An open-label, multicentre, phase IV study to investigate the infliximab serum concentration of Remsima* (infliximab biosimilar) after switching from Remicade (infliximab) in subjects with Crohn*s Disease (CD), Ulcerative Colitis (UC) or Rheumatoid Arthritis (RA) in stable remission.

Inflammatory autoimmune diseases like RA, CD, and UC are generally chronic and
life-long. Their impact on patients* quality of life and on healthcare budgets
is considerable.

Treatment with tumor necrosis factor alpha (TNF-α) inhibitors like infliximab
is an important treatment option for the above mentioned inflammatory
autoimmune disease. The introduction of biologic therapeutics (biologicals) for
treatment of inflammatory bowel disease (IBD) and for the treatment of RA has
significantly improved patient outcomes. TNF-α inhibitors and other biologicals
are costly compared with conventional DMARDs and have led to increased costs to
healthcare systems. For this reason, much interest in biosimilar products has
developed. A biosimilar is a biotherapeutic product similar in quality, safety,
and efficacy to an already licensed reference biotherapeutic product. Unlike
generics, which are identical copies of traditional small molecules,
biosimilars are not the same as the original biologic medicine. This is an
inevitable because biologicals are made of living cells as opposed to the
chemical composition of traditional drugs. Because of unavoidable differences
in the manufacturing processes, a biosimilar and its respective reference
product will not be entirely identical.

Remsima* (CT-P13) is one of the world*s first biosimilar infliximab approved by
the European Medicines Agency (EMA). It is produced in the same type of cell
line and has an identical amino acid sequence to the originator infliximab
(Remicade). Remsima* is approved for the management of inflammatory autoimmune
disorders for all indications as the reference infliximab (Remicade). The
approval is based on the fact that Remsima* demonstrated similarity to
reference infliximab in an extensive comparability exercise, including
bioanalytical, preclinical and clinical analyses. Remsima* demonstrated an
equivalent pharmacokinetic profile, efficacy and safety to that of reference
infliximab in ankylosing spondylitis patients and also equivalent efficacy and
safety to that of reference infliximab in RA patients. Remsima* is generally
well tolerated, with a similar tolerability profile to that of the reference
infliximab.

Despite the establishment of a specific approval pathway, the issuance of
detailed scientific guidelines for the development of biosimilars and the
approval of several biosimilars in the European Union (EU), acceptance of
biosimilars in the medical community continues to be low. This is especially
true in therapeutic indications for which no specific clinical trials with the
biosimilar have been performed, like CD and UC, and which have been licensed
based on pharmacokinetics and extrapolation of efficacy and safety data from
other indications.

This is also shown in a recently performed web based survey at ECCO, most IBD
specialists have the opinion that biosimilar infliximab is not interchangeable
with the originator, unless strong evidence is shown about similarity for each
indication. Most of the 272 clinicians regarded cost-sparing (89%) as the main
advantage of biosimilars, immunogenicity (serum drug levels and antibodies to
the drug) (69%) as their main concern. Most clinicians thought that medical
societies should promote information about biosimilars (66%), collaborate with
health institutions to develop rules (78%) and guidelines (57%) on the use of
biosimilars, and create multispecialty safety registries (80%).

Limited clinical data in CD and UC are available. Case series in Korea
indicated the clinical efficacy, safety, and interchangeability of CT-P13 in
the treatment of IBD compared with its originator. Furthermore,
antibodies-to-Remicade in sera of Remicade-treated IBD patients recognized
Remsima* to a similar extent, suggesting shared immuno-dominant epitopes on
these two infliximab agents.

To demonstrate that the infliximab serum concentration of Remsima* is
non-inferior to the infliximab serum concentration of Remicade , 16 weeks after
switch from Remicade to Remsima* in subjects with CD, UC or RA in stable
remission for > 30 weeks measured by a bridging enzyme-linked immunosorbent
assay (ELISA).

Study IFX4501 is an open-label, multicentre, phase IV study. All study subjects
exposed to Remsima* treatment serve as their own controls, using the data
collected before the first infusion with Remsima* (Day 0, V1), as baseline data.

All subjects treated with Remsima* will be followed up until 16 weeks after
switch from Remicade.

Assessments will be performed as follows:
V1 (day 0) before infusion with Remsima*:
- Demography
- Pregnancy test (if applicable)
- Medical history, including details of treatment regimen for Remicade
- Remicade infliximab serum concentration (bridging ELISA)
- Antibody-to-Infliximab (RIA test)
- Prior medication use (previous year)
- Disease activity:
o For CD: HBI, faecal calprotectin and serum CRP
o For UC: SCCAI, faecal calprotectin and serum CRP
o For RA: DAS-28 and serum CRP
- Quality of Life; EQ-5D
- ADRs of Remicade
- Infliximab dose

V1 (day 0) after infusion with Remsima*:
- Concomitant medication
- (S)AEs
- Remsima* dose

V2 (week 8±1) and V3 (week 16±2)
- Concomitant medication
- Remsima* infliximab serum concentration by ELISA
- ATI Remsima* by RIA test
- Disease activity:
o For CD: HBI and serum CRP. Faecal calprotectin only at V3.
o For UC: SCCAI and serum CRP. Faecal calprotectin only at V3.
o For RA: DAS-28 score and serum CRP
- Quality of Life: EQ-5D (only at V3)
- (S)AEs
- Remsima* dose
In case of early discontinuation (i.e. before V3), the same data will be
collected as described for V3. In addition, the reason for early
discontinuation as well as the discontinuation date will be recorded.

The IMP in this study is the by EMA approved infliximab biosimilar, Remsima.
Eligible subjects will have been treated for more than 30 weeks with Remicade
before they are enrolled in this study. Eligible subjects are switched from
Remicade, which will be used in this study as a reference drug. During the
study, subjects will be treated with two intravenous infusions of Remsima at
Day 0 (visit 1), Week 8 (visit 2). Subjects will be treated in the hospital.
The starting dose of Remsima will be identical to the dose of Remicade before
and remains stable over the study period.

The biosimilar infliximab (Remsima*) has been approved by EMA for the
management of inflammatory autoimmune disorders rheumatoid arthritis,
ankylosing spondylitis, CD, UC, psoriatic arthritis and psoriasis, based on
quality, safety and efficacy profiles comparable to those of infliximab
(Remicade).

Since Remsima* is biosimilar to the originator, it is estimated that risk of
treatment is limited. The benefit for the patient in the clinical trial is the
monitoring of the switch for this individual patient in the trial. The overall
benefit for the health care is the collection of more clinical data in the
switch to the biosimilar for controlled patients. This will contribute to more
confidence in the biosimilar and herewith to a reduction in costs in the Health
Care.