A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Efficacy and Safety of LY2439821 to Etanercept and Placebo in Patients with Moderate-to-Severe Plaque Psoriasis

LY2439821 (ixekuzimab) is a humanized immunoglobulin G subclass 4 (IgG4)
monoclonal antibody (MAb) that neutralizes the cytokine interleukin-17A
(IL-17A, also known as IL-17). It has a high affinity for and neutralizes the
activity of both human and monkey IL 17. It has high specificity to IL-17A
(IL-17) and has no cross-reactivity to other IL-17 family members (IL 17B F).
LY2439821 blocks IL-17 binding to the IL 17 receptor (IL-17R). Specific
inhibition of IL-17 represents a targeted approach to the management of
psoriasis (Ps) and a novel mechanism of action compared to other Ps therapies.
As such, LY2439821 may provide 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 current marketed drugs.
LY2439821 may provide an alternative therapy providing a favorable benefit/risk
profile. Specifically, targeting IL-17 with LY2439821 is hypothesized to
provide optimal therapeutic benefit while reducing the risk of impacting host
defenses, which may be inherent with some other biologic-based immunomodulatory
treatments.

For futher details please see pages 24-26 of the protocol.

Objectives: The primary objectives of the study are to assess whether 80 mg
LY2439821 every 2 weeks (Q2W) or every 4 weeks (Q4W) is:
* Superior to placebo at Week 12 in the treatment of patients with
moderate-to-severe plaque Ps as measured by:
o Proportion of patients with a static Physician Global Assessment (sPGA)
(0,1) with at least a 2-point improvement from baseline.
o Proportion of patients achieving a *75% improvement in Psoriasis Areas and
Severity Index (PASI 75) from baseline.
* Non-inferior to etanercept at Week 12 in the treatment of patients with
moderate-to-severe plaque Ps as measured by:
o Proportion of patients achieving a *75% improvement in PASI (PASI 75) from
baseline.
o Proportion of patients with an sPGA (0,1) with at least a 2-point
improvement from baseline.
* Superior to etanercept at Week 12 in the treatment of patients with
moderate-to-severe plaque Ps as measured by:
o Proportion of patients achieving a *75% improvement in PASI (PASI 75) from
baseline.
o Proportion of patients with an sPGA (0,1) with at least a 2-point
improvement from baseline.

The major secondary objectives of the study are to assess whether:
* Efficacy of 80 mg LY2439821 Q2W or Q4W induction dosing is superior to
placebo at Week 12 as measured by:
o Proportion of patients achieving an sPGA (0) (remission).
o Proportion of patients achieving a *90% improvement in PASI (PASI 90).
o Proportion of patients achieving a 100% improvement in PASI (PASI 100).
* Efficacy of 80 mg LY2439821 Q2W or Q4W induction dosing is superior to
etanercept at Week 12 as measured by:
o Proportion of patients achieving an sPGA (0) (remission).
o Proportion of patients achieving a PASI 90.
o Proportion of patients achieving a PASI 100.
* Efficacy of 80 mg LY2439821 Q4W or Q12W maintenance dosing compared to
placebo as measured by:
o Proportion of patients maintaining an sPGA (0,1) from Week 12 after
re-randomization at start of the Maintenance Dosing Period to Week 60.

The other secondary objectives of the study are as follows:
* To assess the efficacy of 80 mg LY2439821 Q2W or Q4W compared to placebo and
to etanercept at Week 12 and over the 12-week study period by evaluating:
o Time course of response to treatment as measured by the proportion of
patients with an sPGA (0,1) with at least a 2-point improvement from baseline.
o Time course of response to treatment as measured by the proportion of
patients with an sPGA (0).
o Proportion of patients with sPGA (0, 1) at Week 4 for 80 mg LY2439821 Q2W
or Q4W is superior to proportion of patients with sPGA (0, 1) treated with
etanercept.
o Time course of response to treatment as measured by the proportion of
patients achieving *50% improvement in PASI score from baseline (PASI 50), PASI
75, PASI 90, and PASI 100.
o Time course of response to treatment as measured by change and percent
improvement of PASI from baseline.
o Proportion of patients with PASI 75 at Week 4 for 80 mg LY2439821 Q2W or
Q4W is superior to proportion of patients with PASI 75 treated with etanercept.
o Time to sPGA response as measured by an sPGA (0,1).
o Time to PASI 75 response.
o Percent of body surface area (BSA) involvement of Ps.
o Change from baseline in NAPSI score in patients with fingernail involvement.
o Change from baseline in Ps Scalp Severity Index (PSSI) score in patients
with scalp involvement.
o Change from baseline in itching severity (Itch numeric rating scale [NRS])
score.
o Change from baseline on dermatology-specific quality of life (DLQI).
o Change from baseline in joint pain (Joint Pain visual analog scale [VAS])
score in patients with psoriatic arthritis (PsA).
o Change from baseline in other health outcome endpoints: Quick Inventory of
Depressive Symptomatology-Self Report (16 items) (QIDS-SR16), all scores of the
Work Productivity Activity Impairment questionnaire-Psoriasis (WPAI-PSO)
(Absenteeism, Presenteeism, Work Productivity Loss, and Activity Impairment),
Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Physical
Component Summary (PCS) and Mental Component Summary (MCS) scores, and
patient*s global assessment of disease severity.
o Change from baseline in Palmoplantar PASI (PPASI) and proportion of
patients achieving *50% improvement in PPASI score from baseline (PPASI 50),
*75% improvement in PPASI score from baseline (PPASI 75), and a 100%
improvement in PPASI score from baseline (PPASI 100) in patients with
palmoplantar involvement.
* To assess maintenance of efficacy of 80 mg LY2439821 Q4W or Q12W compared to
placebo at Week 60 and during the Maintenance Dosing Period among patients who
had an sPGA (0,1) at Week 12 and were re-randomized by evaluating:
o Time to relapse (sPGA *3).
o Time course of the loss of response to treatment until relapse as measured
by an sPGA *3.
o Proportion of patients who maintain or achieve remission (that is, an sPGA
[0]).
o Time course of response to treatment as measured by change from baseline of
sPGA score.
o Time course of response to treatment as measured by the proportion of
patients who maintain an sPGA (0,1), and by the proportion of patients who
maintain an sPGA (0).
o Time course of response to treatment as measured by change from baseline
and percent improvement of PASI from baseline.
o Percent of BSA involvement of Ps.
o Incidence of disease rebound within 8 weeks (worsening of Ps severity over
baseline sPGA score or change in Ps phenotype [for example, from plaque to
pustular]) after re-randomization to placebo at Week 12.
o Time course of response to treatment as measured by the proportion of
patients who maintain a PASI 75, PASI 90, and PASI 100.
o Change from baseline in NAPSI score in patients with fingernail
involvement.
o Change from baseline in PSSI score in patients with scalp involvement.
o Change from baseline in itching severity (Itch NRS) score.
o Change from baseline on dermatology-specific quality of life (DLQI).
o Change from baseline in joint pain (Joint Pain VAS) score in patients with
PsA.
o Change from baseline in other health outcome endpoints: QIDS-SR16, all
scores of the WPAI-PSO (Absenteeism, Presenteeism, Work Productivity Loss, and
Activity Impairment), SF-36 PCS and MCS scores, and patient*s global assessment
of disease severity.
o Change from baseline in PPASI and proportion of patients achieving *50%
improvement in PPASI score from baseline (PPASI 50), *75% improvement in PPASI
score from baseline (PPASI 75), and a 100% improvement in PPASI score from
baseline (PPASI 100) in patients with palmoplantar involvement.
* To assess the efficacy of 80 mg LY2439821 Q4W following disease relapse after
re-randomization to placebo treatment in the Maintenance Dosing Period by
evaluating:
o Proportion of patients who regain an sPGA (0,1) within 12 weeks after
LY2439821 retreatment.
o Proportion of patients who achieve a PASI 75, PASI 90, PASI 100 within 12
weeks after LY2439821 retreatment.
* To evaluate the potential development of anti-LY2439821 antibodies and its
impact on patient safety, and efficacy.

The exploratory objectives of the study are to be evaluated in patients with
moderate-to-severe plaque Ps as follows:
* To explore the impact of LY2439821 on change from baseline in measures of
health utility (European Quality of Life * 5 Dimensions 5 Level [EQ-5D 5L]),
Skin Pain VAS, healthcare resource utilization, and self-reported skin
appearance bothersomeness (Ps Skin Appearance Bothersomeness scale [PSAB])
compared to placebo.
* To assess the psychometric properties (including reliability, validity, and
responsiveness) of the Itch NRS and PSAB.
* To form and evaluate subgroups that may have different risk for benefit or
harm from therapy using the Enterprising Selective Multi-Instrument Blend for
Heterogeneity-analysis (ENSEMBLE) Minimum Data Set (MDS).
* To explore biomarkers of disease, drug activity, or that are predictive of
response to LY2439821 treatment that may be contained in serum, plasma,
messenger ribonucleic acid (mRNA), and deoxyribonucleic acid (DNA) samples.
* To explore the impact of LY2439821 compared to placebo at Weeks 4 and 12 on
change from baseline in presence or absence of facial psoriasis (as indicated
by the investigator in the case report form [CRF]) and measures of quality of
life (SF-36 MCS and DLQI) and bothersomeness of skin appearance (PSAB) in the
subgroup of patients with Ps located on the face.
* To assess the efficacy of ixekizumab 80 mg Q2W or 80 mg Q4W compared to
placebo on joint pain at Week 12 and over the 12-week study period, as well as
at Week 60 and during the Maintenance Dosing Period in patients with an sPGA
(0,1) at Week 12 and were re-randomized, by evaluating change from baseline in
joint pain (Joint Pain visual analog scale [VAS]) score in patients with PsA at
baseline

Study I1F-MC-RHBA (RHBA) RHBA is a Phase 3, multicenter, randomized,
double-blind, placebo-controlled, active-comparator, parallel-group study
examining the effect on primary efficacy endpoint measures at 12 weeks of 2
dose regimens of 80 mg LY2439821 (every 2 weeks [Q2W] or every 4 weeks [Q4W];
each with a starting dose of 160 mg) versus placebo and versus etanercept (50
mg twice weekly) in patients with moderate-to-severe plaque psoriasis (Ps).
All investigational products are administered subcutaneously. A blinded
Maintenance Dosing Period will follow to evaluate the maintenance of response
at Week 60 with 2 different dosing intervals of 80 mg LY2439821 (every 4 weeks
[Q4W] or every 12 weeks [Q12W]), as well as relapse or rebound following
treatment withdrawal, and response to retreatment with LY2439821 following
relapse. Long-term efficacy and safety of LY2439821 will be evaluated for up
to a total of 5 years in patients who participate through the entire study.
The study consists of 5 periods:
* Period 1: Screening Period (Visits 1 and 1A) lasting from 7 to 30 days prior
to Period 2 (baseline; Week 0; Visit 2)
* Period 2: Induction Dosing Period will be a double-blind, double-dummy (both
LY2439821 and etanercept will have matching placebos), treatment period that
will occur from Week 0 (baseline; Visit 2) to Week 12 (Visit 7); dosing will
occur twice weekly from Weeks 0 up to Week 12 and evaluation of primary
endpoints will occur at Week 12 prior to the Week 12 dose.
* Period 3: Maintenance Dosing Period will be a double-blind treatment period
with LY2439821 and placebo for LY2439821 that will occur from Week 12 (Visit 7)
to Week 60 (Visit 19). Three treatment groups (80 mg LY2439821 Q4W, 80 mg
LY2439821 Q12W, and placebo) will be evaluated to determine the optimum dosing
interval for the maintenance of response/remission, to evaluate relapse or
rebound following treatment withdrawal, and to measure response to retreatment
following relapse. At Week 12 (Visit 7), patients who enter Period 3 will be
classified as a responder or non-responder according to the following criteria:
* Responder = sPGA score of *0* or *1* with at least a 2-point improvement
from baseline
* Non-responder = sPGA score of >1.
* Period 4: Long-Term Extension Period from Week 60 (Visit 19) up to Week 264
(Visit 36).
* Period 5: Post-Treatment Follow-Up Period occurring from last treatment
period visit or Early Termination Visit (ETV) up to a minimum of 12 weeks
following that visit.

Investigational Product, Dosage, and Mode of Administration or Intervention:
Induction Dosing Period
* 80 mg LY2439821 Q2W = A starting dose of 160 mg (Week 0) given as 2
subcutaneous (SC) injections followed by 80 mg given as 1 SC injection Q2W
(Weeks 2, 4, 6, 8, and 10). To maintain blinding, placebo for etanercept is
given twice weekly starting at Week 0 up to Week 12.
* 80 mg LY2439821 Q4W = A starting dose of 160 mg (Week 0) given as 2 SC
injections followed by 80 mg given as 1 SC injection Q4W (Weeks 4 and 8). To
maintain blinding, placebo for etanercept is given twice weekly starting at
Week 0 up to Week 12.
Maintenance Dosing and Long-Term Extension Period
* 80 mg LY2439821 Q4W = A dose of 80 mg given as 1 SC injection + placebo for
LY2439821 as 1 SC injection at Week 12; 80 mg given as 1 SC injection Q4W
thereafter.
* 80 mg LY2439821 Q12W = A dose of 80 mg given as 1 SC injection + placebo for
LY2439821 as 1 SC injection at Week 12; 80 mg given as 1 SC injection Q12W
thereafter. To maintain blinding with Q4W dose regimen, placebo will given as
1 SC injection at Weeks 16, 20, 28, 32, 40, 44, 52, 56, and so on, until the
study is unblinded.
* No dose of LY2439821 will be given at Week 256.

Planned Duration of Treatment: Up to 5 years for investigational product
administration (LY2439821) and up to 5 years and 28 weeks for participation
over 5 Periods (Screening Period: 7 to 30 days; Induction Dosing Period: 12
Weeks; Maintenance Dosing Period: 48 weeks; Long-Term Extension Period: 196
weeks; Post-Treatment Follow-Up Period: 12 to 24 weeks after the date of the
patient*s ETV or last regularly scheduled visit).

Reference Therapy, Dose, and Mode of Administration or Comparative
Intervention:
Induction Dosing Period
* 50 mg Etanercept twice weekly = Etanercept 50 mg (1 SC injection) given twice
weekly starting at Week 0 and up to Week 12. To maintain blinding to
LY2439821, placebo for LY2439821 given as 2 SC injections (Week 0) followed by
placebo for LY2439821 Q2W given as 1 SC injection (Weeks 2, 4, 6, 8, and 10).
* Placebo = Placebo for LY2439821 (Week 0) given as 2 SC injections followed by
placebo for LY2439821 Q2W (Weeks 2, 4, 6, 8, and 10). Placebo for etanercept
(1 SC injection) given twice weekly starting at Week 0 up to Week 12.
Maintenance Dosing and Long-Term Extension Period
* Placebo for LY2439821 = Placebo given as 2 SC injections at Week 12 followed
by placebo given as 1 SC injection Q4W thereafter.

Risks and Discomforts Associated with LY2439821
Common events (which refer to events observed in greater than 1% and less than
10% of people):
- Infections commonly reported included urinary tract infection, upper
respiratory infection, runny nose, and sore throat.
- Increased blood pressure.
- In patients with RA, other common events were low white blood cell counts.
When a person has low white blood cell counts that person may get infections
more often, including serious infections.
- When proteins like LY2439821 are given to people, the body may react by
making antibodies to the protein that was given. If such antibodies develop
against LY2439821, they may get rid of LY2439821 more quickly or disable it
from working.
- Allergic reactions may also occur in people who develop antibodies to
proteins like LY2439821. Mild allergic reactions may include itching, rash, or
hives. Serious allergic reactions may include fever, chills, headache, muscle
ache, dizziness, very low blood pressure, and difficulty breathing. Sometimes,
these reactions can be life-threatening.
- Proteins may also cause swelling, redness, or irritation at the injection
site.
- Other events at the site of injection were redness, bleeding, rash, or
hives.

Other commonly reported events in LY2439821-treated people with RA in 2 of the
studies include:
* back pain * flu
* broken bones * headache
* bronchitis * nausea
* bruising * pain in muscle or joint
* cough * rash with itchy skin
* diarrhea * stomach pain
* dizziness * trouble getting to sleep or staying asleep
* dry mouth * vomiting
* fatigue * worsening of rheumatoid arthritis
* fever

Other commonly reported events in LY2439821-treated people with psoriasis in 2
of the studies include:
* a cut on the skin * headache
* anxiety * herpes infection (cold sores)
* arthritis * infection on the eye lid
* athletes foot * infection under the skin
* burning or prickling sensation on the skin * itching
* cough * low blood pressure
* diarrhea * nausea
* dizziness * pain
* dry skin * pain in the muscle or joints
* ear infection * rash or redness on the skin
* fatigue * stomach pain
* fever * worsening psoriasis