Apremilast: A Novel Oral Treatment for Psoriasis and Psoriatic Arthritis

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1 For Personal Use Only. Not For Distribution. Am J Clin Dermatol DOI /s REVIEW ARTICLE Apremilast: A Novel Oral Treatment for Psoriasis and Psoriatic Arthritis Tiago Torres 1,2 Luis Puig 3,4 Ó Springer International Publishing Switzerland 2017 Abstract Psoriasis is a chronic immune-mediated disease associated with several co-morbidities and negative impacts on a patient s quality of life. Despite the advances in biologic therapy, there are still unmet needs in the treatment of psoriasis, as current treatments are limited in terms of long-term efficacy, tolerability, safety, route of administration, and cost. Apremilast is an oral, smallmolecule phosphodiesterase 4 inhibitor that works intracellularly by blocking the degradation of cyclic adenosine 3 0,5 0 -monophosphate, resulting in increased intracellular cyclic adenosine 3 0,5 0 -monophosphate levels in phosphodiesterase 4-expressing cells. This inhibition results in the reduced expression of proinflammatory mediators, and an increased expression of anti-inflammatory mediators, providing apremilast with an anti-inflammatory rather than immunosuppressive mode of action. Apremilast offers a novel therapeutic option for patients with psoriasis and psoriatic arthritis and may fulfill some of the unmet needs in patients with psoriasis. Potential advantages of apremilast include moderate activity for both psoriasis and psoriatic arthritis and efficacy in difficult-to-treat forms of psoriasis, a good safety profile, no need of laboratory & Tiago Torres torres.tiago@outlook.com prescreening or ongoing monitoring for laboratory parameters, owing to the absence of organ toxicity, a potentially advantageous weight loss effect, and a convenient oral administration and dosing. Cost effectiveness and health economics considerations will be decisive in determining the ultimate place of apremilast in the therapeutic armamentarium for psoriasis. Key Points Apremilast is an oral, small-molecule phosphodiesterase 4 inhibitor with an antiinflammatory rather than immunosuppressive mode of action. Apremilast has shown activity for both psoriasis and psoriatic arthritis, efficacy in difficult-to-treat forms of psoriasis, a favorable safety and tolerability profile, a potentially advantageous weight loss effect, and convenient oral administration and dosing. Apremilast offers a novel therapeutic option for patients with psoriasis and psoriatic arthritis and may fulfill some of the unmet needs in patients with psoriasis Department of Dermatology, Centro Hospitalar Universitário do Porto, Edifício das Consultas Externas, Ex. CICAP, Rua D. Manuel II, s/n, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain 1 Introduction Psoriasis is a chronic immune-mediated disease that affects up to 2% of the population worldwide, and is associated with several co-morbidities including metabolic syndrome,

2 T. Torres, L. Puig cardiovascular disease, and psychiatric disorders with an overall impairment of a patient s quality of life [1]. Up to one in four patients develop psoriatic arthritis (PsA), characterized by persistent joint pain, morning stiffness, dactylitis, and enthesitis [2]. Moreover, psoriasis usually affects difficult-to-treat areas such as the nails, scalp, palms, and soles, which may be associated with functional disability and have particularly detrimental effects on a patient s quality of life. Psoriasis treatment primarily depends on disease severity, but also on co-morbidities, concomitant medications, previous therapies, adverse reactions, risk of infections (tuberculosis and opportunistic infections), concomitant chronic infections (hepatitis C virus, hepatitis B virus, human immunodeficiency virus), pregnancy in women of childbearing potential, patient s preference and compliance, and the burden of psoriasis on a patient s quality of life. Mild-to-moderate psoriasis is usually treated with topical treatments and phototherapy, while systemic agents (nonbiologic and biologic) are used for moderate-to-severe skin disease. These therapies can be used either as monotherapy or in combinations. Conventional systemic therapy (methotrexate, cyclosporine, and acitretin, as well as fumarates in some countries) and phototherapy are usually used as first-line therapies for moderate-to-severe psoriasis. However, the long-term continuous use of conventional systemic treatments is not recommended because of their potential organ toxicity, which frequently leads to treatment discontinuation or is a reason for contraindication. Biologic agents target key mediators of psoriasis pathogenesis [tumor necrosis factor (TNF)-a, interleukin (IL)-12/23 p40 subunit, and IL-17A] and have proved to be highly effective in the treatment of psoriasis with a favorable safety profile [3] and increased drug survival (a marker of drug effectiveness, safety, and tolerability) [4]. Nevertheless, there are several limitations associated with biologic therapy, mainly primary and secondary failure, need for parenteral administration, and cost. Indeed, the main reasons for biologic treatment discontinuation have been shown to be lack of efficacy, problems associated with the parenteral administration, also known as needle fatigue, and access limitations or incapacity to afford the medication [5]. Nearly 50% of patients who have ever been treated with any biologic agents (current or former users) consider their therapy as burdensome, mainly owing to fear, anxiety, or inconvenience of injections, development of adverse effects or abnormal blood tests, and fear or anxiety of adverse effects [6]. Thus, despite the advances in biologic therapy that currently allow complete or almost complete clearance of psoriasis in most patients, there are still unmet needs that could be partially filled by new, oral, safer, and more cost-effective treatments. This review discusses the mechanism of action of apremilast, the results from key clinical trials in psoriasis and PsA, and the potential role of apremilast in the management of these diseases. A search in the PubMed database (up until April 2017) for articles with the specific keywords psoriasis; psoriatic arthritis; apremilast present in the title, abstract, or body was performed. The reference lists of those articles were examined to retrieve other studies that were considered relevant and contributed to the scientific purpose of the present review but had not been retrieved by the database search. 2 Apremilast: Mechanism of Action Phosphodiesterase (PDE) 4 is involved in regulating the inflammatory response by degrading cyclic adenosine 3 0,5 0 - monophosphate (camp), a key second messenger. Selective expression of PDE4 in cells of the immune system leads to their activation and upregulation in chronic plaque psoriasis and other inflammatory conditions. Phosphodiesterase 4 is also expressed in structural cell types, such as keratinocytes, vascular endothelium, and synovium [7]. Apremilast is an oral small-molecule PDE4 inhibitor that works intracellularly by blocking the degradation of camp, resulting in increased intracellular camp levels in PDE4-expressing cells. This inhibition results in the reduced expression of proinflammatory mediators such as TNF-a and IL-23, and an increased expression of antiinflammatory mediators such as IL-10 [7]. In a phase II clinical trial, apremilast reduced epidermal and dermal infiltration of myeloid dendritic cells, T cells, and natural killer cells, and inhibited the expression of genes in the T helper-1, T helper-17, and T helper-22 pathways in the psoriatic skin lesions, including IL-12/IL-23p40, IL-23p19, IL-17A, and IL-22 [8] (Fig 1). Interestingly, A2A adenosine receptor agonism has been shown to potentiate TNF-a inhibition by apremilast, consistent with the camp-elevating effects of that receptor [9]. Because the A2A adenosine receptor is also involved in the anti-inflammatory effects of methotrexate, the mechanism of action of both drugs involves camp-dependent pathways, is therefore partially overlapping in nature, and makes any potential synergism between both drugs unlikely. Apremilast has been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of moderate-to-severe chronic plaque psoriasis and active PsA in adults. 3 Apremilast for the Treatment of Psoriasis and Psoriatic Arthritis 3.1 Psoriasis The efficacy and safety of apremilast in the treatment of moderate-to-severe plaque psoriasis have been evaluated in

3 Apremilast for Psoriasis and Psoriatic Arthritis Fig. 1 Apremilast mechanism of action. Apremilast blocks phosphodiesterase 4 (PDE4), by inhibiting the degradation of cyclic adenosine monophosphate (camp), resulting in increased intracellular camp levels in PDE4-expressing cells. Cyclic adenosine monophosphate activates protein kinase A (PKA) and phosphorylates camp response element binding (CREB) protein, while also phase II and III clinical trials, with Psoriasis Area and Severity Index 75 (PASI75) responses to apremilast 30 mg twice daily (BID) ranging from 29 to 41% at week 16 [10] (Table 1). In a 12-week trial (n = 259), the PASI75 response was 24.4% in patients treated with apremilast 20 mg BID vs. 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, and 17.4% with placebo [11]. A phase IIb crossover trial (n = 352) was designed to compare apremilast 10 mg BID, apremilast 20 mg BID, apremilast 30 mg BID, and placebo BID for 16 weeks [12]. 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 PASI75 response (the primary endpoint) was observed in 11% of the apremilast 10-mg BID group, 29% of the apremilast 20-mg BID group, 41% of the apremilast 30-mg BID group, and 6% of the placebo group. At week 16, the difference between apremilast 10 mg BID and placebo was not significant. Among the phase III trials, the LIBERATE study (in which there was an etanercept active treatment arm) included solely biologic-naive patients, whereas in the ESTEEM trials up to one third of patients had received prior biologic therapy [13 15]. In ESTEEM 1 (n = 844) [13] and ESTEEM 2 (n = 413) [14], patients with a PASI score of 12 or higher, body surface area involvement of C10%, and static Physician Global Assessment of C3, who were candidates for phototherapy or systemic therapy, were inhibiting nuclear factor-jb (NF-jB)-driven gene transcription. This results in the reduced expression of proinflammatory mediators and an increased expression of anti-inflammatory cytokines. AMP adenosine monophosphate, IFN interferon, IL interleukin, TNF tumor necrosis factor randomized 2:1 to receive apremilast 30 mg BID or placebo. At 16 weeks, all patients were treated with apremilast through week 32, followed by a randomized withdrawal phase through week 52 and an optional 4-year open-label extension phase to assess safety. For both ESTEEM 1 and ESTEEM 2, the mean baseline body surface area involvement and PASI scores were 25.2 and 19.1%, respectively. The baseline static Physician Global Assessment was 3 in 70.0% of patients, and 4 in 29.8% of patients, and 54% of patients had received prior systemic therapy with conventional agents and/or biologics. At week 16, the proportion of patients achieving a PASI75 response was significantly greater (p \ ) in the apremilast-treated group than in the placebo group in both studies (ESTEEM 1: 33 vs. 5%, respectively; ESTEEM 2: 29% vs. 6%, respectively), and significantly more apremilast-treated patients achieved a score of 0 or 1 on the static Physician Global Assessment in ESTEEM 1 (4 vs. 22%) and in ESTEEM 2 (4 vs. 20%); p \ for all comparisons. In the patients re-randomized to placebo at week 32, the median time to loss of PASI75 response was 5.1 weeks (95% confidence interval, ) in ESTEEM 1[13]. For patients re-randomized to placebo in ESTEEM 2, the median time to first loss of response was 12.4 weeks; of the 32 patients who did lose the PASI50 response, 21 (66%) regained this response upon retreatment with apremilast prior to week 52 [14]. The phase IIIb LIBERATE clinical trial [15] evaluated the efficacy and safety of apremilast 30 mg BID compared with placebo and etanercept 50 mg once weekly compared with placebo at week 16 in patients with moderate-to-

4 T. Torres, L. Puig Table 1 Summary of key psoriasis and psoriatic arthritis phase II and III study results Trial N Treatment arms Main results Psoriasis CC PSOR-003 [11] Phase II mg QD, 20 mg BID, and PASI75 response (week 12): apremilast 24.4% vs. placebo 10.3% placebo CC PSOR-005 [12] Phase IIb , 20, 30 mg BID, and PASI75 response (week 16): apremilast 10, 20, 30 mg BID 11, 29, placebo 41%, respectively, vs. placebo 6% ESTEEM 1 [13] Phase III mg BID and placebo PASI75 response (week 16): apremilast 33.1% vs. placebo 5.3% NAPSI-50 response: apremilast 33.3% vs. placebo 14.9% ESTEEM 2 [14] Phase III mg BID and placebo PASI75 response (week 16): apremilast 28.8% vs. placebo 5.8% NAPSI-50 response: apremilast 44.6% vs. placebo 18.7% PPPGA clear/almost clear: apremilast 65.4% vs. placebo 31.3% LIBERATE [15] Phase IIIb mg BID, placebo and etanercept 50 mg QW PASI75 response (week 16): apremilast 39.8% vs. etanercept 48.2% vs. placebo 11.9% PASI75 response (week 52): apremilast/apremilast 47.3% vs. etanercept/apremilast 49.4% vs. placebo/apremilast 47.9% Psoriatic arthritis PALACE 1 [24] Phase III , 30 mg BID, and placebo ACR20 response (week 16): apremilast 20, 30 mg BID 30.4% and 38.1%, respectively, vs. placebo 19.0% ACR20 response (week 52): 20, 30 mg BID 63.0% and 54.6%, respectively PALACE 2 [25] Phase III , 30 mg BID, and placebo ACR20 response (week 16): apremilast 20, 30 mg BID 37.4% and 32.1%, respectively, vs. placebo 18.9% PALACE 3 [26] Phase III , 30 mg BID, and placebo ACR20 response (week 16): apremilast 20, 30 mg BID 28.0% and 41.0%, respectively, vs. placebo 18.0% PALACE 4 [27] Phase III , 30 mg BID, and placebo ACR20 response (week 16): apremilast 20, 30 mg BID 28.0% and 30.7%, respectively, vs. placebo 15.9% ACR20 response (week 52): apremilast 20, 30 mg BID 55.4% and 58.0% ACR American College of Rheumatology, BID twice daily, NAPSI Nail Psoriasis Severity Index, PASI Psoriasis Area and Severity Index, PPPGA Palmo-plantar Physician Global Assessment, QD every day, QW once weekly

5 Apremilast for Psoriasis and Psoriatic Arthritis severe plaque psoriasis. During the 16-week placebo-controlled phase, patients were randomized 1:1:1 to receive apremilast 30 mg BID (n = 83), etanercept 50 mg once weekly (n = 83), or placebo (n = 84). At week 16, all patients in the placebo and etanercept groups were switched to apremilast 30 mg BID through week 52. The PASI75 response rates at week 16 were 39.8% for apremilast, 48.2% for etanercept, and 11.9% for placebo (p \ vs. placebo for both comparisons). The PASI75 response at week 52 was 47.9 and 49.4% for the patients who switched from placebo and etanercept to apremilast, respectively, and 47.3% for the patients who were maintained on apremilast [15]. Additionally, apremilast also demonstrated improvements in nail, scalp [16, 17], and palmoplantar psoriasis [18] that were sustained over time, indicating that it may be an effective option for these difficult-to-treat forms of psoriasis. Pruritus severity was also shown to decrease with apremilast, as early as week 2, with improvement maintained through to week 32 [13, 14, 19]. The mean change from baseline in the pruritus Visual Analog Scale (VAS) score in apremilast vs. placebo subjects was vs mm in ESTEEM 1 (p \ ) [14] and vs mm in ESTEEM 2 (p \ 0.001) [15]. Post-hoc analyses revealed a correlation between improvements in pruritus VAS scores and Dermatology Life Quality Index scores and between improvements in Patient Global Assessment of Psoriasis Disease Activity VAS scores and pruritus or skin discomfort/pain VAS scores at weeks 16 and 32 [19]. Real-world experience in the treatment of psoriasis with apremilast has been recently reported in 99 patients who were prescribed apremilast, 81 of whom took at least one dose. In 63 patients, apremilast improved clinical disease severity, with 37% of patients achieving a body surface area involvement of\1%. As a treatment, it was generally well tolerated and caused no serious adverse events (AEs) [20]. 3.2 Psoriatic Arthritis Apremilast has also been shown to be effective in PsA (Table 1). In a phase II trial, 165 of the 204 patients with PsA who were randomized to a treatment group completed the treatment phase (week 12), when 43.5% of patients receiving apremilast 20 mg BID (p \ 0.001) and 35.8% of those receiving 40 mg once daily (p = 0.002) achieved an American College of Rheumatology 20 (ACR20) response, compared with 11.8% of those receiving placebo. At the end of the treatment-extension phase (week 24), [40% of patients in each group (patients receiving apremilast 20 mg BID, patients receiving apremilast 40 mg once daily, and patients in the placebo group re-randomized to receive apremilast) achieved the ACR20 level of improvement [21]. The PALACE program, a large phase III clinical program including a wide spectrum of patients with active PsA [previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and/or TNF inhibitors] demonstrated that ACR20 responses at week 16 were significantly higher in the active arm than in the placebo arm [22]. In PALACE 1, patients were randomized to placebo (n = 168), apremilast 20 mg BID (n = 168), or apremilast 30 mg BID (n = 168). An ACR20 response at week 16 was attained by significantly more patients receiving apremilast 20 mg BID (30.4%, p = ) or 30 mg BID (38.1%, p = ) than placebo (19.0%) [23]. Among patients receiving apremilast continuously for 52 weeks (n = 254), the ACR20 response at week 52 was observed in 63.0% (75/ 119, 20 mg BID) and 54.6% (71/130, 30 mg BID) of patients [24]. PALACE 2 had an identical design. In the intent-to-treat population (n = 484), ACR20 at week 16 was achieved by more patients receiving apremilast 20 mg BID [37.4% (p = )] and 30 mg BID [32.1% (p = )] vs. placebo (18.9%) [25]. In PALACE 3, a total of 505 patients were enrolled, 169 were randomized to apremilast 20 mg BID, 167 to apremilast 30 mg BID, and 169 to placebo [26]. As with PALACE 1 and PALACE 2, those on placebo were re-randomized at week 16 ( early escape ) or week 24, to either dose of apremilast. At week 16, significantly more patients receiving apremilast 20 mg BID (28%) and 30 mg BID (41%) achieved ACR20 response vs. placebo (18%; p = and p \ , respectively), and the mean decrease in the Health Assessment Questionnaire- Disability Index score was significantly greater with apremilast 30 mg BID (-0.20) vs. placebo (-0.07; p = ) [26]. PALACE 4 compared apremilast with placebo in DMARD and biologic-naïve PsA patients. A total of 527 patients were recruited (175 received apremilast 20 mg BID, 176 apremilast 30 mg BID, and 176 received placebo). As with PALACE 1 3, placebo patients were switched to either dose of apremilast at weeks 16 or 24. Endpoints measured at week 52 showed the ACR20 response with apremilast 30 mg BID was achieved in 58.0% of patients (119/205). With apremilast 20 mg BID, ACR20 was achieved in 55.4% of patients (107/193). A follow-up to week 104 showed this response rate was maintained (61.4% with apremilast 30 mg and 64.2% with apremilast 20 mg) [22, 27]. In phase III clinical trials, apremilast also showed significant improvement in physical function, enthesitis, and dactylitis [23 26]. However, it should be noted that data on the ability of apremilast to inhibit structural joint damage are currently unavailable.

6 T. Torres, L. Puig 4 Safety Overall, in the ESTEEM studies, apremilast was mostly well tolerated, and AEs were mostly mild to moderate in severity in all the study periods (short and long term). The most frequent AEs were diarrhea (17.8%), nausea (16.6%), and upper respiratory tract infections (8.4%) [28]. Tension headache, headache, nasopharyngitis, and upper respiratory infection were also reported frequently. The incidence of diarrhea and nausea was higher during the first 2 weeks of treatment compared with other study periods, and commonly resolved within 4 weeks. Long-term safety data (52 weeks of exposure) did not show a higher incidence of AEs (including serious AEs) based on exposure-adjusted incidence rates per 100 patient-years. During the ESTEEM program, only three deaths were observed: one in the placebo group for suicide and two in the apremilast group, both for cardiovascular accidents. Discontinuations because of AEs occurred in 6.1 and 4.1% of patients receiving apremilast and placebo, respectively, during weeks 0 16 (mainly owing to diarrhea 0.9% and nausea 1.4%) and did not increase with longer apremilast exposure for up to 52 weeks [28]. The pooled safety analysis for C156 weeks from ESTEEM 1 and 2 confirmed the acceptable safety profile of apremilast in the treatment of patients with moderate-to-severe plaque psoriasis, identifying no new safety concerns with long-term exposure to the drug [29]. A similar safety profile has been described in patients with PsA: common AEs were generally similar regardless of concomitant conventional DMARD use, and no additional safety signals were observed in those patients. During the 24-week placebo-controlled phase of PALACE 1, AEs occurring in C5% of any treatment group included diarrhea, nausea, headache, and upper respiratory tract infection. Most AEs were mild to moderate in severity, and discontinuations because of AEs were comparable across groups [placebo: 8/168 (4.8%); apremilast 20 mg BID: 10/168 (6.0%); apremilast 30 mg BID: 12/168 (7.1%)]. Gastrointestinal AEs were predominantly mild or moderate in severity, presented early, were self-limited, and did not recur. A low rate of discontinuation was associated with gastrointestinal AEs [placebo: 4/168 (2.4%); apremilast 20 mg BID: 3/168 (1.8%); apremilast 30 mg BID: 7/168 (4.2%)] [23]. The safety profile was similar in PALACE 2, and the occurrence of weight loss, as in psoriasis clinical trials with apremilast, was reported in a small proportion of patients during the 24-week placebo-controlled phase as well as during the 52-week apremilast-exposure phase. By week 24, the mean change in weight from baseline to the last value measured was kg (placebo), -1.2 kg (20 mg), and -1.2 kg (30 mg) [25]. Marked abnormalities in vital signs, hematology, and clinical chemistry variables were infrequent and occurred at a similar frequency with placebo or apremilast [21 30]. In everyday clinical practice, the most commonly reported side effects resulting in the discontinuation of treatment of apremilast are nausea and vomiting. Eighteen of 81 patients (22%) in a recently published series discontinued treatment with apremilast, and 13 (16%) attributed their discontinuation to side effects they believed to be associated with apremilast therapy, a higher incidence of discontinuation than reported in pivotal clinical trials, for instance, 7.3% in the ESTEEM 1 study [20]. The gastrointestinal side effects of PDE inhibition are believed to be due to increased camp in the gastrointestinal mucosa, resulting in a secretory diarrhea pattern in some patients [31]. This is important as it supports that gastrointestinal side effects associated with PDE4 inhibition have not been related to the induction of inflammatory gastrointestinal disease. Reporting of diarrhea in clinical trials included a change in the frequency of bowel movements (such as twice vs. once daily) and/or change in quality (e.g., looser stools than usual), and do not necessarily reflect an immediate need for defecation, such as with more explosive or urgent diarrhea. Xanthines (e.g., caffeine) found in coffee, tea, and some soft drinks can increase camp through PDE inhibition, and reducing their intake might be helpful in reducing the incidence of diarrhea [31]. During controlled clinical trials, a 5 10% decrease in body weight occurred in 10% of patients treated with apremilast 30 mg BID and 3.3% with placebo. Unexplained or clinically significant weight loss should be evaluated, and discontinuation of apremilast should be considered [32], even though the weight loss in apremilast-treated patients does not appear to be associated with diarrhea or nausea/ vomiting events, and has no overt clinical consequences. Interestingly, in the LIBERATE study, the weight gain observed in the etanercept group during the placebo-controlled phase was reversed with the transition to apremilast [15]. The weight loss associated with apremilast seems to be a class effect of PDE4 inhibitors, such as roflumilast [33], and may be associated with an increase in glucagon-like peptide-i levels, which may have potentially beneficial effects on type 2 diabetes mellitus [34]. As is the case with roflumilast, apremilast has been associated with an increased frequency of depression. Depression or depressed mood was reported by 1.0% of apremilast-treated patients in the PsA studies and 1.3% in the psoriasis studies (vs. 0.8 and 0.4% with placebo, respectively) [35]. Recently, using real-world AE reporting programs and a large, urban, single-center, US patient population center, no safety signal between apremilast and

7 Apremilast for Psoriasis and Psoriatic Arthritis suicidality was detected [36]. Nevertheless, while the overall incidence is low, it is recommended that the risks and benefits of apremilast be evaluated carefully prior to initiating therapy in patients with a history of depression and/or suicidal thoughts or behavior; close monitoring for worsening of such events during therapy is also advised [37]. Apremilast has an anti-inflammatory rather than immunosuppressive mode of action. No increased risk for opportunistic serious infection has been detected, and no reactivation of tuberculosis was reported during the clinical trials. Recently, the successful use of apremilast has been reported in a patient with human immunodeficiency virus and hepatitis C [38]. Moreover, in addition to its lack of significant organ toxicity, exposure to apremilast, in the short and long term, does not result in any relevant laboratory abnormalities, thus no ongoing laboratory monitoring is required. The safety in terms of pharmacokinetic parameters in renal and hepatic impairment was evaluated in phase II studies. While unlike other oral DMARDs, apremilast does not need dose adjustment in patients experiencing hepatic impairment [moderate (Child-Pugh B) and severe (Child- Pugh C) hepatic impairment], the dosage of apremilast should be reduced in patients with severe impairment of renal function [39]. Apremilast has previously been referred to as a thalidomide analog because of its common structural feature, the phthalimide ring. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the molecular target of thalidomide action and responsible for the teratogenic effects of thalidomide. Thus, currently, apremilast is no longer considered to be a functional analog of thalidomide, and probably it is not associated with teratogenic effects [7]. Apremilast is a Pregnancy Category C drug, which makes its use appropriate during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no controlled studies with apremilast in pregnant women and the rate of pregnancy loss and/or malformation has not yet been established [30]. Drug interactions are a minor concern: apremilast exposure is decreased when co-administered with strong cytochrome P450 inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) and may result in the loss of efficacy of apremilast [28]. 5 Discussion Apremilast may have a significant role in the treatment of patients with psoriasis (with or without PsA) who have not responded or have contraindications to traditional systemic agents, when either the patient or the physician is concerned about using a biologic therapy. Apremilast should be preferentially recommended for biologic-naïve patients because its efficacy appears to be better in this subgroup of patients [14]. The efficacy of apremilast in psoriasis seems to be comparable to that of methotrexate, but it has significant advantages from a safety perspective because of its lack of organ-specific or cumulative toxicity, which obviates the need for analytical monitoring. Apremilast has not been associated with any type of immunosuppressive effect, and deserves high consideration in patients with underlying active or latent infectious diseases such as latent tuberculosis or viral hepatitis. This is especially relevant for patients in whom the potential toxicity associated with anti-tuberculous chemoprophylaxis outweighs its advantages (older patients or those with liver disease). Apremilast may also be a good therapeutic alternative for patients with underlying diseases associated with an increased risk of infection (diabetes, liver cirrhosis, chronic obstructive pulmonary disease) and other causes of disease-associated or iatrogenic immunosuppression, as well as those with a history of neoplasia, or even those undergoing antineoplastic treatment. The currently existing alternatives for those patients are phototherapy, fumarates, or acitretin, which may not be effective or feasible in many cases and can be associated with laboratory abnormalities. Apremilast may be an attractive option for patients with psoriasis and a history of multiple/serious infections with either traditional systemic or biologic therapies. It is also a promising therapy in older patients, especially those with multiple co-morbidities and taking concomitant medications because potential interactions only affect the serum levels and the potential efficacy of apremilast itself when administered together with potent cytochrome P450 inducers. Although apremilast is currently approved for the treatment of moderate-to-severe psoriasis, it has been shown to be effective and may also be considered for difficult-to-treat forms of psoriasis, such as scalp, face, palmoplantar, nail, genital, and palmo-plantar pustulosis [40]. Apremilast may also have some clinical value as maintenance therapy after conventional systemic treatment, helping to prevent disease exacerbations following withdrawal of cyclosporine, and delaying the introduction of biologic agents; as a post-biologic alternative, for patients not responding to one or more biologic therapies as a result of immunogenicity or other mechanisms; or even as an alternative combination therapy to traditional systemic treatments (usually methotrexate) alongside biological agents, with an improved safety profile. In fact, there is recent evidence of the combined use of apremilast with biological agents and conventional therapies for recalcitrant psoriasis, suggesting a safe and synergic profile of this

8 T. Torres, L. Puig new therapeutic strategy [41]. Furthermore, the combination of apremilast with traditional systemic therapies could allow lowering of the dose of conventional systemic agents, reducing the risk of eventual dose-dependent side effects. Moreover, owing to the association of psoriasis with obesity and obesity-related co-morbidities, apremilast may be particularly interesting in these patients (patients with cardiometabolic risk factors, metabolic syndrome, and severe psoriasis), who may benefit from the side effect of weight loss, which in turn may impact directly on the components of metabolic syndrome. However, caution should be taken at the start of treatment with underweight patients, who should have their body weight monitored regularly. The efficacy of apremilast in both psoriasis and PsA is also an advantage. Currently, in patients with moderate-tosevere psoriasis with PsA, the only effective traditional systemic therapy is methotrexate (except for axial involvement). When methotrexate is contraindicated or ineffective, a second DMARD is unlikely to succeed, and biologic agents used to be the only therapeutic option before the advent of apremilast. Nausea, vomiting, diarrhea, and gastrointestinal intolerance are usually adequately managed by dose titration, and weight loss may be considered beneficial in obese patients with psoriasis, but may be a cause of concern in patients with underlying gastrointestinal disorders or those with a low body mass index, who might require close monitoring. Several observational and real-life clinical practice studies are being conducted and will aid in determining the long-term efficacy and safety of apremilast in an everyday clinical practice setting [42]. 6 Conclusion In summary, the main advantages of apremilast include: (1) moderate activity (when compared with biologic agents) for both psoriasis and PsA and efficacy in difficult-to treat forms of psoriasis; (2) satisfactory safety profile (no identified risk of tuberculosis or opportunistic infections in clinical trials); (3) no need of laboratory prescreening or ongoing monitoring for laboratory parameters, such as liver and kidney functions, owing to the absence of organ toxicity; and (4) a potentially advantageous weight loss effect that could be particularly interesting in psoriasis that is associated with obesity and obesity-related conditions. New therapeutic classes provide improvements in therapy personalization, as opposed to the limitations of a standardized paradigm. Apremilast offers a new therapeutic option for patients with psoriasis and PsA, with no requirement for laboratory monitoring, a favorable safety profile, and convenient oral administration. This can be especially useful when considering various factors such as co-morbidities (metabolic, liver, renal, and cardiovascular diseases), concomitant medications, risk of infections, patient s age, and individual needs (work activity, social life, fear/anxiety of injections) that should drive treatment decision making. Finally, cost-effectiveness and health economics considerations will obviously be decisive in determining the ultimate place of apremilast in the therapeutic armamentarium for psoriasis. Compliance with Ethical Standards Funding No sources of funding were received for the preparation of this article. 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