Skin Therapy Letter HOME
Written for dermatologists by dermatologists. Indexed by the US National Library of Medicine.
Skin Information
NETWORK
Skin Therapy Letter About STL Subscribe Today Dermatology Dictionary SkinCareGuide Network Site Map
CUSTOM DERMATOLOGY SEARCH:
Loading

A Review of Ixekizumab, an Anti-Interleukin-17A Monoclonal Antibody, for Moderate-to-Severe Plaque Psoriasis

Andrew J. Peranteau, MD1; Ashley E. Turkeltaub2; Yun Tong, MD3; Zeena Nawas, MD4; Stephen K. Tyring, MD, PhD1,4
1Center for Clinical Studies, Houston, TX, USA
2Baylor College of Medicine, Houston, TX, USA
3Department of Dermatology, University of California San Diego, San Diego, CA, USA
4Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA


Conflicts of Interest: Dr. Tyring has been an investigator for clinical trials sponsored by Abbvie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Contravir, Cutanea, Dermira, Galderma, Genocea, Innovaderm, Janssen, Eli Lilly and Company, Leo Pharma, Merck, MSD, Medimmune, Novan, Novartis, Pfizer, Promius, Regeneron, Tolmar, Vitae, Watson-Actavis, and Xoma. Drs. Peranteau, Tong, and Nawas have been sub-investigators on clinical trials sponsored by the same companies listed above. Ashley Turkeltaub has no conflicts of interest to declare.

ABSTRACT

Psoriasis is a multifactorial chronic skin disease that can have significant detrimental effects on patients' physical, mental, and psychosocial wellbeing. Patients often suffer from a decreased quality of life along with numerous comorbidities. Recent advances in our understanding of the innate and adaptive immune systems have led to the identification of interleukin (IL)-17 as a key pro-inflammatory mediator in psoriasis. This knowledge has in turn led to the development of newer biologic agents that have been shown to be more effective than traditional therapies. In this article, we review phase 1-3 clinical trials of the anti-IL-17 monoclonal antibody, ixekizumab, for treatment of moderate-to-severe plaque psoriasis.

Key Words: IL-17, interleukin-17, interleukin-17A, monoclonal antibody, chronic plaque psoriasis, Talz®

Introduction

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by inflamed, thickened, scaly, and pruritic plaques.1 Although prevalence estimates vary by study, about 2-3% of the world's population - approximately 125 million people - are affected by psoriasis.2-4 While topical therapies alone are generally sufficient to control mild psoriasis, patients with moderate-to-severe disease typically require systemic therapy.5,6

Systemic treatments target specific immunological pathways implicated in the pathogenesis of psoriasis.5-7 This includes biologics such as etanercept, adalimumab, and infliximab - inhibitors of tumor necrosis factor alpha (TNFα).5 Use of these biologics is often preferred due to non-compliance and frustration caused by the lack of efficacy with traditional topical therapies and phototherapy.8 Moreover, topical treatments and phototherapy do not address the underlying joint disease seen in psoriatic arthritis, which can affect up to 30% of patients with psoriasis.9

Despite the advantages of TNFα treatment, some patients experience insufficient response, loss of efficacy, or side effects that preclude them from using these drugs long-term. Additionally, newer trials with biologics targeting interleukin (IL)-12/23 and IL-17 have shown increased efficacy in a greater proportion of patients,5 prompting further investigations of these therapeutic options.10

Rationale for IL-17 Inhibition in Psoriasis

Dysregulation of both the innate and adaptive immune systems has long been implicated in psoriasis. Early studies indicated that TNFα-producing T-helper (Th)1 cells drives much of the inflammatory cycle, as evidenced by the favorable clinical response to TNFα antagonists.1 In recent years, however, novel pathways have been discovered that implicate the p40 subunit of IL-12 and IL-23 in the induction of autoimmunity. IL-23 has also been found to be a key driver of Th17 cells, a T-cell subset distinct from both Th1 and Th2 cells. This subgroup of CD4+ T cells provides protection against extracellular bacterial and fungal pathogens, and are now understood to play a central role in the pathogenesis of psoriasis.5,10

In the psoriatic pathway, activated dendritic cells act as antigen presenting cells that produce an array of inflammatory cytokines, including TNFα and IL-23. IL-23 drives activation of Th17 cells, which in turn produce IL-17, IL-6, TNF, and other proinflammatory cytokines.11 These cytokines induce changes in keratinocytes and the skin vasculature through production of IL-20 (a modulator of keratinocyte function) and nitric oxide (a vasodilator).12 Keratinocytes then respond to these inflammatory signals by producing chemokines, cytokines, and antimicrobial peptides (AMP), which enhance recruitment of neutrophils and other inflammatory cells.12,13

One of the cytokines produced by activated Th17 cells, IL-17A, is particularly central to the pathophysiology of psoriasis. IL-17A has several crucial functions including activation, recruitment, and inhibition of apoptosis in neutrophils, enhancement of angiogenesis, the propagation of other inflammatory cytokines (TNFα, IL-1, IL-6), and the direct activation of keratinocytes leading to increased production of chemokines. These chemokines in turn cause macrophages, fibroblasts, and endothelial cells to be recruited, amplifying the inflammatory response in psoriatic lesions.14-18

Therapeutic interventions that target IL-17 and, thus, this critical pathway have become a promising new area of development in the armamentarium of antipsoriatic agents. Currently, three monoclonal antibodies targeting IL-17 exist for psoriasis: brodalumab (an anti-IL-17-receptor) as well as the FDA-approved drugs secukinumab and ixekizumab, which both selectively bind and neutralize IL-17A. In this review we will focus on clinical trial results from phase 1-3 studies of ixekizumab.

Phase 1 and 2 Studies in Plaque Psoriasis

Forty patients diagnosed with psoriasis were studied in a 20-week-long, randomized, double-blind, placebo-controlled, phase 1 trial. Patients were randomized to receive 5, 15, 50, or 150 mg of subcutaneous (SC) ixekizumab or placebo at weeks 0, 2, and 4. Punch biopsies were taken from the same lesional site at weeks 0, 2, and 6. The study was designed to determine the effect of IL-17 neutralization on the clinical features of psoriasis and to identify roles of IL-17 in inflammatory pathways underlying psoriasis.10

Significant dose-dependent reductions in keratinocyte proliferation, hyperplasia, epidermal thickness, T-cell and dendritic cell infiltration into the dermis and epidermis, and keratinocyte expression of innate defense peptides were seen after 2 weeks compared with week 0. A biopsy done at week 6 showed near normalization of skin in patients treated with the two highest doses of ixekizumab (50 and 150 mg). Clinical efficacy was measured with Psoriasis Area and Severity Index (PASI) 75 and PASI 90 (a ≥75% or ≥90% reduction in baseline PASI, respectively) after 2, 6, and 20 weeks. The results were significant at weeks 6 and 20 for subjects who received 15, 50, and 150 mg of ixekizumab compared with placebo and relative to subjects who received 5 mg of ixekizumab.10

In a randomized, double-blind, placebo-controlled, phase 2 trial, ixekizumab was evaluated in 142 patients with chronic, moderate-to-severe plaque psoriasis. Patients were randomized to receive placebo or 10, 25, 75, or 150 mg of SC ixekizumab at weeks 0, 2, 4, 8, 12, and 16. At week 12, the proportion of patients who achieved PASI 75 was significantly greater in the groups that received ixekizumab (except for the low dose, 10 mg group) than in the placebo group (77% in 25 mg group, 83% in 75 mg group, and 82% in 150 mg group, as opposed to 8% of patients who received placebo).19 For patients suffering from scalp psoriasis, nail psoriasis, and psoriatic arthritis, significant improvements were observed with the higher doses. Scalp psoriasis in particular showed rapid clinical improvement, which was maintained through 48 weeks of open label treatment.20 Significant reductions in the mean dermatology life quality index (DLQI) scores were detected at 8 weeks and sustained through 16 weeks at the three highest doses relative to placebo.19 In a post hoc analysis derived from the same study, the early clinical improvements in disease symptoms at weeks 4 and 6 were predictive of improvement in PASI 75 at week 12 in more than 90% of the cases.21 An open-label treatment study showed that clinical responses to ixekizumab were maintained after 52 weeks.22

Phase 3 Results

Ixekizumab was studied in the largest phase 3 program to date in 3,866 patients with moderate-to-severe plaque psoriasis and evaluated against placebo and etanercept. Study participants had to meet inclusion criteria of ≥18 years of age, confirmed diagnosis of psoriasis for more than 6 months before randomization, ≥10% body-surface area involvement at screening and baseline visits, at least a moderate clinical severity score based on the clinicianrated static physician global assessment (sPGA), and have a score of ≥12 on the PASI.23 Baseline characteristics were similar across all patients in the US phase 3 studies (Table 1).24,25

UNCOVER-1 UNCOVER-2 UNCOVER-3
Placebo (n=431) Ixekizumab every 4 weeks (n=432) Ixekizumab every 2 weeks (n=433) Placebo (n=168) Etanercept (n=358) Ixekizumab every 4 weeks (n=347) Ixekizumab every 2 weeks (n=351) Placebo (n=168) Etanercept (n=358) Ixekizumab every 4 weeks (n=347) Ixekizumab every 2 weeks (n=351)
Age (years) 46 ±13 46 ±13 45 ±12 45 ±12 45 ±13 45 ±14 45 ±13 46 ±12 46 ±14 46 ±13 46 ±13
Men 303 (70%) 289 (67%) 291 (67%) 120 (71%) 236 (66%) 244 (70%) 221 (63%) 137 (71%) 269 (70%) 258 (67%) 254 (66%)
Ethnic origin 431 432 433 168 354 343 350 193 382 386 385
Asian 21 (5%) 23 (5%) 18 (4%) 6 (4%) 8 (2%) 11 (3%) 12 (3%) 7 (4%) 11 (3%) 11 (3%) 12 (3%)
Black/African 8 (2%) 10 (2%) 8 (2%) 10 (6%) 13 (4%) 11 (3%) 5 (1%) 8 (4%) 10 (3%) 9 (2%) 5 (1%)
American White 401 (93%) 397 (92%) 401 (93%) 149 (89%) 331 (94%) 315 (92%) 330 (94%) 176 (91%) 351 (92%) 360 (93%) 361 (94%)
Other 1(0.2%) 2(0.4%) 6(1%) 3 (2%) 2 (1%) 6 (2%) 3 (1%) 2 (1%) 10 (3%) 9 (2%) 5 (1%)
Weight(kg) 92 ±25 92 ±24 92 ±23 92 ±22 93 ±22 93 ±33 89 ±22 91 ±21 92 ±24 91 ±24 90 ±23
<100 289 (67%) 290 (67%) 288 (67%) 111 (67%) 232 (65%) 227 (66%) 256 (73%) 138 (72%) 256 (67%) 274 (72%) 275 (72%)
≥100 142 (33%) 142 (33%) 145 (34%) 55 (33%) 125 (35%) 119 (34%) 95 (27%) 54 (28%) 126 (33%) 107 (28%) 109 (28%)
BMI (kg/m2) Unknown Unknown Unknown 31 ±7 31 ±7 31 ±7 30 ±7 30 ±6 31 ±8 31 ±7 30 ±7
Psoriasis duration (years) 20 ±12 19 ±12 20 ±12 19 ±13 19 ±12 19 ±13 18 ±12 18 ±13 18 ±12 18 ±12 18 ±12
BSA involved (%) 27 ±18 27 ±16 28 ±18 27 ±18 25 ±16 27 ±17 25 ±16 29 ±17 28 ±17 28 ±16 28 ±17
sPGA ≥4 227 (53%) 235 (54%) 202 (47%) 82 (49%) 172 (48%) 181 (52%) 173 (49%) 101 (52%) 192 (50%) 177 (46%) 178 (46%)
PASI 20 ±9 20 ±7 20 ±8 21 ±8 19 ±7 20 ±7 19 ±7 21 ±8 21 ±8 21 ±8 21 ±8
Previous biologic therapy 181 (42%) 168 (39%) 173 (40%) 43 (26%) 76 (21%) 85 (25%) 84 (24%) 33 (17%) 60 (16%) 58 (15%) 58 (15%)
Table 1:Baseline demographics and clinical characteristics in all UNCOVER trials24,25

Data are mean ± standard deviation or n (%).
BMI = body mass index; BSA = body surface area; sPGA = static physicians global assessment; PASI = psoriasis area and severity index

In the three UNCOVER studies, patients were randomized to either placebo or SC ixekizumab 80 mg every 2 or 4 weeks for a 12-week induction period, following a 160 mg loading dose. In the two active comparator studies (UNCOVER-2 and UNCOVER-3), additional cohorts were randomized to receive etanercept 50 mg twice weekly for 12 weeks. In UNCOVER-1, treatment responders either continued to receive placebo or ixekizumab 80 mg every 4 or 12 weeks for up to 60 weeks. In the UNCOVER-3 trial, patients who completed the 12-week induction period were entered into a long-term extension period at the discretion of the investigator and patient. All of these patients received ixekizumab every 4 weeks. The patients who had received placebo during the 12-week induction period received a 160 mg loading dose of ixekizumab at week 12, followed by 80 mg every 4 weeks. The patients who had received etanercept during the induction period underwent a 4-week washout period before receiving 80 mg of ixekizumab every 4 weeks starting at week 16.24 During UNCOVER-1 and UNCOVER-2 trials, patients who received ixekizumab were classified as having had a response or not having had a response at week 12. Responders were those who had a 0 (clear) or 1 (almost clear) on the sPGA and non-responders were defined as patients with a sPGA score of >1. Responders then entered a randomized withdrawal period (weeks 12-60) in which they were restratified in a 1:1:1 ratio to receive SC placebo injections every 4 weeks, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks.24

Both dosing regimens of ixekizumab resulted in significantly greater levels of skin clearance vs. placebo and etanercept. At week 12 of the UNCOVER-1 trial, PASI 75 was achieved by 89.1 % and 82.6%% of patients and PASI 90 by 70.9% and 64.8% of patients treated with ixekizumab either every 2 or 4 weeks, respectively. PASI 90 was achieved in 71% and 68% of patients given ixekizumab every 2 weeks in UNCOVER-2 and UNCOVER-3, respectively, and 60% and 65% in the ixekizumab 4 week dosing regimens vs. 0.6% and 3% given placebo and 19% and 26% given etanercept. PASI 100 was achieved by 33-39% of patients treated with ixekizumab across all three UNCOVER studies vs. 6% of patients treated with etanercept (Figure 1). The patients given ixekizumab every 2 weeks achieved higher PASI 90 and PASI 100 rates in both trials as compared to those dosing with ixekizumab every 4 weeks. In both UNCOVER-2 and UNCOVER-3, patients achieved clearance at a much quicker rate than with etanercept. For both studies and dosing groups, a greater proportion of patients reached PASI 75 as early as week 1 compared with etanercept. By week 4 of both studies, about 50% of patients given ixekizumab achieved PASI 75 vs. 8-12% of patients on etanercept.

Figure 1

Figure 1. Proportion of patients achieving PASI-75, PASI-90, PASI-100 from baseline through to week 12 in (A) UNCOVER-1, (B) UNCOVER-2, and (C) UNCOVER-3

High response rates seen in the induction period of UNCOVER-3 generally persisted during the long-term extension period. By week 60, over 70% of patients irrespective of ixekizumab every 2 or 4 weeks had achieved at least a PASI 90 and >50% had achieved a PASI 100 response. In the UNCOVER-1 and UNCOVER-2 trials, 73.8% of patients that were randomly reassigned to ixekizumab every 4 weeks maintained an sPGA score of 0 or 1 at week 60, compared to 39.0% in the ixekizumab every 12 weeks group and only 7.0% in the placebo group.24

Additionally, according to subgroup analysis, PASI 75 response rates in those given ixekizumab were comparable in biologic naïve patients vs. those with previous biologic exposure. Patients were also monitored with secondary endpoints of itch numeric rating scale (NRS) as well as the DLQI. In both UNCOVER-2 and UNCOVER-3, patients receiving ixekizumab had greater improvements in their DLQI scores (with results seen as early as 2 weeks) compared with placebo and etanercept. In both studies, greater improvements in NRS scores were reported in ixekizumab groups compared to placebo and etanercept.23,26

Similarly impressive PASI results were also observed in a phase 3, single-arm, open-label study in Japanese patients diagnosed with plaque psoriasis (PP), erythrodermic psoriasis (EP), and generalized pustular psoriasis (GPP). In this study, patients received two 80 mg SC ixekizumab injections (160 mg dose) followed by an 80 mg injection every 2 weeks through week 12 of the study (see Table 2 for pooled results of all phase 3 trials in patients with PP). Thereafter, patients received an 80 mg maintenance dose every 4 weeks for up to 52 weeks. In total 78 patients with PP, 8 with EP, and 5 with GPP were enrolled. At week 12, 98.7% (77/78) of PP patients achieved PASI 75, 83.3% (65/78) achieved PASI 90, and 32.1% (25/78) achieved PASI 100 with 46.2% (36/78) of patients eventually reaching PASI 100 by week 24. Improvements similar to those in the UNCOVER trials were also seen for the secondary endpoints of Nail Psoriasis Severity Index (NAPSI), DLQI, and visual analogue scale (VAS) scales. Of those with EP, 100% achieved PASI 75, 62.5% (5/8) achieved PASI 90, and 25% (2/8) achieved PASI 100 at week 12. At week 24, all patients continued to achieve PASI 75, with 87.5% (7/8) achieving PASI 90, and 12.5% (1/8) achieving PASI 100. In GPP patients, 80% (4/5) achieved PASI 75, 60% (3/5) achieved PASI 90, and 20% (1/5) achieved PASI 100. Week 24 result were 80% (4/5), 40% (2/5), and 40% (2/5) achieving PASI 75, 90, and 100, respectively.27

PASI-75 PASI-90 PASI-100
Placebo* 4.4% 1.1% 0.1%
Etanercept+ 47.7% 22.3% 6.3%
Ixekizumab every 4 weeks* 80.9% 62.5% 32.9%
Ixekizumab every 2 weeks^ 89.3% 70.7% 37.3%
Table 2:Percent of patients achieving PASI-75/90/100 in phase 3 trials at 12 weeks, pooled24,27

* Average of UNCOVER-1, UNCOVER-2, and UNCOVER-3 phase 3 trials
+ Average of UNCOVER-2 and UNCOVER-3 phase 3 trials
^ Average of open-label trial of ixekizumab treatment in Japanese patients with plaque psoriasis, UNCOVER-1, UNCOVER-2, and UNCOVER-3

Safety and Tolerability Profile

In the phase 2 study, adverse events (AEs) were similar for the combined ixekizumab and placebo groups. The most common adverse events were nasopharyngitis, upper respiratory infection, injection site reaction and headache.19 A total of 4 patients discontinued the study due to the hypertriglyceridemia (1 placebo patient), peripheral edema (1 patient in the 10 mg ixekizumab group), hypersensitivity (1 patient in the 10 mg ixekizumab group), and urticaria (1 patient receiving 25 mg of ixekizumab). There were 2 cases of grade 2 neutropenia (i.e., 1000 to <1500 cells per cubic millimeter) in the 75 mg and 150 mg dosing groups with no reported symptoms. In 1 patient in the ixekizumab 150 mg group with a history of treated basal cell carcinoma, 2 new basal cell carcinomas were detected during the study. No other cancers were reported.19 Two patients who received ixekizumab had elevation of creatine kinase and aspartate aminotransferase levels. No serious adverse events or death were reported in phase 2 trials.10

In all phase 3 studies (UNCOVER-1, UNCOVER-2 and UNCOVER-3), the percentage of patients with AEs was higher in the ixekizumab groups compared to those in placebo groups. The most common AEs were the same as those in the phase 2 studies (Table 3). As well, infections did occur more frequently in patients on ixekizumab compared with etanercept. During the induction period, 16 cases of likely Candida spp. infections were reported in patients receiving ixekizumab every 2 weeks (1.6%), 7 of those receiving ixekizumab every 4 weeks (0.6%), and 4 on placebo (0.5%). The exposure-adjusted incidence rates of at least 1 serious AE and of discontinuation of study due to AEs were similar in patients receiving either ixekizumab or placebo.24 No deaths were reported in any of the studies during the induction period but 3 people who had received ixekizumab at some point during the trial did die between weeks 12 and 60. Two of the deaths were related to vascular causes (1 myocardial infarction and 1 ischemic stroke) while the third died of unknown causes. Among patients who received ixekizumab at some point during the 60-week combined treatment period, 7 developed ulcerative colitis and 4 developed Crohn's disease compared with no cases of Crohn's or ulcerative colitis in those who received only placebo. At 12 weeks, 3.2% of placebo patients were found to be neutropenic while 8.5% and 9.3% were found to be neutropenic in the 4-week and 2-week ixekizumab dosing groups, respectively.24 No other clinically significant changes in lab values, vital signs, or ECGs were noted in the ixekizumab groups compared with placebo. Five cases of treatment emergent depression were noted in the ixekizumab groups, and 2 suicide attempts were reported in patients in the ixekizumab group. One patient had a previously undisclosed suicide attempt and both had psychosocial triggers preceding the attempt, which was not felt to be related to the study drug.28

Placebo (n=791) Etanercept (n=739) Ixekizumab every 4 weeks (n=1161) Ixekizumab every 2 weeks (n=1167)
Nasopharyngitis 69 (8.7%) 55 (7.4%) 104 (9%) 111 (9.5%)
Upper respiratory tract infection 28 (3.5%) 34 (4.6%) 45 (3.9%) 51 (4.8%)
Injection-site reaction 9 (1.1%) 80 (10.8%) 89 (7.7%) 117 (10.0%)
Headache 23 (2.9%) 31 (4.2%) 50 (4.3%) 51 (4.4%)
Arthralgia 17 (2.1%) 17 (2.3%) 22 (1.9%) 29 (2.5%)
Table 3:Pooled common adverse events data for all three UNCOVER trials*24

*Common is defined as treatment-emergent adverse event with frequency of ≥2% in both ixekizumab dose groups and numerically higher in ixekizumab dose groups compared to placebo.

Discussion

The results from phase 1-3 trials with ixekizumab unquestionably demonstrate incredible promise in the treatment of moderateto- severe plaque psoriasis. With several IL-17 blocking drugs currently on the market or in late stage clinical trials (i.e., ixekizumab, brodalumab, and secukinumab), data from these investigations adds to the mounting body of evidence implicating IL-17A as a cytokine integral to the pathogenesis of psoriasis.29 Several authors have noted that in previous clinical trials of biologics, PASI 75 was often used as a benchmark to measure clinical success, however, because of the exceptional efficacy of the IL-17A inhibitors in the treatment of psoriasis, PASI 90 may now become the new standard for primary endpoints in clinical investigations.30 In addition to high response rates in the 2-week dosing group (68-71% of patients achieving PASI 90), roughly 40% of patients in those same dosing groups experienced complete remission of their psoriasis (i.e., PASI 100) by week 12, with 55% achieving a PASI 100 by week 60 after every 2-week induction dosing followed by 4-week maintenance dosing through week 60. Among patients in the 2-week and 4-week dosing groups who had a sPGA score of 0 or 1 at week 12 and were randomly reassigned to ixekizumab every 4 weeks through week 60, 78.3% and 68.7%, respectively, maintained an sPGA score of 0 or 1, indicating the high initial response to ixekizumab persists with 4-week maintenance dosing.24 Secondary endpoints such as health related quality of life and itch scores were similarly impressive. The overall safety profile of ixekizumab in phase 2 and 3 studies has also been comparable with etanercept, although slightly higher in ixekizumab groups compared with etanercept or placebo.23

Additionally, it is important to note that previous biologic exposure did not seem to affect the efficacy of ixekizumab. This is in contrast to patients treated with etancercept, where prior biologic exposure resulted in lower response rates compared to biologic naïve patients. These results have been demonstrated in previous studies as well.23 Treatment emergent anti-drug antibodies (TE-ADA) was also assessed during the study, as higher levels can result in reduced biologic efficacy over time. However, the vast majority of patients in both the 2-week and 4-week ixekizumab dosing groups showed no or low levels of TE-ADA.31

As Th17 cells contribute to the pathogenesis of several inflammatory diseases, it is important to continue to monitor these diseases in long-term studies. One of the main functions of Th17 cells and IL-17 is in the adaptive immune response against bacterial and fungal infections. IL-17A is needed for mucocutaneous immunity against Candida albicans (C. albicans), and it has been shown in humans that genetic deficiency in IL-17RA is associated with recurrent or persistent mucocutaneous infections caused by C. albicans as well as infections with Staphylococcus aureus. IL-17A deficiency is also associated with chronic mucocutaneous candidiasis. Although more cases of candida infections were seen in ixekizumab groups as opposed to etanerecpt or placebo, overall the infections were non-invasive in nature, infrequent, and treatable.23, 28

In total, 11 patients developed inflammatory bowel disease during the phase 3 trials with 4 of those patients having a prior history of the disease.24 Moreover, another IL-17 inhibitor, secukinumab, was not only shown to be ineffective in treating Crohn's disease, but rather exacerbated the condition in a previous trial, although this study is limited by a small sample size.32 In combination, these results indicate that patients taking drugs that block IL-17A should be monitored for such potential AEs and further research is needed to understand the gastrointestinal effects of IL-17 inhibition.28

Although studies have demonstrated that low levels of IL-17 have been associated with repeat myocardial infarctions and may negatively impact atherosclerotic plaque stability, the interactions are complex and merit further investigation. Although 3 patients died in the 60 week phase 3 studies (2 from vascular causes and 1 from unknown cause), the exposure-adjusted incidence rates of major adverse cardiovascular and cerebrovascular events (MACE) in the induction period were similar in the placebo group and the 4-week dosing group (0.6 and 0.8 incidence rate per 100 patient years, respectively). No patients in the 2-week dosing group experienced a MACE.24

A side effect of particular importance is depression and suicidal behavior. In May 2015, the pharmaceutical companies developing brodalumab, a human anti-IL-17RA monoclonal antibody, abruptly halted phase 3 clinical trials based on suicidal ideation and behavior observed in the brodalumab groups.33 A pivotal question then becomes whether suicide risk might be a class effect of IL-17 related products. Key differences do exist however, most notably that brodalumab blocked the receptor and not the inflammatory cytokine. Secukinumab, the IL-17A blocking drug recently approved by the FDA, has not demonstrated a link to increased suicide risk.34 Additionally, some have questioned whether the studies were even powered sufficiently to detect this effect in a population that has higher baseline depression rates.32,34 Another possible confounder is that suicide rates have accelerated dramatically in the US since 2008, particularly in white men, who are overrepresented in clinical studies on psoriasis, including the brodalumab trials.34 Finally, recently published details from the brodalumab trials noted that the investigators felt there was no reasonable possibility that the suicides were related to the investigational product.35

Overall, ixekizumab demonstrates high levels of skin clearance as evidenced by the sum of available clinical data. Long-term data on safety and efficacy beyond 60 weeks of treatment remains to be seen, therefore, ongoing trials will shed more light on how ixekizumab will be incorporated into the treatment paradigm for psoriasis.

References

  1. Chandrakumar SF, Yeung J. Interleukin-17 antagonists in the treatment of psoriasis. J Cutan Med Surg. 2015 Mar-Apr;19(2):109-14.
  2. Parisi R, Symmons DP, Griffiths CE, et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013 Feb;133(2):377-85.
  3. International Federation of Psoriasis Associations (IFPA). Psoriasis is a serious disease deserving global attention. 2012.
  4. World Health Organization. Psoriasis: report by the secretariat. 5 Apr 2013; EB133/5:1-4. Available at: http://apps.who.int/gb/ebwha/pdf_files/EB133/ B133_5-en.pdf. Accessed October 2, 2016.
  5. Ren V, Dao H, Jr. Potential role of ixekizumab in the treatment of moderate-tosevere plaque psoriasis. Clin Cosmet Investig Dermatol. 2013 6:75-80.
  6. Boehncke WH, Schon MP. Psoriasis. Lancet. 2015 Sep 5;386(9997):983-94.
  7. Reich K. Anti-interleukin-17 monoclonal antibody ixekizumab in psoriasis. N Engl J Med. 2012 Jul 19;367(3):274; author reply 275.
  8. Christophers E, Segaert S, Milligan G, et al. Clinical improvement and satisfaction with biologic therapy in patients with severe plaque psoriasis: results of a European cross-sectional observational study. J Dermatolog Treat. 2013 Jun;24(3):193-8.
  9. Gladman DD. Psoriatic arthritis. Dermatol Ther. 2009 Jan-Feb;22(1):40-55.
  10. Lonnberg AS, Zachariae C, Skov L. Targeting of interleukin-17 in the treatment of psoriasis. Clin Cosmet Investig Dermatol. 2014 7:251-9.
  11. McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 2006 Jan;27(1):17-23.
  12. Wolk K, Witte E, Warszawska K, et al. The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis. Eur J Immunol. 2009 Dec;39(12):3570-81.
  13. Blumberg H, Conklin D, Xu WF, et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell. 2001 Jan 12;104(1):9-19.
  14. Ruddy MJ, Wong GC, Liu XK, et al. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem. 2004 Jan 23;279(4):2559-67.
  15. Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003 Apr 1;101(7):2620-7.
  16. Dragon S, Saffar AS, Shan L, et al. IL-17 attenuates the anti-apoptotic effects of GM-CSF in human neutrophils. Mol Immunol. 2008 Jan;45(1):160-8.
  17. Harper EG, Guo C, Rizzo H, et al. Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Invest Dermatol. 2009 Sep;129(9):2175-83.
  18. Rizzo HL, Kagami S, Phillips KG, et al. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J Immunol. 2011 Feb 1;186(3):1495-502.
  19. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012 Mar 29;366(13):1190-9.
  20. Langley RG, Rich P, Menter A, et al. Improvement of scalp and nail lesions with ixekizumab in a phase 2 trial in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol. 2015 Sep;29(9):1763-70.
  21. Zhu B, Edson-Heredia E, Cameron GS, et al. Early clinical response as a predictor of subsequent response to ixekizumab treatment: results from a phase II study of patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2013 Dec;169(6):1337-41.
  22. Gordon KB, Leonardi CL, Lebwohl M, et al. A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with chronic plaque psoriasis. J Am Acad Dermatol. 2014 Dec;71(6):1176-82.
  23. Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015 Aug 8;386(9993):541-51.
  24. Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 Trials of Ixekizumab in Moderateto- Severe Plaque Psoriasis. N Engl J Med. 2016 Jul 28;375(4):345-56.
  25. Armstrong AW, Lynde CW, McBride SR, et al. Effect of Ixekizumab treatment on work productivity for patients with moderate-to-severe plaque psoriasis: analysis of results from 3 randomized phase 3 clinical trials. JAMA Dermatol. 2016 Jun 1;152(6):661-9.
  26. Gooderham M, Posso-De Los Rios CJ, Rubio-Gomez GA, et al. Interleukin-17 (IL-17) inhibitors in the treatment of plaque psoriasis: a review. Skin Therapy Lett. 2015 Jan-Feb;20(1):1-5.
  27. Saeki H, Nakagawa H, Ishii T, et al. Efficacy and safety of open-label ixekizumab treatment in Japanese patients with moderate-to-severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1148-55.
  28. Yiu ZZ, Griffiths CE. Interleukin 17-A inhibition in the treatment of psoriasis. Expert Rev Clin Immunol. 2016 12(1):1-4.
  29. Blauvelt A. Ixekizumab: a new anti-IL-17A monoclonal antibody therapy for moderate-to severe plaque psoriasis. Expert Opin Biol Ther. 2016 16(2):255-63.
  30. Puig L. PASI90 response: the new standard in therapeutic efficacy for psoriasis. J Eur Acad Dermatol Venereol. 2015 Apr;29(4):645-8.
  31. Blauvelt A, Langley R, Leonardi C, et al. Ixekizumab, a novel anti-IL-17A antibody, exhibits low immunogenicity during long-term treatment in patients with psoriasis. J Am Acad Dermatol. 2016 May;74(5 Suppl 1): AB258.
  32. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012 Dec;61(12):1693-700.
  33. Danesh MJ, Kimball AB. Brodalumab and suicidal ideation in the context of a recent economic crisis in the United States. J Am Acad Dermatol. 2016 Jan;74(1):190-2.
  34. Rennert P. Brodalumab for psoriasis - what a mess. SugarCone Biotech. 2015 May 25. Available at: http://www.sugarconebiotech.com/?p=912. Accessed October 2, 2016.
  35. Karon A. Broadalumab met primary endpoints, deaths called 'unrelated'. Dermatology News. 2016 Mar 7. Available at: http://www.edermatologynews. com/specialty-focus/psoriasis/single-article-page/brodalumab-met-primaryendpoints-deaths-called-unrelated/85bffcfa68fe2882abe466f3d1104a23.html. Accessed October 2, 2016.

In this issue:

  1. A Review of Ixekizumab, an Anti-Interleukin-17A Monoclonal Antibody, for Moderate-to-Severe Plaque Psoriasis
  2. Update on Efinaconazole 10% Topical Solution for the Treatment of Onychomycosis
  3. Update on Drugs and Drug News - November-December 2016