A Phase 2b Double-Blind, Multi-Dose, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MEDI2070 in Subjects with Moderate to Severe Crohn*s Disease Who Have Failed or Are Intolerant to Anti-Tumor Necrosis Factor-Alpha Therapy

Crohn*s disease (CD) is a chronic transmural inflammatory disease of unknown
etiology that most commonly affects the distal ileum and colon, and may occur
in any part of the gastrointestinal (GI) tract. Commonly used medical therapies
include aminosalicylates (including sulfasalazine and
mesalamine), systemic corticosteroids, immunosuppressive agents (eg,
azathioprine and methotrexate), antibacterial agents, and biologic agents (eg,
adalimumab, infliximab, certolizumab, and vedolizumab). Despite the
availability of these medical therapies, the remaining morbidity and the
complications of CD (eg, intestinal obstruction and or perforation, fistula
formation, malnutrition) continue to warrant new therapies.
Interleukin (IL)-23, a member of the IL-12 family of cytokines, is a
heterodimeric cytokine consisting of 2 subunits: p40 and p19. The p40 subunit
is shared by IL-12 and IL-23 as a common subunit, and is targeted by inhibitors
of IL-12/23 (eg, ustekinumab and briakinumab). The main known effects of IL-23
are to drive the differentiation of T-helper 17 cells, as well as macrophages,
natural killer (NK) cells, dendritic cells, and
innate lymphoid cells leading to up-regulation of IL-17, IL-22, tumor necrosis
factor-alpha (TNF*), granulocyte-macrophage colony-stimulating factor, and
interferon-gamma (IFN*), and down-regulation of IL-10.
Studies in patients have demonstrated that IL-23 is upregulated in cells and
target tissues of CD and ulcerative colitis, while IL-12 is not.
In the clinic, anti-IL-12/23p40 antibodies (eg, ustekinumab and briakinumab)
have been shown to induce clinical responses in CD (Phase 2 studies) and
psoriasis (Phase 2 and Phase 3 studies. Phase 1 and Phase 2 clinical studies
with anti-IL-23 antibodies MEDI2070 (Amgen Study 20080767) and CNTO 1959 in
subjects with psoriasis have demonstrated clinical efficacy comparable with
antibodies targeting both IL-12 and IL-23, indicating that therapeutic effects
of the anti-IL-12/23p40 antibodies may be due to neutralization of IL-23 alone.

MEDI2070, previously known as AMG 139, is a human, Chinese hamster ovary
cell-derived, immunoglobulin G2 (IgG2) monoclonal antibody (mAb) consisting of
2 heavy chains of the IgG2 subclass and 2 light chains of the lambda subclass,
which are covalently linked through disulfide bonds.

Non clinical experience
MEDI2070 selectively binds to human and cynomolgus monkey IL-23 and prevents
IL-23 from interacting with IL-23R. MEDI2070 is specific for IL-23 and does not
bind or block human or cynomolgus monkey IL-12.

Clinical experience
Three clinical studies with MEDI2070 are complete or ongoing; 2 studies are
complete (Phase 1a Study 20080767 and Phase 1b Study 20090519) and 1 study is
ongoing (Phase 2a Study CD-IA-MEDI2070-1147). study is a 2-part, Phase 2a study
comprising a 12-week, double-blind, placebo-controlled period followed by a
100-week, open-label period to evaluate the short-term efficacy and the short-
and long-term safety of MEDI2070
in subjects with moderate to severe, active CD who have failed or are
intolerant to anti-TNF* therapy. The primary efficacy endpoint of the study,
Crohn*s Disease Activity Index (CDAI) response at Week 8 (defined by either a
CDAI score of < 150 or a reduction from baseline of at least
100 points) was met.

CD is a chronic, relapsing-remitting, inflammatory disease of the GI tract.
Some patients may have persistent clinically active disease. The current
treatment options for patients with moderate to severe CD, refractory to
standard therapies that include 5-aminosalicylates,
glucocorticosteroids, 6-mercaptopurine, azathioprine, methotrexate, anti-TNF*
mAbs, and vedolizumab are limited. MEDI2070 is being developed as a treatment
for CD to reduce intestinal inflammation and improve signs and symptoms. Study
CD-IA-MEDI2070-1147 demonstrated improved clinical responses and remission
rates as measured by CDAI. This study, D5170C00002, seeks to confirm those
observations, and to extend them to include assessments of clinical responses
as demonstrated by improvement of symptoms and of colonic mucosal appearance as
observed on endoscopy.

The primary objective of this study is to evaluate the efficacy of MEDI2070
versus placebo to induce clinical remission based on the CDAI
score at Week 8 in subjects with moderate to severe CD who have failed or are
intolerant to anti-TNF* therapy.

Secondary objectives:
To evaluate the efficacy of MEDI2070 to induce remission based on the SES-CD
To evaluate the efficacy of MEDI2070 to induce response based on the SES-CD
To evaluate the efficacy of MEDI2070 to induce remission based on the PRO2
To evaluate the efficacy of MEDI2070 to induce response based on the PRO2
To assess the safety and tolerability of MEDI2070
To evaluate the PK and IM of MEDI2070
To characterize MEDI2070's dose-exposure & exposure-response relationships
To evaluate the efficacy of MEDI2070 to induce clinical response based on the
CDAI
To evaluate the efficacy of MEDI2070 to induce clinical remission based on the
CDAI
To evaluate the efficacy of MEDI2070 on modified sustained remission, based on
the SES-CD
To evaluate the efficacy of MEDI2070 on modified sustained remission based on
the PRO2
To evaluate the efficacy of MEDI2070 on modified sustained remission based on
the CDAI
To assess the relationship of biomarker 1 & biomarker 2 to CDAI remission

This is a 3-part Phase 2b study comprising a 16-week, double-blind,
placebo-controlled, induction period; a 12-week, double-blind,
placebo-controlled, maintenance period; and a 24-week, open-label period
designed to evaluate the short-term efficacy and the short- and long-term
safety of MEDI2070 in subjects with moderate to severe, active CD who have
failed or are intolerant to anti-TNF* therapy as determined by
the investigator. Subjects will be stratified based on the number of prior
anti-TNF* agents that failed or were not tolerated (1 vs > 1).
Approximately 342 subjects will be randomly assigned to 1 of 5 treatment groups
to receive IV and SC investigational product (MEDI2070 or placebo) once Q4W
during the double-blind, placebo-controlled, induction and maintenance periods.
Subjects who complete the double-blind, placebo-controlled, maintenance period
(Week 28) will have the option to enter a 24-week, open-label period in which
they will receive open-label MEDI2070 (210 mg SC) Q4W (Weeks 28 through 48).
All subjects will be followed for safety at 3 visits over 28 weeks (Weeks 60,
70, and 80 for subjects completing the open-label period) after their last dose
of investigational product. An interim analysis may be conducted when at least
75% of the total planned number of subjects has completed the Week 16 Visit or
withdrawn prior to the Week 16 Visit. The study site personnel and sponsor
personnel who are directly associated with the conduct of this study and the
study subjects would remain blinded to the subject-specific treatment
assignment as well as the results of this analysis until the completion of the
double-blind, maintenance period. No changes to the conduct of this study or
data analysis are planned
based on the interim analysis. The primary analysis will be performed when all
subjects complete the initial 16-week, induction period. A further analysis is
planned when all subjects complete the 28-week, randomized, placebo-controlled,
double-blind period. The final analysis, including all study periods and all
data, will be performed at the end of the study.

Five groups:

Group 1 - high dose (76 subjects)
Dose 1: 700 mg study drug infusion (into a vein) + placebo injection (under the
skin)
Dose 2: 700 mg study drug infusion (into a vein) + placebo injection (under the
skin)
Dose 3 - 7: 210 mg study drug injection (under the skin)
Dose 8 onwards: 210 mg study drug injection (under the skin)

Group 2 - high*medium dose (76 subjects)
Dose 1: 280 mg study drug infusion * (into a vein) + placebo injection (under
the skin)
Dose 2: 210 mg study drug injection** (under the skin) + placebo infusion*
(into a vein)
Dose 3-7: 210 mg study drug injection** (under the skin)
Dose 8 onwards: 210 mg study drug injection** (under the skin)

Group 3 - low*medium dose (76 subjects)
Dose 1: 210 mg study drug injection ** (under the skin) + placebo infusion*
(into a vein)
Dose 2: 105 mg study drug injection** (under the skin) + placebo infusion*
(into a vein)
Dose 3-7: 105 mg study drug injection** (under the skin)
Dose 8 onwards: 210 mg study drug injection** (under the skin)

Group 4 - low dose (38 subjects)
Dose 1: 70 mg study drug injection (under the skin)** + placebo infusion* (into
a vein)
Dose 2: 35 mg study drug injection (under the skin)** + placebo infusion* (into
a vein)
Dose 3-7: 35 mg study drug injection** (under the skin)
Dose 8 onwards: 210 mg study drug injection** (under the skin)

Group 5 - placebo (76 subjects)
Dose 1: Placebo injection** (under the skin) and infusion* (into a vein)
Dose 2: Placebo injection** (under the skin) and infusion* (into a vein)
Dose 3-7: Placebo injection** (under the skin)
Dose 8 onwards: 210 mg study drug injection** (under the skin)

Results from previous clinical studies have provided safety and tolerability
data for MEDI2070 and shown significantly greater efficacy for MEDI2070
compared with placebo for achieving CDAI response, CDAI 100-point improvement,
and decreases in C-reactive protein (CRP) and fecal calprotectin (Study
CD-IA-MEDI2070-1147). No safety risk of MEDI2070 was identified.

Although no safety risks for MEDI2070 have been identified, the
immunoregulatory role of IL-23 in humans is not completely understood.
Potential risks include infections, malignancies, complications associated with
vaccination, infusion reactions, injection-site reactions, hypersensitivity,
immune complex disease, and neurological and visual toxicities. Subjects will
be closely monitored during the study with regular full blood analysis
including differential white cell count and serum chemistry to monitor the risk
of infection. Visual acuity tests, ophthalmoscopy, and complete physical and
neurologic examinations will be performed at screening and during the study. In
addition, live/attenuated vaccinations will not be permitted during the study.
Exclusion criteria have been formulated to ensure that subjects at increased
potential risk due to the mechanism of action of MEDI2070 are not enrolled in
the study.