The Rationale for Targeting IL-17 in Psoriasis

Plaque psoriasis is a chronic inflammatory skin disease affecting 1–3% of the general population causing a significant impairment of quality of life, particularly if diffuse and recalcitrant to treatments [1]. Psoriasis is commonly associated with multiple comorbidities including psoriatic arthritis (PsA), inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), cardio-metabolic disorders (such as myocardial infarction hypertension, obesity, diabetes, dyslipidemia, fatty liver disease, and hyperuricemia) [2–5]. The association between psoriasis and cardio-metabolic comorbidities could be explained considering unhealthy life habits (i.e., smoking, over-eating, and sedentary life), the systemic nature of psoriasis-related inflammation, as well as common genetic and pathogenic pathways [5, 6]. The current understanding of the psoriasis pathogenesis assigns central importance to an interaction between acquired and innate immunity [7]. At the onset of the disease, plasmocytoid dendritic cells are activated in the dermis and produce tumor necrosis factor (TNF)-α and interleukin (IL)-23, which promote the development of T helper (Th)1 and Th17 lymphocytes which largely infiltrate psoriatic skin [8]. Th17 cells are a recently identified cluster of differentiation (CD4)+ helper T cell subset which produce mainly IL-17A, IL-17F, IL-6, and, to a lesser extent, TNF-α and IL-22, which in turn are responsible for inflammatory changes and epidermal hyperplasia [9]. Notably, TNF-α also synergizes with IL-17A to induce many psoriasis-related genes in human epidermal keratinocytes [10]. IL-17A is produced not only by Th17 cells, but also by neutrophils, mast cells, and T cytotoxic cells. IL-17A promotes inflammation by several actions including: overexpression of antimicrobial peptides such as lipocalin2, human β-defensin 2 and S100A proteins; secretion of several CXCR1- or CXCR2-bearing neutrophil chemoattractants such as CXCL1, CXCL3, CXCL5, CXCL6, and CXCL8, leading to neutrophil accumulation in psoriatic epidermis; increased production of CCL20, which is essential for the recruitment of both CCR6-expressing dendritic cells and T cells in lesional skin; high expression of intercellular adhesion molecule-1 on endothelial cells, which is essential for T-cell extravasation; dominant role in inducing the expression of psoriasis signature genes that are synergistically or additively co-regulated together with TNF-α, including IL-19, a potent inducer of epidermal hyperplasia, IL-6 and IL-23A (IL-23p19) [11–13]. Blocking IL-17A results in amelioration of psoriasis-like pathology in animal models [14]. Secukinumab (Novartis Pharma AG, Basel, Switzerland) is a fully human IgG1κ monoclonal antibody (mAb) that selectively binds and neutralizes IL-17A. Here, we report the efficacy and safety results of phase II clinical trials that investigated the efficacy and safety of secukinumab in the therapy of chronic plaque psoriasis and PsA.

The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors. Patient consent was obtained for the publication of the Fig. 1.

Fig. 1
figure 1

Diffuse erythematous plaques of the lower limbs at baseline (a) and after 12 weeks of treatment with secukinumab 150 mg subcutaneously week 0, 4, and 8 (b)

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Secukinumab in Chronic Plaque Psoriasis

Secukinumab demonstrated a favorable safety and tolerability profile with robust clinical activity, including improvements in psoriasis area and severity index (PASI) scores and investigator global assessment scores in patients with moderate-to-severe plaque psoriasis. A single infusion of secukinumab (3 mg/kg) resulted in rapid and sustained improvement of psoriasis in a double-blind, placebo-controlled, parallel-group, phase IIA proof-of-concept study on 36 patients [15]. At week 4, secukinumab was associated with an early significant reduction from baseline in mean PASI score compared to placebo (58% vs. 4%; P = 0.0001) [15]. Accordingly, 83% of secukinumab patients versus 11% of placebo patients achieved significant decreases from baseline in investigator global assessment score (P = 0.0004) [15]. Benefits were maintained at week 12, with similar rates of adverse events (AEs), including infections, in both groups [15]. Consistent with the significant decrease in skin inflammation that was clinically evident, molecular profiling of psoriatic skin samples following treatment with secukinumab showed selective modulation of cytokines, including IL-12B, IL-17A, IL-17F, IL-21, IL-22, IL-26, interferon (IFN)-γ, and TNF-α [15]. These molecules are expressed by leukocyte and by tissue lineages, pointing to a diverse impact of IL-17A on multiple cellular lineages involved in psoriasis pathophysiology [15].

Secukinumab was further evaluated in phase IIB subcutaneous (SC) dose-ranging and intravenous (IV) regimen-finding studies. In particular, a randomized, double-blind, parallel-group, placebo-controlled, dose-ranging study evaluated four SC doses of secukinumab [16]. Patients (n = 125) were randomized 1:1:1:1:1 to receive doses of placebo (n = 22) or secukinumab [1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21), or 3 × 150 mg (n = 27)] at weeks 0, 4, and 8. After the 12-week treatment, patients entered a follow-up period of 24 weeks. Secukinumab 150 mg and 75 mg (each administered at weeks 0, 4, and 8) were associated with significantly greater rates of PASI 75 response at week 12 compared with placebo (82% and 57% vs. 9%; P < 0.001 and P = 0.002, respectively; Table 1). Results also indicated that doses of secukinumab higher than 75 mg led to higher efficacy and higher doses of secukinumab may be required for some patients with greater body weight. Rates of AEs and serious AEs (SAEs) were comparable between secukinumab and placebo cohorts.

Table 1 PASI 75 response rate at week 12 in secukinumab phase II clinical trials
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On the basis of the findings indicating the safety and efficacy of secukinumab 150 mg, a placebo-controlled phase IIB trial was conducted to assess 3 regimens of SC secukinumab 150 mg in patients (n = 404) with moderate-to-severe plaque psoriasis, including single regimen (week 0; n = 67), early (weeks 0, 1, 2, 4; n = 133), and monthly (weeks 0, 4, 8; n = 138) [17]. Early and monthly regimens resulted in significantly greater rates of PASI 75 response at week 12, the primary efficacy endpoint of the study, compared to placebo (54.5% and 42% vs. 2%; P < 0.001 for both comparisons; Table 1) [17]. The trial also investigated maintenance treatment strategies and secukinumab showed to offer patients and physicians the choice of either a fixed interval treatment regimen (every 4 weeks) or flexible dosing [17]. However, the maintenance period revealed a favorable efficacy profile of fixed interval period (84.6% of patients) versus the on-demand regimen (67.2%) in achieving PASI 75 at least once from week 20 to week 28. In this study, an initial induction period (loading dosage) followed by the continuous treatment determined the optimal therapeutic regimen using SC 150 mg secukinumab (Fig. 1). Secukinumab was associated with a safety profile comparable to placebo [17].

A similar phase IIB regimen-finding study was conducted to evaluate IV secukinumab induction regimens [18]. All secukinumab IV induction regimens were associated with significantly greater rates of PASI 75 and 90 responses at week 12 compared with placebo. Although there were six SAEs in the secukinumab treatment cohort, none were considered by the investigators to be drug-related. Currently, secukinumab is being tested in several phase III clinical trials including a study evaluating efficacy of withdrawal-and-retreatment, a study comparing secukinumab with etanercept, a study concerning moderate-to-severe palmoplantar psoriasis and another trial on PsA [19].

Secukinumab in Psoriatic Arthritis

The efficacy and safety of secukinumab in patients with moderate-to-severe PsA was investigated in a 24-week, randomized, double-blind, placebo-controlled, phase II proof-of-concept trial [20]. Patients (n = 42) with active PsA were randomized (2:1) to receive two IV secukinumab doses (10 mg/kg; n = 28) or placebo (n = 14) 3 weeks apart. The primary objective of the study was the proportion of American College of Rheumatology 20 responses at week 6 for secukinumab versus placebo. At week 6, ACR20 responses were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (P = 0.27). In contrast, no differences were registered for ACR 20 between secukinumab versus placebo at week 12 and week 24 [19]. At week 6, ‘good’ European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) in placebo group. Compared with placebo at week 6, significant reductions were observed among secukinumab patients for C reactive protein (P = 0.039), erythrocyte sedimentation rate (P = 0.038), Health Assessment Questionnaire Disability Index (P = 0.002) and Short Form Health Survey (SF-36; P = 0.030) scores. The overall AE frequency was similar between secukinumab and placebo. Six SAEs were reported in four secukinumab patients and one SAE in one placebo patient. Clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, although the primary endpoint was not achieved. Phase III clinical trials investigating secukinumab in PsA are ongoing.

Safety of Secukinumab in Chronic Plaque Psoriasis and PsA

The crucial role of IL-17 in the innate immune response, poses IL-17 as the main driver of the host defense against extracellular bacterial (Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae), parasitic (Toxoplasma gondii) and fungal (Candida spp.) infections [21–23]. Importantly, both IL-17A and IL-17F are needed for muco-cutaneous immunity against Candida albicans, but their effects are largely redundant. Genetic deficiency in IL-17RA, in humans, is associated with recurrent or persistent muco-cutaneous infections caused by C. albicans and, to a lesser extent, S. aureus [24].

In the aforementioned studies, secukinumab was well tolerated, with an overall good safety profile; none of the patients developed anti-secukinumab antibodies and there were no reports of injection-site reactions. Most of the AEs were mild or moderate in severity, particularly infections (Table 2) [16–18]. Vaccination against influenza is currently recommended to patients suffering from psoriasis [25]; previous studies have shown that vaccination against influenza virus and pneumococcus is safe with concomitant treatment with biologics like adalimumab and etanercept, and that it induces a satisfactory humoral response, whereas other agents, like rituximab, impaired vaccine effectiveness [26, 27]. Chioato et al. [28] have shown that blockade of IL-17A by secukinumab does not interfere with efficacy of influenza and meningococcal vaccinations, as assessed by the achievement of protective antibody levels.

Table 2 The most frequent adverse events (occurring in more than 5% of patients) reported in phase II clinical trial with different IL-17 inhibitors
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Other IL-17A Inhibitors in Chronic Plaque Psoriasis

Targeting of the IL-17A pathway for the treatment of psoriasis is being investigated with high interest now and other two agents that inhibit IL-17A are in phase III of clinical development, i.e., ixekizumab and brodalumab. Ixekizumab is a humanized IgG4 mAb neutralizing IL-17A. The safety and efficacy of ixekizumab was evaluated in a phase II, double-blind, placebo-controlled trial with 142 patients affected by moderate-to-severe plaque-type psoriasis [29]. Patients were randomized into five groups receiving 150, 75, 25, 10 mg ixekizumab or placebo, subcutaneously at 0, 2, 4, 8, 12, and 16 weeks [29]. The achievement of 75% reduction of PASI 75 after 12 weeks occurred in 82.1%, 82.8%, 76.7%, 29.0%, and 7.7% of patients, respectively. Regarding the safety profile, the occurrence of AEs, including nasopharyngitis, upper respiratory infection, injection-site reaction, and headache, was similar across all study groups, and no SAEs were reported (Table 2). Phase III studies are currently ongoing including a two head-to-head trials with etanercept and adalimumab in patients with PsA [30]. Ixekizumab is undergoing evaluation as a treatment for moderate-to-severe psoriasis in three phase III studies, UNCOVER-1 (Clinicaltrials.gov #NCT01474512), UNCOVER-2 (Clinicaltrials.gov #NCT01597245), and UNCOVER-3 (Clinicaltrials.gov #NCT01646177). These three studies have estimated completion dates between February 2018 and April 2019 [31].

Brodalumab is a human mAb blocking IL-17RA, the receptor subunit shared by IL-17A, IL-17F, and IL-17A/F heterodimer ligands. The antagonism of IL-17 signaling by brodalumab was initially proven effective in inducing clinical, histologic, and genomic resolution of psoriasis after only 1 week of treatment in a phase I, proof-of-concept study enrolling 10 patients with psoriasis [32]. Further substantiating the efficacy is a more recent phase II, randomized, double-blind, placebo-controlled, dose-ranging study involving 198 patients randomly assigned to receive SC brodalumab at the dosage of 280 mg monthly, or 70, 140, 210 mg or placebo at weeks 0, 1, 2, 4, 6, 8, and 10 [33]. This 12-week study assessed the efficacy of brodalumab in treating psoriasis with a mean percentage improvement of 45.0%, 85.9%, 86.3%, 76.0% and 16.0% of PASI score using 280, 210, 140, 70 mg, or placebo, respectively (P < 0.001 for all comparison vs. placebo) [33]. Common AEs occurred with greater frequency in the high-dose brodalumab group; among the SAEs, two cases of mild neutropenia (Grade III) were reported (Table 2) [33].

Conclusion

Psoriasis is facing very rapid advances in the understanding of its pathogenesis that drives a fast expanding availability of new therapeutic agents. Although anti-TNF-α drugs have markedly improved the therapeutic options of patients with autoimmune diseases, there is still a need for new treatment options for patients who lose response, fail to respond, or are intolerant to their current treatment [34]. More specific treatment options, with fewer side effects and a milder effect on the immune system, need to be identified. As more studies are performed, more clinical experience is gained, and more biomarkers of clinical response are identified, we will be able to determine which drugs are the most suitable for the long-term treatment of psoriasis. Pharmacogenetics studies may also help to tailor a more stratified therapeutic approach [35, 36]. Experimental and clinical studies have identified IL-17 as a ‘driver’ cytokine of psoriasis and thus as an important therapeutic target. Based on good tolerability of IL-17 antagonists in phase II trials, it is expected that these agents are likely to become major future therapeutics for the treatment of psoriasis, although the exact place of these drugs needs further study. However, large-scale, phase III clinical trials are ongoing and they will provide informative data about the long-term efficacy and safety. Secukinumab is now in an advanced phase of development, but other anti-IL-17 agents have been designed and they, too, may expand the future therapeutic armamentarium. Still, the physiologic impact of long-term IL-17 antagonism will need to be demonstrated in larger and longer clinical trials and there might be important differences in antagonizing IL-17A versus the IL-17 receptor, which subtends broader cytokine effects. Also, there is a need for a better understanding of how IL-17 antagonism will impact PsA and other comorbidities that are associated with psoriasis and have a presumptive inflammatory etiology. Of these, the role of IL-17 in cardiovascular diseases holds special interest since there is increasing recognition that IL-17 is a major risk cytokine for atherosclerosis in model systems and that reduced expression or blockade of IL-17 can reduce formation of atherosclerosis lesions [37].