A Multicenter, Long-Term Extension Study of 104 Weeks, Including a Double-Blind, Placebo-Controlled 40-Week Randomized Withdrawal-Retreatment Period, to Evaluate the Maintenance of Treatment Effect of Ixekizumab (LY2439821) in Patients with Axial Spondyloarthritis

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly
affecting the axial skeleton (sacroiliac joints and spine) with onset of
symptoms that typically appear in the second or third decade of life. AxSpA
affects up to 1.4% of the Caucasian adult population worldwide. Current
standard of care for nonrad-axSpA includes regular exercise, physical therapy,
and nonsteroidal anti-inflammatory drugs (NSAIDs). TNF inhibitors have also
demonstrated efficacy in nonrad-axSpA; however, they are not yet approved
globally for this indication, and approximately 40% of patients only obtain a
partial response on TNF inhibitors. 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. In contrast to
patients with RA, patients with axSpA do not respond well to conventional
disease-modifying antirheumatic drugs (cDMARDs) or systemic corticosteroids.
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). Compelling scientific evidence exists indicating
an important role of the IL-23/IL-17 pathway in axSpA pathogenesis. Recently
disclosed data from Phase 3 studies with secukinumab (Cosentyx®), a drug with a
similar mechanism of action (MoA) as ixekizumab, have demonstrated the
effectiveness of inhibiting IL-17A in patients with radiographic-axial
spondyloarthritis (rad-axSpA, also called Ankylosing Spondylitis) who were
biological disease modifying antirheumatic drug (bDMARD) naive or had
previously received tumor necrosis factor (TNF) inhibitors. The present study
evaluates the efficacy and safety of ixekizumab in nonradiographic-axSpA
(nonrad-axSpA) patients who are bDMARD naive.

Primary objective:
-To evaluate in patients having achieved a state of sustained remission whether
the ixekizumab treatment group is superior to the placebo group in maintaining
response during the randomized-withdrawal period

Secondary objectives:
-To compare the combined ixekizumab treatment group to historical control for
2-year radiographic progression in spine in patients with active radiographic
axSpA
-To evaluate in patients having achieved a state of sustained remission whether
the ixekizumab 80 mg every 2 weeks (Q2W) treatment group or ixekizumab 80 mg
every 4 weeks (Q4W) treatment group is superior to placebo in maintaining
response
-To evaluate in patients having achieved a state of sustained remission whether
the combined ixekizumab treatment group is superior to the placebo group in
maintaining response after treatment withdrawal
-To evaluate in patients having achieved a state of sustained remission whether
the ixekizumab 80 mg Q2W treatment group or ixekizumab 80 mg Q4W treatment
group is superior to placebo in maintaining response after treatment withdrawal

Study I1F-MC-RHBY (RHBY) is a Phase 3, multicenter, long-term extension study
that provides patients who have completed any of the originating studies (RHBV,
RHBW, and RHBX) an opportunity to continue ixekizumab (LY2439821) treatment for
up to 2 additional years. Study RHBY includes 4 study periods:

-Lead-In [Period 1]: 24 weeks (Week 0 to Week 24)
-Extension Period including Double-Blind, Placebo-Controlled, Randomized
Withdrawal-Retreatment [Period 2]: 40 weeks (Week 24 to Week 64)
-Long-Term Extension Period [Period 3]: 40 weeks (Week 64 to Week 104)
-Post-Treatment Follow-Up [Period 4]: at least 12 weeks and up to 24 weeks
after the date of the patient*s early termination visit (ETV) or last regularly
scheduled visit

During the Lead-In Period (Period 1; 24 weeks), patients will receive active
treatment in the form of ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W (open
label or blinded depending on the previous originating study).

During the Extension Period, including blinded, randomized
withdrawal-retreatment (Period 2; 40 weeks):
(Group A): Patients who do not meet entry criteria for participation in the
randomized withdrawal-retreatment period will continue to receive uninterrupted
ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W.
(Group B): For patients having achieved a state of sustained remission who do
meet the criteria for participation in the 40-week double-blind
placebo-controlled randomized withdrawal-retreatment period
o Patients in the ixekizumab 80 mg Q2W treatment group will be re-randomized to
either ixekizumab 80 mg Q2W or placebo. Patients who experience a flare will
receive ixekizumab 80 mg Q2W.
o Patients in the ixekizumab 80 mg Q4W treatment group will be re-randomized to
either ixekizumab 80 mg Q4W or placebo. Patients who experience a flare will
receive ixekizumab 80 mg Q4W.

During the Long-Term Extension Period (Period 3; 40 weeks),
o (Group A): Patients in Group A will continue their assigned treatment regimen
uninterrupted. Patients in Group A receiving ixekizumab 80 mg Q4W may have
their dose escalated to ixekizumab 80 mg Q2W if the investigator determines
that the patient may benefit from an increase in frequency of dosing to achieve
adequate disease control.
o (Group B): Patients in Group B will continue the same treatment that they
were receiving at the end of Period 2. However, if a patient experiences a
flare and meets criteria for retreatment, the patient will be retreated with
the ixekizumab treatment regimen (ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W)
that he or she was receiving prior to withdrawal to evaluate whether the
patient can regain his or her original response.
During the Long-Term Extension Period, patients in Group B receiving ixekizumab
80 mg Q4W may also have their dose escalated to ixekizumab
80 mg Q2W if the investigator determines that the patient may benefit from an
increase in frequency of dosing to achieve adequate disease control.

All patients receiving at least 1 dose of investigational product will enter
the Post-Treatment Follow-Up (Period 4) for a minimum of 12 weeks and up to 24
weeks after their last regularly scheduled visit (or the date of their ETV).

The Investigational Product and other medication required by Protocol and the
study procedures are associated with certain risks and discomforts, as
described in the patient information leaflet. The combination of experimental
medicine and study procedures may be associated with additional risks or
discomforts that at this point are not fully known. 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
subjects undergo an number of study procedures such as SC injections, blood
collections, TB skin test, x-rays, MRI, and ECG tests. These procedures may
also be accompanied by certain risks. The procedures may also have other
unknown risks. These risks are described in the Informed consent form.
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 have failed NSAIDs and for
patients who have lost response, failed to respond, or are intolerant to
current marketed drugs. Ixekizumab may offer a more favorable safety profile
compared to currently marketed therapies.