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, PhD<sup>1,4

1</sup>Center 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

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.
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

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

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.

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