA. The drug has demonstrated significant although moderate improvements in ACR20, swollen and tender joint counts, enthesitis, synovitis and quality of life. Its safety profile may allow treatment without the monthly liver and/or renal lab work that is necessary with DMARDs. The most common side effects seen are URIs and transient, reversible diarrhea; the drug has not shown an increased risk of serious infections, including tuberculosis. Although comparative studies have not yet been performed, apremilast may be of benefit as an adjunctive agent to other DMARDs and/or the injectable biologics. The effect of apremilast on the structural damage of PsA has not yet been studied, while inhibition of radiographic progression has been shown with TNF-a blockade and ustekinumab

Drug Profile

therapy [93]. A lack of knowledge regarding the effect of apremilast on radiographic progression of PsA may influence its order of use in the therapeutic repertoire. A second variable that may influence use of apremilast will be its cost as compared with biologics and tofacitinib. It is important to have multiple options to treat both PsA and psoriasis. Apremilast will hopefully be a welcome addition to our therapeutic choices. Conclusion

Results of early studies on the use of apremilast in PsA have been encouraging. Apremilast may become a valid therapeutic option for patients with moderate-to-severe PsA; however, its long-term efficacy and safety remain to be determined. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Psoriatic arthritis (PsA) therapy is currently centered on non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs and biologics that target the key proinflammatory cytokines of the Th1 and Th17 immune pathways. • Current systemic therapies for PsA can be compromised by loss of efficacy over time, adverse events, safety and tolerability issues, required subcutaneous or intravenous administration and high cost. • Apremilast, a novel, orally available inhibitor of phosphodiesterase type 4, may represent an effective, well-tolerated, safe and easily administered treatment for PsA. • Apremilast’s use will depend upon its cost as well as evidence of long-term safety and efficacy.

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Expert Rev. Clin. Pharmacol. 7(3), (2014)

Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis.

Clinical potential of apremilast in the treatment of psoriatic arthritis.

Apremilast in the treatment of psoriatic arthritis: a perspective review.

Drug safety evaluation of apremilast for treating psoriatic arthritis.

Apremilast: A Phosphodiesterase 4 Inhibitor for the Treatment of Psoriatic Arthritis.

Apremilast (Otezla): A New Oral Treatment for Adults With Psoriasis and Psoriatic Arthritis.

Ustekinumab for the treatment of psoriatic arthritis.

Ustekinumab for the treatment of psoriatic arthritis.

A meta-analysis of apremilast on psoriatic arthritis long-term assessment of clinical efficacy (PALACE).

Use of antimalarial drugs for the treatment of psoriatic arthritis.

Certolizumab pegol for the treatment of psoriatic arthritis.

Ustekinumab for the treatment of psoriatic arthritis: an update.

Comprehensive treatment of dactylitis in psoriatic arthritis.

Pharmacogenetics of treatment response in psoriatic arthritis.

Otezla (Apremilast), an Oral PDE-4 Inhibitor, Receives FDA Approval for the Treatment of Patients with Active Psoriatic Arthritis and Plaque Psoriasis.

Screening psoriatic arthritis tools: analysis of the Early Arthritis for Psoriatic Patients questionnaire.

Erratum to: Secukinumab: A New Treatment Option for Psoriatic Arthritis.

Psoriatic arthritis treatment and the risk of herpes zoster.

Secukinumab: A New Treatment Option for Psoriatic Arthritis.

Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis.

Infliximab-Induced Aseptic Meningitis during the Treatment of Psoriatic Arthritis.

A review on golimumab in the treatment of psoriatic arthritis.

Apremilast for treatment of recalcitrant aphthous stomatitis.

Screening for Psoriatic Arthritis in Korean Psoriasis Patients Using the Psoriatic Arthritis Screening Evaluation Questionnaire.