A Multicenter, Randomized, Double-Blind Study Comparing the Efficacy and Safety of Ixekizumab Versus Placebo in Patients with Moderate-to-Severe Genital Psoriasis

Chronic plaque psoriasis is a common, lifelong, and life-shortening chronic
inflammatory skin disease with an estimated prevalence in populations of
approximately 3% which manifests as prototypic red, thick, and scaly plaques
(Greaves and Weinstein 1995). Psoriasis has been shown to have a significant
impact on the overall health of patients with considerable effects on social
functioning and quality of life.

Approximately 29% to 63% of patients with chronic plaque psoriasis are impacted
by psoriatic lesions in the genital area at some point during the course of the
disease (Fouéré et al. 2005; Meeuwis et al. 2010, 2011a; Ryan et al. 2015). Due
to moisture and maceration, genital psoriasis
can sometimes lack the characteristic scale present at other body sites
(Buechner 2002; Weichert 2004). Both penile and vulvar psoriatic lesions
generally appear as symmetrical, bright red thin plaques with a well-defined
edge (Buechner 2002; Welsh et al. 2003; ISSVD 2014 [WWW];
Meeuwis et al. 2015). Painful fissures and erosions can also be a problematic
clinical feature of genital psoriasis (Barchino-Ortiz et al. 2012; Guglielmetti
et al. 2012; Meeuwis et al. 2015), and severe pruritus may lead to scratching
with significant excoriations and lichenification (Weichert
2004; Guglielmetti et al. 2012).

When compared to psoriasis patients without genital involvement, quality of
life was found to be significantly worse in patients with genital lesions
(Meeuwis et al. 2011b, Ryan et al. 2015). Overall Dermatology Life Quality
Index (DLQI) score, all domain scores, and DLQI Question 9
(skin caused sexual difficulties) were significantly worse for those psoriasis
patients with current genital involvement compared to those without genital
lesions. Itch and sexual impairment have been reported as key bothersome issues
for patients with genital psoriasis (Meeuwis et al. 2015;
Ryan et al. 2015).

Despite the significant impact on quality of life and sexual health, genital
psoriasis is often not discussed by patients (AAD Work Group et al. 2011;
Meeuwis et al. 2012; Andreassi and Bilenchi 2014), and health care
professionals do not routinely question or examine patients for its presence in
clinical practice (Farber and Nall 1992; AAD Work Group et al. 2011). While
patients with genital psoriasis often do not discuss their symptoms with health
care providers, many patients report actively treating their genital lesions
(Meeuwis et al. 2012). Therefore, this may indicate a risk of self-treatment in
the genital area using medications that were originally prescribed for
treatment of other body locations. Inappropriate self-treatment has the
potential to result in less than optimal or over-treatment (for example, with
potent corticosteroids) and significant adverse reactions. Although genital
psoriasis appears to be pathophysiologically identical to plaque psoriasis in
other skin regions, the skin in this area is highly sensitive and at increased
risk of adverse reactions to topical treatments (CDA 2009 [WWW]; Meeuwis et al.
2011a; Guglielmetti et al. 2012). Moreover, currently available topical agents
may not offer an optimal or even appropriate level of clinical improvement or
tolerability, especially for patients with moderate-to-severe genital
psoriasis. Weaker potency corticosteroids often have limited efficacy for use
in maintenance treatment (Welsh et al. 2003), and the use of higher potency
corticosteroids is limited due to the development of skin atrophy and striae
(Linden and
Weinstein 1999). Irritation is commonly reported with vitamin D analogs (Scott
et al. 2001; Mason et al. 2013), and they may not be tolerated in the genital
region (CDA 2009 [WWW]). Topical calcineurin inhibitors such as pimecrolimus
and tacrolimus may improve genital psoriasis but can cause irritancy or a
burning sensation, are not helpful in many patients (Menter et al. 2009;
Meeuwis et al. 2011[a]), and are not indicated for the treatment of psoriasis.
Beyond such topical therapies, there is rather limited evidence for viable
therapeutic options to adequately manage genital psoriasis. For instance,
psoralen and ultraviolet A (PUVA) and narrowband ultraviolet B (UVB) are not
advised for use in the genital region due to potential carcinogenic adverse
effects (Stern et al. 1990; Stern et al. 1994; Stern et al. 2002).

Currently, there are limited data from clinical trials, particularly
well-controlled therapeutic interventional studies, which measure the efficacy
of treatments for genital psoriasis. To date, the only published treatment
studies of genital psoriasis include open-label studies of topical treatments
(Jemec and Baadsgaard 1993; Rallis et al. 2005; Martín Ezquerra et al. 2006;
Bissonnette et al. 2008), a recent open-label study of a stepwise treatment
algorithm (Meeuwis et al. 2015), and scattered case reports.

Primary objective:

To assess whether ixekizumab is superior to placebo at Week 12 in the treatment
of patients with moderate-to-severe genital psoriasis

Major Secondary Objective:

To assess whether ixekizumab is superior to placebo at Week 12 in the treatment
of patients with moderate-to-severe genital psoriasis as measured by change in
itch

Study I1F-MC-RHBQ (RHBQ) is a Phase 3, multicenter, randomized, double-blind,
placebo-controlled, parallel-group, outpatient study examining the efficacy and
safety of ixekizumab as compared to placebo in patients with moderate-to-severe
genital psoriasis. The study consists of 4 periods: Screening Period, Blinded
Treatment Period, Period 3: Open-Label Treatment Period and Post-Treatment
Follow-Up

The Blinded Treatment Period (Period 2) involves a comparison of ixekizumab 80
mg Q2W (starting dose of 160 mg) and placebo Q2W. All doses are administered
via SC injection.

All patients assigned to ixekizumab 80 mg Q2W regimen will receive a starting
dose of 160 mg ixekizumab as 2 SC injections. The placebo group will receive 2
SC injections of placebo at this visit as well, to maintain the blind.
Afterwards, the dose of investigational product will consist of 1 SC injection
of ixekizumab or placebo.

At Week 12, during the Open-Label Treatment Period (Period 3), all patients
will be reassigned to ixekizumab 80 mg Q4W. Patients originally assigned to
placebo will receive a blinded ixekizumab starting dose of 160 mg as 2 SC
injections. To maintain blinding, patients originally
assigned to ixekizumab 80 mg Q2W will receive a blinded ixekizumab 80-mg dose
and a placebo dose at Week 12. Dosing may be increased in the Open-Label
Treatment Period (Period 3) to ixekizumab 80 mg Q2W, starting at Week 24
through Week 40 (at Visit 9 [Week 24], Visit 10 [Week 28], or Visit 11 [Week
40]), if the patient is eligible to receive additional investigational product.

There are several risks involved with the study drug. The most common side
effects associated with lxekizumab are: Runny nose and sore throat; cold
symptoms; Upper respiratory tract infection; injection site reaction; Headache;
Worsening of rheumatoid arthritis; Urinary tract Infection; Sinus irritation;
Injection site pain; Injection site redness; Diarrhea; Back pain; Bronchitis;
High blood pressure; Dizziness; Joint pain; Cough; Nausea; Vertigo.The subject
undergo a number of study procedures, such as filling out questionnaires, blood
draws, subcutaneous Injections, x rays and genetic testing. These procedures
may also be accompanied by certain risks. The procedures may also have other
unknown risks.

Subjects taking part In this study suffer from moderate to severe genital
psoriasis. While patients with genital psoriasis often do not discuss their
symptoms with health care providers, many patients report actively treating
their genital lesions (Meeuwis et al. 2012). Therefore, this
may indicate a risk of self-treatment in the genital area using medications
that were originally prescribed for treatment of other body locations.
Inappropriate self-treatment has the potential to result in less than optimal
or over-treatment (for example, with potent corticosteroids) and
significant adverse reactions. Although genital psoriasis appears to be
pathophysiologically identical to plaque psoriasis in other skin regions, the
skin in this area is highly sensitive and at increased risk of adverse
reactions to topical treatments (CDA 2009 [WWW]; Meeuwis et al.
2011a; Guglielmetti et al. 2012). Moreover, currently available topical agents
may not offer an optimal or even appropriate level of clinical improvement or
tolerability, especially for patients with moderate-to-severe genital
psoriasis. Weaker potency corticosteroids often have limited
efficacy for use in maintenance treatment (Welsh et al. 2003), and the use of
higher potency. By Inhibiting IL-17A a larger and long-lasting effect may be
obtained. Previous studies with ixekizumab showed positive benefit/risks.Based
on the Phase 3 psoriasis clinical trial outcomes, ixekizumab therapy in
patients with moderate-to-severe genital psoriasis could address an unmet
patient need and a clinical research gap identified by the dermatology
community and the American Academy of Dermatology Psoriasis Guidelines of Care
Working Group (Ryan et al. 2014).