A Multicenter, Randomized, Double-Blind, Active and Placebo-Controlled 16 Week Study Followed by Long Term Evaluation of Efficacy and Safety of Ixekizumab (LY2439821) in bDMARD-Naive Patients with Radiographic Axial Spondyloarthritis

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly
affecting the axial skeleton (sacroiliac joints [SIJ] and spine) (Poddubnyy
2013). AxSpA is now recognized as a single disease entity, with a subset
defined by the presence of radiographically defined structural damage of the
SIJ (rad-axSpA) and a subset without clear structural damage defined
radiographically (nonrad-axSpA). When comparing axSpA with rheumatoid
arthritis (RA), it can be noted that while RA can be divided into erosive and
nonerosive or seropositive and seronegative subsets, it is well accepted that
it is still one disease. AxSpA, in a similar fashion, also has subsets, and
thus can be considered a single disease (Deodhar et al. 2014).

Radiographic axSpA (rad-axSpA), formerly called ankylosing spondylitis (AS),
represents a disease in which there is evidence of disease features on
radiographic imaging. It is a chronic inflammatory disease characterized by
chronic inflammation of the axial and SIJ and variable involvement of the
peripheral joints (Braun and Sieper 2007). As the disease progresses, it can
lead to new bone formation in the form of syndesmophytes and joint ankylosis,
primarily in the axial skeleton. Patients with rad-axSpA may also have
extra-articular manifestations of the disease such as enthesitis, anterior
uveitis, psoriasis, and inflammatory bowel disease as well as comorbidities of
aortitis or cardiac conduction abnormalities. Compared with the general
population, patients with rad-axSpA have increased rates of work disability,
unemployment, and mortality (Boonen and van der Linden 2006).

AxSpA affects up to 1.4% of the adult population worldwide (Braun and Sieper
2007; Reveille et al. 2012; Strand et al. 2013). Although the exact etiology
is unknown, it has been indicated that genetic factors and several loci are
likely to be involved in susceptibility to the disease (Reveille 2011). There
is a strong association with the major histocompatibility complex, human
leukocyte antigen (HLA)*B27. About 90% to 95% of patients with rad-axSpA are
positive for HLA-B27, and the risk of this disease developing is as high as
about 5% in HLA-B27 positive individuals and substantially higher in HLA-B27*
positive relatives of patients (Braun and Sieper 2007). Most of the other
known genetic susceptibility comes from genes involved in cytokine production,
specifically including genes in the T helper (Th)17 pathway (Maksymowych 2010;
Reveille 2011).
Current standard of care for rad-axSpA includes regular exercise, physical
therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and tumor necrosis
factor (TNF) alpha inhibitors (Braun et al. 2011; Ward et al. 2015).
Corticosteroid injections may also be of some benefit. Though NSAIDs are the
first line of drug treatment for axSpA, they are not effective or well
tolerated in all patients (Braun and Sieper 2009). In contrast to patients
with RA, patients with axSpA do not respond well to conventional
disease-modifying antirheumatic drugs (cDMARDs) including methotrexate (MTX) or
systemic corticosteroids (Braun and Sieper 2009; Haibel and Specker 2009).

Tumor necrosis factor inhibitors are effective and frequently prescribed when
NSAID treatment has failed or cannot be tolerated (Zochling et al. 2006).
While TNF inhibitors have proven to be effective treatments for axSpA, an unmet
need remains, as not all patients respond well to or tolerate TNF inhibitor
treatments (van der Heijde et al. 2006; Heiberg et al. 2008; Inman et al. 2008;
Glintborg et al. 2010). While TNF inhibitors have demonstrated significant
impact on signs and symptoms, function, and quality of life, they have not been
able to demonstrate significant effect on structural progression in prospective
clinical studies. The use of these biologic therapies in various diseases also
is associated with safety concerns, such as opportunistic infections,
demyelinating disorders, blood dyscrasias, reactivation of tuberculosis (TB),
and exacerbation of congestive heart failure (Moreland 2005; Smith et al.
2009). There remains, therefore, a significant unmet need for safer, more
effective treatments for patients with axSpA (Dougados and Baeten 2011).
Ixekizumab may offer an alternative treatment approach to TNF inhibitor therapy
in patients with axSpA.

Ixekizumab (LY2439821) is a humanized immunoglobulin G subclass 4 (IgG4)
monoclonal antibody (MAb) that neutralizes the cytokine interleukin-17A
(IL-17A, also known as IL-17). Ixekizumab treatment is administered by
subcutaneous (SC) injections. Compelling scientific information exists to date
suggesting an important role of the IL-23/IL-17 pathway in the pathogenesis of
axSpA (Baeten et al. 2010, 2014a; Maksymowych 2010; Baraliakos et al. 2011;
Reveille 2011; Yeremenko et al. 2014). The demonstration of increased IL-17
producing Th17 lymphocyte numbers and serum IL-17 levels in rad-axSpA is
consistent with a direct role of Th17 lymphocytes in this disease (Wendling et
al. 2007; Jandus et al. 2008; Mei et al. 2011). IL 17 secreting cells have
also been detected in situ in the bone marrow of facet joints obtained from
patients with rad-axSpA (Appel et al. 2008).

Selectively targeting IL-17A with ixekizumab is hypothesized to provide
therapeutic benefit without unduly impacting host defenses. As such,
ixekizumab may offer a therapeutic option for patients who are candidates for
initial systemic treatment as well as those patients who have lost response,
failed to respond, or are intolerant to currently marketed drugs, and may also
offer a more favorable safety profile compared to currently marketed therapies.

Primary
The primary objective is to compare both ixekizumab regimens (80 mg every 2
weeks [Q2W] or 80 mg every 4 weeks [Q4W]) versus placebo in patients with
active radiographic axial spondyloarthritis (rad-axSpA) at Week 16.

Secondary
The major secondary objective is:
To compare both ixekizumab regimens (80 mg Q2W or 80 mg Q4W) to placebo at Week
16

Study I1F-MC-RHBV is a Phase 3, multicenter, randomized, double-blind, active
and placebo-controlled, parallel-group, outpatient study examining the efficacy
and safety of ixekizumab treatment regimens (80 mg Q2W and 80 mg Q4W SC), as
compared to placebo SC in patients with active rad-axSpA who are biologic DMARD
naïve, during a double-blind, 16-week treatment period. Starting doses of 80
mg and 160 mg (at Week 0) will be evaluated for each ixekizumab regimen.
Adalimumab (at the approved dosing regimen of 40 mg SC Q2W) has been selected
as the active control for comparison with placebo.

Study RHBV will also evaluate long-term efficacy and safety of ixekizumab
during the Extended Treatment Period (Period 3) for a total treatment duration
of 1 year (52 weeks). Patients that complete Study RHBV may be eligible to
enroll into a long-term study (Study I1F-MC-RHBY [RHBY]) for up to 2 additional
years. Patients that do not enroll into Study RHBY will complete the
Post-Treatment Follow-Up Period (Period 4) in Study RHBV.

Study RHBV has 4 treatment groups during the 16-week Blinded Treatment Dosing
Period; ixekizumab 80 mg Q4W, ixekizumab 80 mg Q2W, placebo, and adalimumab 40
mg Q2W at 1:1:1:1 ratio. Randomization will be stratified by country and
baseline high sensitivity C-reactive protein (CRP) status (normal or elevated,
elevated defined as >5.00 mg/L). All patients randomized to an ixekizumab
treatment group will receive a starting dose of ixekizumab 80 mg or 160 mg (1:1
ratio) at Week 0 followed by ixekizumab 80 mg Q4W or Q2W thereafter; all
patients randomized to adalimumab will receive adalimumab 40 mg Q2W from Week 0
to Week 14. All administrations are SC. At Week 16, placebo patients will be
rerandomized at a 1:1 ratio to ixekizumab 80 mg Q2W or Q4W with a 160 mg
starting dose. At Week 16, adalimumab patients will be re randomized to
ixekizumab 80 mg Q4W or Q2W (with a 160mg starting dose). All patients will be
on an ixekizumab regimen for the Extended Treatment Period (Weeks 16 to 52)
(for safety reasons, adalimumab patients will have a 6-week washout period
before receiving ixekizumab). As needed, investigators can modify concomitant
medication during the wash-out period to maintain symptom control. The study
duration will be up to 1 year for ixekizumab administration, and up to 1 year
and approximately 4 months for study participation over 4 periods ([1]
Screening Period: up to 42 days; [2] Blinded Treatment Dosing Period: 16
weeks; [3] Extended Treatment Period: 36 weeks; [4] Post-Treatment Follow-Up
Period: at least 12 weeks after the date of the patient*s early termination
visit [ETV] or last regularly scheduled visit). Patients who complete Study
RHBV may have the opportunity to continue into a long term study instead of the
Post-Treatment Follow-Up Period.

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.

Compelling scientific information exists to date suggesting an important role
of the IL-23/IL-17 pathway in the pathogenesis of axSpA (Baeten et al. 2010,
2014a; Maksymowych 2010; Baraliakos et al. 2011; Reveille 2011; Yeremenko et
al. 2014). The demonstration of increased IL-17 producing Th17 lymphocyte
numbers and serum IL-17 levels in rad-axSpA is consistent with a direct role of
Th17 lymphocytes in this disease (Wendling et al. 2007; Jandus et al. 2008; Mei
et al. 2011). IL 17 secreting cells have also been detected in situ in the
bone marrow of facet joints obtained from patients with rad-axSpA (Appel et al.
2008).

Selectively targeting IL-17A with ixekizumab is hypothesized to provide
therapeutic benefit without unduly impacting host defenses. As such,
ixekizumab may offer a therapeutic option for patients who are candidates for
initial systemic treatment as well as those patients who have lost response,
failed to respond, or are intolerant to currently marketed drugs, and may also
offer a more favorable safety profile compared to currently marketed therapies.