Melinda Gooderham, MD, MSc, FRCPC1,4; Claudia J. Posso-De Los Rios, MD1; Gustavo A. Rubio-Gomez, MD1,2; Kim Papp, MD, PhD, FRCPC3,4
1Skin Centre for Dermatology, Peterborough, ON, Canada
2Division of Dermatology, University of Toronto, Toronto, ON, Canada
3K. Papp Clinical Research, Waterloo, ON, Canada
4Probity Medical Research, Waterloo, ON, Canada
Acting on keratinocytes to produce antimicrobial peptides and chemokines, which in turn attract neutrophils and other inflammatory cells, interleukin-17 (IL-17) is believed to be a potent driver of plaque psoriasis. Its proinflammatory characteristics make IL-17 an attractive therapeutic target for addressing immune dysregulation. This review examines the role of IL-17 in the pathogenesis of plaque psoriasis and the potential implications of its inhibition. The efficacy and safety results from Phase 2 and 3 trials with monoclonal antibodies targeting IL-17RA (brodalumab), and IL-17A (ixekizumab and secukinumab) validate IL-17 as an effective therapeutic target for the treatment of plaque psoriasis.
IL-17, interleukin-17, interleukin-17A, interleukin-17R, monoclonal antibody, chronic plaque psoriasis, psoriatic arthritis
Pathogenesis of Plaque Psoriasis
Psoriasis vulgaris (plaque psoriasis) is a chronic, inflammatory, immune-mediated disease.1 Genetically-susceptible individuals subjected to various environmental factors develop inflammation and subsequent keratinocyte proliferation.2
In psoriasis both the innate and adaptive immune system are dysregulated.3 The current pathogenic model in psoriasis highlights the role of T helper 17 (Th 17)/interleukin 17 (IL-17) axis dysfunction as an important source of inflammation.3,4 Initially, activated dendritic cells may drive the activation of a subgroup of T cells (Th 17 cells) through IL-23, producing IL-17, interferon-γ (IFN-γ) and other proinflammatory cytokines. This array of cytokines results in keratinocyte and vascular response changes.3-5 A consequence of keratinocyte response to the proinflammatory cytokines is production of chemokines and cytokines, which enhance cell recruitment. Specifically, neutrophil recruitment creates a positive feedback loop.4,6 Because of its potential action on keratinocytes, IL-17 has been considered a “driver” cytokine in psoriasis.3,7 Treatments targeting the IL-17 pathway using monoclonal antibodies have shown significant clinical efficacy in reducing the inflammation in this condition.3,4,8-14
Psoriasis affects 2-3% of the population worldwide15, and it is associated with significant impairment of quality of life and work productivity16. Multiple efforts are being made to better understand its pathogenesis and to develop treatments with specific targets.
The purpose of this manuscript is to review the current literature regarding the efficacy and safety of IL-17 inhibitors in the treatment of moderate-to-severe plaque psoriasis.
T cell Differentiation and Impact of Th 17 Cells
Although T-helper 1(Th1) subset of activated T cells is the predominant cell type in plaque psoriasis, Th17 plays an integral role in the pathogenesis of plaque psoriasis.17,18
In a bridging of the innate and adaptive immune system, undifferentiated T cells bind antigen presenting cells (APCs) and through T cell receptor (TCR)-binding, co-stimulation and the cytokine milieu, T cells differentiate into an effector phenotype.19
APC-derived cytokine, interleukin-12 (IL-12), causes differentiation of Th1 cells, and IL-1β, IL-6 and transforming growth factor-β (TGFβ) cause differentiation of Th17 cells. IL-23 is necessary for stabilization, survival and proliferation of the Th17 cell type.19
IL-17: A Driver of Plaque Psoriasis
IL-23-activated Th17 cells were discovered to produce IL-17, IL-6 and tumor necrosis factor (TNF) through antigen-specific stimulation.18,20 IL-17 acts on epithelial cells such as keratinocytes to produce antimicrobial peptides and chemokines, which attract neutrophils and other inflammatory cells.17
The IL-17 family is a group of molecules involved in host defense against pathogens and inflammatory processes.21-26 There are six known subtypes (A, B, C, D, E and F) and increased expression of three of them (A, C and F) has been implicated in the pathogenesis of inflammation in psoriasis. However, their functions are not fully elucidated.23,24,27,28 These molecules interact with a group of transmembrane receptor subunits known as IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE.27,29-32
IL-17A, composed of 155 amino acids and with a molecular weight of 15 kDa, is the best studied member of this family. It has been related to important roles in different disorders including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and psoriasis;23,27,33-36 IL-17A forms homodimers or heterodimers with molecules of IL-17F, which interact with heteromeric receptors (two IL-17RA subunits and one IL- 17RC subunit). This interaction triggers downstream gene activation.21,23,30 IL-17 isoforms have been identified as products of Th17 cells. However, other cells involved in the immune response, such as CD8+ T cells, eosinophils, mast cells, natural killer cells, neutrophils, Tc17 cells and a subset of gamma delta (γδ) T cells (Vγ9Vδ2) related to the activation of keratinocytes in psoriasis, are able to produce these molecules as well.21,22,30,37,38
IL-17A induces recruitment of cells to psoriatic lesions through stimulation of keratinocyte production of chemokines. For example, CCL20 recruits myeloid dendritic cells and Th17 cells that perpetuate the inflammatory process.3,21,39-41 IL-17A also stimulates keratinocytes to produce other chemokines such as CXCL1, CXCL3, CXCL5, CXCL6, CXCL8 and B-defensin that act as neutrophil chemoattractants.20,21,39,40,42,43 IL-17A-mediated stimulation of macrophages, fibroblasts and endothelial cells contributes to the amplification of the inflammatory response in psoriatic lesions. This amplification is the result of increased production of molecules such as CXCL8 (IL-8), IL-1, IL-6 and TNF-α.21,25,44 Additionally, IL-17A potentiates skin barrier disruption through downregulation of the expression of filaggrin.45 IL-17C, which interacts with receptor subunits IL-17RA and IL-17RE, is also present in psoriatic lesions and has been reported as the most abundant isoform. IL-17C localizes to keratinocytes, endothelial cells and leukocytes. Its effect on the production of TNF-α and synergistic actions are similar to those produced by IL-17A.27,46
Therapeutic Implications of IL-17 Inhibition
The molecular features of IL-17 made it an attractive therapeutic target and specifically as targeted therapy in plaque psoriasis. Currently, three monoclonal antibodies targeting IL-17 are in clinical development – brodalumab, ixekizumab and secukinumab.8-13
Brodalumab is a human, anti-IL-17-receptor (anti–IL-17RA) monoclonal antibody that binds with high affinity to human interleukin-17RA. IL-17RA blockade inhibits the biologic activity of interleukins 17A, 17F, 17A/F heterodimer and 17E (IL-25).8 Ixekizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody9 and secukinumab is a fully human IgG1κ monoclonal antibody10-13 that selectively bind and neutralize IL-17A.
Clinical Efficacy of IL-17 Inhibitors
At the time of this review, Phase 3 trial results for brodalumab and ixekizumab have been reported in press releases (presented later in the manuscript), while results of the Phase 3 program for secukinumab were recently published.8-13 Inclusion criteria for all Phase 2 and 3 programs required chronic plaque psoriasis having severity measures of psoriasis area and severity index (PASI) ≥12, body surface area (BSA) ≥10% and static physician global assessment (sPGA) of ≥3.8-13
Demonstrated Efficacy in Phase 2 Trials
Four Phase 2 studies on three IL-17 inhibitors for plaque psoriasis have been published to date.8-11
In a Phase 2 randomized, double-blind, placebo-controlled, doseranging study of brodalumab included 198 patients, who received either placebo or 70 mg, 140 mg, or 210 mg subcutaneous (SC) brodalumab at weeks 0, 1, 2, 4, 6, 8, and 10 or 280 mg at weeks 0, 4, 8. The PASI 75 at week 12 was 33%, 77%, 82% and 67%, for the 70 mg, 140 mg, 210 mg and 280 mg dosing regimens, respectively. The PASI 75 response at week 12 in all active treatment arms was statistically significant compared to placebo (p<0.001, for all). The PASI 90 of the three highest dose groups was 72% for 140 mg, 75% for 210 mg, and 57% for 280 mg vs. placebo (p<0.001, for all).8
The Phase 2, double-blind, placebo-controlled trial of ixekizumab included 142 patients with chronic moderate-to-severe plaque psoriasis who were treated with either placebo or 10 mg, 25 mg, 75 mg or 150 mg SC ixekizumab at weeks 0, 2, 4, 8, 12, and 16. The PASI 75 responses at week 12 were 29% (10 mg), 77% (25 mg), 83% (75 mg) and 82% (150 mg) vs. placebo (p<0.001, for all). The PASI 90 scores of the 50 mg, 75 mg and 150 mg were notable, at 50%, 59% and 71%, respectively, vs. placebo (p<0.001, for all).9
There were two Phase 2 programs for secukinumab, a doseranging study10 and a regimen-finding study11.
The dose-ranging study examined 125 patients who received placebo, 25 mg, 75 mg or 150 mg SC secukinumab at weeks 0, 4, 8 vs. a single dose of 25 mg. Primary endpoint of PASI 75 at week 12 was met by 57% of patients receiving 75 mg and 82% of patients receiving 150 mg vs. placebo (p=0.002 and p<0.001, respectively). PASI 90 was reached by 52% of patients on the 150 mg dose vs. placebo (p<0.001). This was the only group that reached statistically-significant PASI 90 response vs. placebo.10
The regimen-finding study included 404 patients who were randomized to placebo or one of three SC secukinumab 150 mg dosing regimens: single (week 0), early (weeks 0, 1, 2, 4) and monthly (weeks 0, 4, 8). At week 12, PASI 75 was 54.5% for early and 42% for monthly dosing regimen vs. placebo (1.5%) (p<0.001 for both), and only 10.6% for the single regimen (p=0.0225 vs. placebo). Noteworthy is the somewhat lower PASI 75 response observed in the 150 mg monthly regimen (42%) compared to that in the dose-ranging study (82%). PASI 90 responses were 31.8% and 17.4%, for the early and monthly regimens, respectively, vs. placebo (p<0.001 for both), and 30% for the single regimen (p=0.556 vs. placebo).11
Demonstrated Efficacy in Phase 3 Trials
Secukinumab was further evaluated in four Phase 3 randomized, double-blind, placebo-controlled trials – two 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis)12, one 12-week trial, FEATURE, a bridging study assessing response of self-administration by pre-filled syringe13, and SCULPTURE, a 52-week trial comparing fixed-dose vs. retreatment-as-needed maintenance regimen with 150 mg or 300 mg secukinumab. The SCULPTURE trial is ongoing and results have not yet been published.14
In the ERASURE study, 738 patients were randomly assigned to SC secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks) or placebo.12
In the FIXTURE study, 1,306 patients were randomly assigned to SC secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly) or placebo.12
Co-primary endpoints at week 12 of PASI 75 and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator’s global assessment were met by a higher proportion of patients treated with secukinumab vs. those treated with etanercept or placebo.12
The proportion of patients meeting PASI 75 at week 12 was higher with both secukinumab doses than with placebo or etanercept. In the ERASURE study, the rates were 81.6% with secukinumab 300 mg, 71.6% with secukinumab 150 mg, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with secukinumab 300 mg, 67.0% with secukinumab 150 mg, 44.0% with etanercept, and 4.9% with placebo (p<0.001 for each secukinumab dose vs. comparators).12
The proportion of patients with a response of 0 or 1 on the modified investigator’s global assessment (IGA mod 2011) at week 12 was also higher with each secukinumab dose than with either placebo or etanercept. In the ERASURE study, the rates were 65.3% with secukinumab 300 mg, 51.2% with secukinumab 150 mg, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with secukinumab 300 mg, 51.1% with secukinumab 150 mg, 27.2% with etanercept, and 2.8% with placebo (p<0.001 for each secukinumab dose vs. comparators).12
In the FEATURE trial, 177 patients were randomized to SC secukinumab 300 mg or 150 mg, or placebo. Each treatment was delivered using a pre-filled syringe once a week for 4 weeks, and again at week 8. Co-primary endpoints at week 12 of PASI 75 were met by 75.9% in 300 mg group, 69.5% in 150 mg group, and 0% in placebo group; IGA mod 2011 0/1 were 69.0% in 300 mg group, 52.5% in 150 mg group, and 0% in placebo group (p<0.0001 for all comparisons vs. placebo). The usability of pre-filled syringe reached 100%; all patients successfully self-administered treatment at week 1, and reported high Self-Injection Assessment Questionnaire-assessed acceptability of the pre-filled syringe throughout the trial.13
Ixekizumab was studied in the largest Phase 3 program to date in 3,866 patients with moderate-to-severe plaque psoriasis. It was evaluated against placebo and etanercept. In the three UNCOVER studies, patients were randomized to either placebo or SC ixekizumab 80 mg every 2 or 4 weeks for 12 weeks, following a 160 mg induction dose. In the two active comparator studies (UNCOVER-2 and 3) patients were randomized to receive etanercept 50 mg twice weekly for 12 weeks. In UNCOVER-1, respondents to treatment either continued to receive placebo or ixekizumab 80 mg every 4 or 12 weeks for up to 60 weeks. Both dosing regimens of ixekizumab resulted in significantly greater levels of skin clearance vs. placebo and etanercept. At week 12, PASI 75 was achieved by 78-90% of patients treated with ixekizumab either every 2 or 4 weeks. PASI 100 was achieved by 31-41% of patients treated with ixekizumab vs. 5-7% of patients treated with etanercept. While the results have been reported in a press release by the sponsor Eli Lilly, they have not been formally published at the time of this review. The reader should interpret this data with caution as it has not been peer reviewed and it does not discuss trial design or statistical methodology used. (Source: press release August 21, 2014; www.lilly.com)
In the Phase 3, placebo-controlled, randomized trial, AMAGINE-1, 661 patients with moderate-to-severe plaque psoriasis were treated with placebo, 140 mg or 210 mg SC brodalumab every 2 weeks. At week 12, PASI 75 was achieved by 60.3% of patients in the 140 mg group and 83.3% in the 210 mg group vs. placebo (2.7%, p<0.001). PASI 90 was achieved by 42.5% of patients in the 140 mg group, and 70.3% in the 210 mg group vs. placebo (0.9%, p<0.001). While the results have been reported, they have not been formally published at the time of this review. (Source: Papp KA, Reich K, Leonardi C, et al. Gene to Clinic, London, UK, 2014)
Phase 3 trials evaluating brodalumab are currently underway (ClinicalTrials.gov numbers: NCT01708590, NCT01708603, NCT01708629). As well, clinical trials evaluating secukinumab (NCT01544595, NCT01806597, NCT01365455, NCT01358578, NCT01406938, NCT01636687, NCT01412944, NCT01555125) and ixekizumab (NCT01777191, NCT01597245, NCT01646177, NCT01107457, NCT01624233) are also ongoing.
IL-17 Inhibitors: Safety and Tolerability in Phase 2 and Phase 3 Trials
Phase 2 Trials
The adverse event profiles from each of the anti-IL-17 Phase 2 trials were similar. The most commonly reported events were nasopharyngitis, upper respiratory tract infection, and headache.8-11
Injection site reactions were observed with brodalumab and ixekizumab, but none were reported in either of the secukinumab trials.8-11
Laboratory parameter changes of interest were similar in all trials. Each had cases of neutropenia with the higher doses. There were two cases of grade 3 neutropenia in the brodalumab 210 mg group8, two cases of grade 2 neutropenia in the ixekizumab 75 mg and 150 mg groups9, and two cases of grade 1-2 neutropenia in the secukinumab dose-finding study in the 3 X 150 mg cohort10. There were also cases of grade 1-2 neutropenia in the regimenfinding study in both the induction and maintenance phase, but resolved during the course of the study in all cases.11
Phase 3 Trials
The adverse event profiles from each of the anti-IL-17 Phase 3 trials were also similar. The most common reported events were nasopharyngitis, upper respiratory tract infection, and headache.12,13 (Sources: press release August 21, 2014; www.lilly.com; Papp KA, Reich K, Leonardi C, et al. Gene to Clinic, London, UK, 2014)
The rates of infection were higher with secukinumab than with placebo in all trials, and were similar to those with etanercept.12,13 In the FEATURE study, the incidence of Candida infection in the secukinumab 300 mg group was twice that of the 150 mg group (one oral and one vulvovaginal candidiasis vs. one vulvovaginal candidiasis, respectively). All infections were mild-to-moderate and resolved without treatment.13 Overall, secukinumab had a comparable safety profile to that reported in previous Phase 2 trials, and while mild-moderate neutropenia was observed, it was reversible without the need for treatment interruption.10-13
Injection site reactions were reported with ixekizumab, but most were mild and did not result in treatment discontinuation. The overall rates and severity of adverse events were similar with ixekizumab and etanercept. (Source: press release August 21, 2014; www.lilly.com)
The results from Phase 2 and 3 trials targeting IL-17 with brodalumab, ixekizumab and secukinumab help validate IL-17 as an effective therapeutic target in the treatment of plaque psoriasis.8-13
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