A Novel Paradigm for Treatment of Moderate-to-severe Plaque-type Psoriasis

Secukinumab
Review of Clinical Evidence from the Pivotal
Studies ERASURE, FIXTURE, and CLEAR
a
April W. Armstrong, MD; bKim Papp, MD; cLeon Kircik, MD
a
University of Southern California, Los Angeles, California; bProbity Medical Research,
Waterloo, Ontario, Canada; cIcahn School of Medicine at Mount Sinai, New York, New York

17 inhibitors as a key, novel treatment option for plaque

Introduction psoriasis. In this article, the investigators evaluated the
efficacy and safety of secukinumab for moderate-to-severe
Psoriasis is a chronic, inflammatory skin disease that psoriasis in two Phase 3 studies. The ERASURE (Efficacy of
affects 3.2 percent of the United States population and Response and Safety of Two Fixed Secukinumab Regimens in
approximately 125 million individuals worldwide.1 Psoriasis) study evaluated the efficacy of secukinumab
Translational studies have shown that interleukin (IL)-17A, a versus placebo. In comparison, the FIXTURE (Full Year
pro-inflammatory cytokine, plays a crucial role in the Investigative Examination of Secukinumab vs. Etanercept
pathogenesis of psoriasis.2–5 Secukinumab is a fully human, Using Two Dosing Regimens to Determine Efficacy in
anti-interleukin-17A (IL-17A) monoclonal antibody that Psoriasis) study evaluated the efficacy of secukinumab
binds and neutralizes IL-17A. The action of secukinumab versus etanercept and versus placebo.
leads to a decrease in IL-17A levels, dermal inflammatory
infiltrate, and epidermal thickening. Clinically, psoriasis
patients who have been treated with secukinumab
experience significant improvement in their psoriasis disease Secukinumab versus Placebo: the ERASURE
severity, itching, and quality of life.6–9
study

Primary objective. In the 52-week ERASURE study,

Approved Dosing the primary objective was to evaluate Week 12 superiority of
secukinumab over placebo as measured by two coprimary
Clinical trial results have led to the approval of endpoints: 1) proportion of patients experiencing 75 percent
secukinumab for plaque psoriasis in the United States and or more reduction in psoriasis severity from baseline using
parts of Europe and Asia in 2015. For example, in the United the Psoriasis Area and Severity Index (PASI) score (or
States, the approved dosing for secukinumab for plaque proportion of patients achieving PASI 75), and 2) proportion
psoriasis is 300mg subcutaneously every week for the first of patients achieving 0 (clear) or 1 (almost clear) on a 5-point
five weeks and then 300mg subcutaneously every four weeks. modified Investigator’s Global Assessment (IGA) (scores
As of February 2016, secukinumab has also gained United 0–4).
States Food and Drug Administration (FDA) approval for Study design and study population. The ERASURE
psoriatic arthritis and ankylosing spondylitis. study is a randomized, Phase 3, double-blind, 52-week
In this article, the authors discuss the findings from the clinical trial that took place between June 2011 through April
landmark, pivotal trials regarding secukinumab in the 2013 at 88 sites worldwide. This study had a screening period
treatment of plaque psoriasis: ERASURE (secukinumab vs. of 1 to 4 weeks, an induction period of 12 weeks, a
placebo), FIXTURE (secukinumab vs. etanercept vs. maintenance period of 40 weeks, and a follow-up period of
placebo), and CLEAR (secukinumab vs. ustekinumb). This eight weeks.
discussion serves to improve practitioners’ understanding of The inclusion criteria for the study are as follows. To be
the clinical trial evidence for secukinumab in psoriasis. eligible for the study, the patients had to be 18 years or older
with moderate-to-severe plaque psoriasis that had been
diagnosed at least six months before randomization. In
addition, their plaque psoriasis had to be poorly controlled
Clinical Evidence with topical treatments, phototherapy, systemic therapy, or a
combination of these treatments. Patients had to have a
In 2014, Langley et al6 published the landmark paper in baseline PASI score of 12 or higher, a score of 3 or 4 on the
The New England Journal of Medicine that introduced IL- modified IGA, and body surface area (BSA) of 10 percent or

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greater. after which the response has stabilized.
At the beginning of the study, 738 patients with plaque Safety. Overall, the rates of adverse events were similar
psoriasis were initially randomly assigned to one of three between the secukinumab groups and the placebo during the
arms: secukinumab 300mg (administered once weekly for 5 induction period. However, higher proportions of patients
weeks, then every 4 weeks), secukinumab 150mg, or placebo. with infections were seen in the secukinumab group (29% in
Across the study groups, the patients’ demographic and the 300mg group and 27% in the 150mg group) compared to
baseline clinical characteristics were balanced. In the placebo (16%). Throughout the study, the most common
ERASURE study, the average age of participants were 45 adverse effects were nasopharyngitis, upper respiratory track
years, 69 percent being male, and 79 percent being Caucasian. infection, and headache.
The average weight was between 87kg to 90kg, and the body
mass index (BMI) averaged 30. Patients had 17 years duration
of plaque psoriasis. Among the three study groups, the
baseline average PASI score is between 21.4 to 22.5, and the Secukinumab versus Etanercept and versus
BSA is between 29.7 to 33.3 percent. Approximately two-
thirds of patients had a score of 3 (moderate disease) on Placebo: the FIXTURE Study
modified IGA, and one-third had a score of 4 (severe disease)
on modified IGA. Between 19 to 27 percent of patients have Primary objective. Similar to the ERASURE study, the
psoriatic arthritis. Approximately 30 percent of patients were primary objective of the 52-week FIXTURE study was to
on a previous biologic agent. More patients in the evaluate Week 12 superiority of secukinumab over placebo as
secukinumab groups were previously on a conventional agent measured by two coprimary endpoints: 1) proportion of
(51–52%) compared to placebo group (44%). patients achieving PASI 75, and 2) proportion of patients
Outcomes: Coprimary endpoints and key achieving 0 (clear) or 1 (almost clear) on the modified IGA.
secondary endpoints. Overall, secukinumab was found to The key difference between the ERASURE and the
be superior to placebo in all of the coprimary and key FIXTURE study is that, in the FIXTURE study, etanercept
secondary endpoints. In addition, the 300mg secukinumab was used as one of the comparator arms. This study design is
achieved numerically superior response rates with respect to to reflect the different key secondary objectives in the
efficacy endpoints compared to the 150mg dose. FIXTURE study to compare secukinumab versus etanercept.
Specifically, at the end of 12 weeks, the investigators Study design and study population. The FIXTURE
found that the proportion of patients achieving PASI 75 was study is also a randomized Phase 3, double-blind, 52-week
81.6 percent in the secukinumab 300mg arm, 71.6 percent in clinical trial that took place between June 2011 through June
secukinumab 150mg arm, and 4.5 percent in the placebo arm 2013 at 231 sites worldwide. This study had a screening
(P<0.001 for each secukinumab dose vs. placebo). The period of 1 to 4 weeks, an induction period of 12 weeks, a
proportion of patients achieving IGA 0 or 1 was 65.3 percent maintenance period of 40 weeks, and a follow-up period of
with secukinumab 300mg, 51.2 percent with secukinumab eight weeks.
150mg, and 2.4 percent with placebo (P<0.001 for each The inclusion criteria and exclusion criteria for the
secukinumab dose vs. placebo). FIXTURE study are similar to those of the ERASURE study
The key secondary endpoints that were assessed were except that patients who had used etanercept at anytime
PASI 90, patient-reported psoriasis-related itching, pain, before screening were excluded.
and scaling on the Psoriasis Symptom Diary at Week 12, In the FIXTURE study, 1,306 patients with plaque
maintenance of PASI 75 and IGA 0 or 1 from Week 12 psoriasis were initially randomly assigned to one of the four
through Week 52. The investigators found that the PASI 90 arms: secukinumab 300mg (administered once weekly for 5
responses at Week 12 were 59 percent, 39 percent, and weeks, then every 4 weeks), secukinumab 150mg,
one percent in patients randomized to secukinumab etanercept 50mg (administered twice weekly for 12 weeks
300mg, 150mg, and placebo, respectively. The PASI 100 and then once weekly), or placebo.
responses at Week 12 were 29 percent, 13 percent, and Among the comparison arms in the FIXTURE study, the
one percent in patients randomized to secukinumab patients’ demographic and baseline clinical characteristics
300mg, 150mg, and placebo, respectively. Compared to were similar. Among the groups, the average age of
placebo, both doses of secukinumab also had significantly participants ranged between 44 to 45 years; male patients
greater response on patient-reported psoriasis-related comprised between 69 to 73 percent of the patients;
itching, pain, and scaling on the Psoriasis Symptom Diary Caucasian patients comprised more than two-thirds of the
(P<0.001). The proportion of patients achieving study population. The average weight of participants
Dermatology Life Quality Index (DLQI) 0 or 1 was ranged between 83 to 85kg, and the BMI averaged 28. The
significantly higher in both doses of secukinumab groups average baseline PASI score was 24, and the average
compared to placebo (P<0.001). Both doses of baseline BSA was between 34 and 35 percent.
secukinumab were also superior to placebo in patient- Approximately 60 percent of patients had a score of 3
reported psoriasis-related itching, pain, and scaling. (moderate disease) on modified IGA, and 40 percent had a
Finally, with regard to maintenance (Figure 1), the peak score of 4 (severe disease) on modified IGA. With regards to
response rate appears to be achieved at around Week 16, psoriatic arthritis, 13.5 percent of patients randomized to

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 A Novel Paradigm for Treatment of Moderate-to-severe Plaque-type Psoriasis

Figure 1. Efficacy through Week 52 in the ERASURE study. This figure shows the maintenance of response with regards to PASI 75, 90, and
100, and IGA 0 or 1 in secukinumab 300mg and 150mg through Week 52. Adapted from Langley et al. N Engl J Med. 2014;371(4):326–338.

etanercept and 15 percent of patients randomized secukinumab achieved DLQI of 0 or 1 at Week 12 compared
secukinumab and placebo had psoriatic arthritis. Between to the etanercept or placebo group (P<0.001 for all
11 and 14 percent of patients were previously on a biologic comparisons). One key secondary endpoint is assessing the
in the FIXTURE study. speed of response during the induction period (Figure 2).
Outcomes. Coprimary endpoints and key The investigators found that the median time to a 50-
secondary endpoints. Overall, secukinumab was superior percent reduction in PASI from baseline was significantly
to placebo in all of the coprimary and key secondary shorter in both doses of secukinumab (3 weeks for 300mg
endpoints; secukinumab was also superior to etanercept secukinumab and 4 weeks for 150mg secukinumab)
with respect to all key secondary endpoints. Similar to the compared to etanercept (7 weeks) (P<0.001 for both
ERASURE study findings, the 300mg dose of secukinumab comparisons). With regard to maintenance (Figure 3), the
showed numerically superior response rates compared to rates of response with regard to achievement of PASI 75, 90,
the 150mg dose. and 100 and IGA of 0 or 1 were higher with secukinumab
Specifically in the FIXTURE study, at the end of 12 than etanercept through Week 52.
weeks, the PASI 75 rates were 77.1 percent in the Safety. During both the induction and treatment
secukinumab 300mg arm, 67.0 percent in the secukinumab periods of the FIXTURE study, the rates of adverse events
150mg arm, 44.0 percent in the etanercept arm, and 4.9 were overall similar between the secukinumab and
percent in the placebo arm (P<0.001 for each secukinumab etanercept groups. The most common adverse events in the
dose vs. comparators). The proportion of patients with an secukinumab groups were nasopharyngitis, headache, and
IGA score of 0 or 1 was significantly higher in each of the diarrhea.
secukinumab doses compared to both etanercept and Some differences were observed in adverse event rates
placebo (P<0.001 for each secukinumab dose vs. between secukinumab and etanercept. Though not
comparators). statistically significant, the rate of injection-site reaction
With regard to key secondary endpoints, significantly was numerically lower in the secukinumab groups (0.7%)
greater proportions of patients in both doses of compared to etanercept (11%). Candida infections were

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Figure 2. Speed of Response in the FIXTURE study. This figure shows median time to 50% reduction in the mean PASI score in the
secukinumab and etanercept arms. Adapted from Langley et al. N Engl J Med. 2014;371(4):326–338.

Figure 3. Efficacy through Week 52 in the FIXTURE study. This figure shows maintenance of response with regards to PASI 75, 90, and 100,
and IGA 0 or 1 in secukinumab 300mg and150mg groups and etanercept group through Week 52. Adapted from Langley et al. N Engl J Med.
2014;371(4):326–338.

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 A Novel Paradigm for Treatment of Moderate-to-severe Plaque-type Psoriasis

more common with secukinumab than with etanercept; response compared to ustekinumab group at Week 16
however, none resulted in discontinuation of therapy or (44.3% vs. 28.4%, respectively, p<0.0001). Furthermore,
chronic mucocutaneous candidiasis. A higher rate of a significantly greater proportion of secukinumab-treated
candidiasis was observed with the 300mg secukinumab patients achieved PASI 75 and IGA 0 or 1 at Week 16
group (4.7%) compared to the 150mg secukinumab compared to ustekinumab.
group (2.3%); all cases of candidiasis resolved on their With respect to efficacy during the initial treatment
own or with standard therapy. Of note, very low rates of period, 50 percent of secukinumab-treated patients
neutropenia were observed in both the secukinumab achieved PASI 75 at Week 4 compared to 21 percent in the
groups (1% with Grade 3 neutropenia) and etanercept ustekinumab arm (P<0.0001). The superiority in efficacy
(0.3% with Grade 4 neutropenia). of secukinumab to ustekinumab was also observed with
Finally, anti-secukinumab antibodies were observed PASI 90, PASI 100, or IGA 0 or 1 at Week 4. Furthermore,
in 0.4% of the secukinumab-treated patients. The anti- the proportion of patients achieving DLQI 0 or 1 was
secukinumab antibodies were not neutralizing, and the significantly higher in the secukinumab-treated patients
antibody presence did not appear to be associated with compared to ustekinumab-treated patients.
reduced efficacy or adverse events. Safety. The duration of 16-weeks used in this
analysis was likely not long enough to detect rare events
or events with long latency periods. Nevertheless, the 16-
week safety analysis showed that, overall, secukinumab
Secukinumab versus Ustekinumab: the exhibited a safety profile similar to that of ustekinumab.
In addition, the investigators did not observe new or
CLEAR Study unexpected safety signals that were not observed in the
prior Phase 3 trials.
Thaci et al10 published the 16-week analysis from the
CLEAR study, a Phase 3b study comparing the efficacy
and safety of secukinumab with ustekinumab.
Primary objective. The primary objective of the Discussion
CLEAR study was to determine superiority of
secukinumab versus ustekinumab using PASI 90 The aforementioned studies showed that IL-17A
response at Week 16. appears to be critical in the pathogenesis of psoriasis.
Study design and study population. CLEAR is a Blocking IL-17A ligand leads to excellent clearance of
52-week, randomized, double-blind, active comparator, plaque psoriasis and is associated with an acceptable
parallel-group, superiority Phase 3b study that began in safety profile. A few notable observations remain with the
February 2014. FIXTURE and ERASURE studies. First, compared to the
The inclusion criteria were adult patients with pivotal trials for previously approved biologics, the study
moderate-to-severe plaque psoriasis who had been population in these secukinumab studies enrolled
inadequately controlled by topical treatments, patients with overall lower average body weight than
phototherapy, and/or previous systemic therapy. The key prior biologic trials. Second, compared to previous pivotal
exclusion criteria were prior exposure to any biologics studies with other biologics, the patient population in
directly targeting IL-17 inhibitors or ustekinumab. The these two trials has higher baseline BSA involvement and
eligible participants were randomized 1:1 to secukinumab lower rates of psoriatic arthritis.
300mg or ustekinumab (per-label dosing of 45mg for In the real world where clinical decisions are made in
patients ≤100kg and 90mg for patients >100kg). the context of choosing among multiple available agents,
In the CLEAR study, a total of 676 subjects were it is important to obtain comparative effectiveness data to
randomized. The baseline demographic and clinical help guide our clinical decision-making. Randomized
characteristics were balanced between the two study controlled studies comparing secukinumab to etanercept
groups. The patients were on average 45 years old, with and to ustekinumab are highly informative to clinical
BMI of 29; approximately 67 percent of patients have had decision-making.
prior systemic treatment. Slight numeric imbalance was In conclusion, secukinumab is the first of the IL-17
observed in the proportion of patients with psoriatic inhibitor class of biologics to become available to our
arthritic, with 21 percent and 16 percent in secukinumab psoriasis patients. Its efficacy has been demonstrated to
and ustekinumab groups, respectively. be outstanding based on its clinical trial data, and its role
Outcomes: Coprimary endpoints and key in treating moderate-to-severe psoriasis is critical.
secondary endpoints. With regard to the primary Determining how secukinumab impacts other aspects of
endpoint, at Week 16, 79 percent of patients randomized the patients’ well-being using patient-reported outcomes
to the secukinumab and 58 percent of those randomized is also as important as examining the traditional
to the ustekinumab group achieved PASI 90 response outcomes assessments based on morphology and BSA
(P<0.0001). Several key secondary endpoints were also alone. The safety of secukinumab appears to be
examined. A significantly greater proportion of acceptable at this time, but continued surveillance will be
secukinumab-treated patients achieved PASI 100 necessary to determine its long-term safety.

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