A randomized, partially-blinded, active-controlled multicenter study of secukinumab to demonstrate reduction of radiographic progression versus GP2017 (adalimumab biosimilar) at 104 weeks and to assess the long term safety, tolerability and efficacy up to 2 years in patients with active ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease which belongs to
a group of conditions known as spondyloarthritides (SpA). It is mainly
characterized by involvement of the axial skeleton and sacroiliac (SI) joints,
but also affects peripheral joints, entheses and extra-articular organs. A
significant proportion of patients may present with associated extra -
articular manifestations such as uveitis, psoriasis, inflammatory bowel disease
(IBD), cardiovascular and pulmonary abnormalities. Generalized osteoporosis, as
well as regional osteopenia are common in AS patients and predispose them to
non-traumatic fractures in spite of young age and gender (male). The presence
of the HLA-B27 human leukocyte antigen is strongly associated with AS: 90-95%
of patients with AS who have European ancestry carry this marker. AS affects up
to 1.1% of the population, is associated with significant morbidity and
disability, and thus constitutes a major socio-economic burden.

First-line medication of mild AS consists of non-steroidal anti-inflammatory
drugs (NSAIDs). Treatment of NSAID-refractory AS is hampered by the lack of
efficacy of virtually all standard disease modifying anti-rheumatic drugs
(DMARDs), including methotrexate (MTX). Tumor necrosis factor (TNF) blocking
agents were successfully added to the armamentarium to treat AS and
subsequently demonstrated prolonged efficacy up to eight years of follow-up.
However, upon discontinuation of TNF blockers the disease relapses quickly,
indicating that the inflammatory process may have only been inhibited but not
completely abolished.
Secukinumab, a human monoclonal antibody that inhibits the effector function of
IL-17A, has been previously shown to be better than placebo in improving the
signs and symptoms of AS. In the Phase III MEASURE 1 and MEASURE 2 studies of
590 pat ients with AS, secukinumab significantly improved key clinical domains
of disease versus placebo, including signs and symptoms, physical functioning,
and quality of life.

Secukinumab as well as a number of anti-TNFs including adalimumab are approved
for treatment of patients with active AS (Cosentyx® and Humira® package inserts
and SmPCs). Results on signs and symptoms with both secukinumab and adalimumab
have demonstrated good response along with rapid reduction of SI-joint and
spinal inflammation as evidenced by MRI. One of the key features of AS
contributing to long term disability is the process of structural remodeling in
the axial skeleton and the SI-joints. This process as evidenced by SI and spinal
radiography typically begins with subchondral sclerosis in the SI-joints along
with squaring and marginal sclerosis of the vertebral bodies. Over time SI
joint erosions occur and vertebral body syndesmophytes form, ultimately leading
to spinal fusion. The process is
slow, progresses over 10 - 15 years and includes both osteoproliferative as
well as absorptive processes.
Studies evaluating the effects of the anti-TNF agents adalimumab, etanercept
and infliximab on radiographic damage in patients with AS did not demonstrate
inhibition of radiographic progression after approximately 2 years of therapy
compared to a histo rical cohort. The comparisons to the historical cohorts
that had been treated with NSAIDs only have shown a mean modified Stoke
Ankylosing Spondylitis Spine Score (mSASSS) progression of 0.8 -0.9 over 2
years, regardless of anti-TNF or NSAID treatment.
Two-year spinal X-ray data from the secukinumab pivotal study MEASURE 1 suggest
that IL-17A inhibition may have the potential to decrease spinal structural
progression as evidenced by a mean mSASSS change after 2 years of therapy of ~
0.3. This speaks to the potential of secukinumab to influence the long-term
structural progression in the spine of patients with AS.

However, a need exists for comparative studies to assess how different
mechanisms of action can reverse or slow down structural progression. This will
be the first study comparing an anti-IL17A treatment with an anti-TNF agent in
AS. This study will provide critical scientific evidence that will improve
evidence-based decision making in the treatment of patients with AS and play an
important role in filling the current data gap between clinical research and
day-to-day clinical practice on the therapeutic utility of biologic therapy in
patients with active AS.

The purpose of this study is to demonstrate the impact on progression of
structural damage in the spine as measured by the mSASSS in patients with AS.
Data from this study will be used to support the submission of an AS label
extension to include a claim on radiographic progression.

This is a multicenter, randomized, partially-blinded, active-controlled,
parallel-group study.

At baseline (BSL), approximately 837 subjects whose eligibility is confirmed
will be randomized to one of three treatment groups (1:1:1).
Group 1: secukinumab 150 mg [1 x 1.0 mL s.c. plus placebo (1 x 1.0 mL s.c.)] at
BSL, Weeks 1, 2 and 3, followed by administration every four weeks starting at
Week 4
Group 2: secukinumab 300 mg (2 x 1.0 mL s.c.) at BSL, Weeks 1, 2 and 3,
followed by administration every four weeks starting at Week 4
Group 3: GP2017 (adalimumab biosimilar) 40 mg (1 x 0.8 mL s.c.) at BSL followed
by administration every two weeks

AIN457 secukinumab
GP2017 (adalimumab biosimilar)

Burden:
Study duration: 2 * years.
15 site visits. In case IMP injections not adminstered at home, 60 site visits
(GP2017) or 34 (secukinumab).
5x fasting.
Duration per visit 1 to 2 hours (in case patient visits site for IMP injection
only; duration visit 15 minutes).

GP2017 group: 52 s.c. injections (biweekly)
Secukinumab group: 29 s.c. injections (every 4 weeks (1e 4 weeks; weekly))

Physical examination: approx.14x.
Blood- and urine collection: approx. ca. 15x (blood 5-30 ml)
Optional pharmacogenetic blood sample collection (6 ml): 1x
ECG at baseline
X-Ray Chest: 1x (in case not done within 3 months before start trial).
X-Ray spinal: 3x
X-Ray SI joints: 2x
MRI spinal: 4x
Completion of questionnaires (BASFI, BASDAI, ASQoL, FACIT-Fatigue,
SF-36,WPAI-GH and VAS (backpain and disease activity): at 11 visits. Max
duration half an hour per visit (in case VAS only: max 5 minutes).

Risk:
Side effects study medication and inconveniences study proecdures.