Efficacy, pharmacokinetics, and safety of BI 695500 versus rituximab in patients with moderately to severely active rheumatoid arthritis: a randomized, double-blind, parallel arm, multiple dose, active comparator trial.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease
characterized by synovial inflammation in the joints and consequently,
progressive joint destruction. Depending on the severity of the disease,
systemic manifestations may occur including lung disease, rheumatoid nodules
and cardiovascular system effects. If left untreated, RA may lead to severe
functional disabilities, and therefore a considerable reduction in quality of
life for the patient. The prevalence of RA varies with factors such as gender,
race and smoking status and is approximately 0.5-1%.

B lymphocytes (B cells) are thought to play a crucial role in the pathogenesis
of RA. B cells are highly efficient antigen-presenting cells and therefore
contribute to the auto-immune response through downstream activation of T cells
via co-stimulatory molecules. B cells respond to, and produce, chemokines and
cytokines that facilitate lymphocyte infiltration into joints, formation of
ectopic lymphoid structures (e.g., the formation of T cell-B cell follicles
with germinal center reactions in the synovium of affected joints),
angiogenesis, and synovial hyperplasia that characterize the pathology observed
in the rheumatoid joint. They are also the primary source of rheumatoid factors
(RFs) and anti-cyclic citrullinated peptide (anti-CCP) antibodies which
contribute to the formation of immune complexes and complement activation in
inflamed joints. Thus, B cell targeted therapy could play an important role in
RA through a reduction in the B cell count as well as a reduction in B
cell-mediated downstream effects on other cell types involved in the
inflammatory response.

Primary objectives:
The primary objectives of this trial are:
• To show PK similarity of BI 695500 to MabThera® and Rituxan® and of Rituxan®
to MabThera® (three-way PK similarity).
• To establish statistical equivalence of efficacy of BI 695500 and Rituxan®/
MabThera®, in patients with moderately to severely active RA, based on the
change in Disease Activity Score 28 (DAS-28) score measured at 24 weeks
compared to Baseline and the American College of Rheumatology 20% (ACR20)
response at Week 24.

Secondary objectives:
•The secondary objectives of this trial are to compare the efficacy, safety and
tolerability of BI 695500 and Rituxan®/MabThera® in patients with moderately to
severely active RA.

150 patients with moderately to severely active RA who have had an inadequate
response or intolerance to conventional disease modifying ant-rheumatic drug
(DMARD) therapy including at least one tumor necrosis factor (TNF) inhibitor,
will be randomized into part I of the trial . Patients will be allocated to
treatment 1:1:1 ratio to receive BI 695500 (n=50), Rituxan (n=50) or MabThera
(n=50). Each patient will receive two 1000 mg intravenous (IV) drug infusions:
the first on day 1 and the second on Day 15. Patients randomized to part 1 will
undergo up to 19 visits over the duration of the trial (48 weeks).

If the PK data support equivalent bioavailability among the treatment groups,
and no safety concerns are identified by IDMC then a further 150 patients will
be randomized into Part II.

In Part II, patients (with moderately to severely active RA who had an
inadequate response or intolerance to conventional DMARD therapy including at
least one TNF inhibitor) will be allocated to treatment in a 1:1 ratio to
receive BI 695500 (n=75) or MabThera (n=75). Each patient will receive two 1000
mg drug infusions: the first on Day 1 and the second on day 15. Patients
randomized to Part II will undergo up to 15 visits over the duration of the
trial (48 weeks).

Part I (Phase 1 study) contains three groups:
1) 50 patients receiving BI 695500. each patient will receive two 1000 mg
intravenous (IV) drug infusions: the first on day 1 and the second on Day 15.
Patients randomized to part 1, BI 695500 group will undergo up to 19 visits
over the duration of the trial (48 weeks).

2) 50 patients receiving Rituxan. each patient will receive two 1000 mg
intravenous (IV) drug infusions: the first on day 1 and the second on Day 15.
patients randomized to part 1, Rituxan group will undergo up to 19 visits over
the duration of the trial (48 weeks).

3)50 patients receiving MabThera. each patient will receive two 1000 mg
intravenous (IV) drug infusions: the first on day 1 and the second on Day 15.
patients randomized to part 1, mabThera group will undergo up to 19 visits over
the duration of the trial (48 weeks).


Part II (phase 3 study) contains 2 groups:
1) 75 patients receiving BI 695500. each patient will receive two 1000 mg
intravenous (IV) drug infusions: the first on day 1 and the second on Day 15.
patients randomized to part II, BI 695500 group will undergo up to 15 visits
over the duration of the trial (48 weeks).

2) 75 patients receiving MabThera: each patient will receive two 1000 mg
intravenous (IV) drug infusions: the first on day 1 and the second on Day 15.
patients randomized to part II, mabThera group will undergo up to 15 visits
over the duration of the trial (48 weeks).

Part I and part II patients are eligible to receive a second course of
treatment at 24 weeks if they have shown a minimum improvement of DAS28 of 1.2
or higher from baseline at 16 weeks after initial treatment This treatment will
consist of one infusion of trial medication at week 24 and one infusion of
trial medication at week 26.

Rituximab causes rapid peripheral B cell depletion in vivo. Therefore, CD19+ B
cell counts will be monitored at frequent intervals throughout the trial for
each of the trial medications.

Common adverse reactions reported in greater than 10% of patients include
infusion related reactions, upper respiratory tract infections and urinary
infections. Overall, infusion-related reactions in clinical trials with
MabThera and Rituxan occurred in up to one third of patients approximately,
with the first infusion and decreased with subsequent infusions. Serious
infusion-related reactions were uncommon (<1% of patients) and were
predominantly seen during the initial course.

Although rare, a potential for drug-induced liver injury (DILI) is under
constant surveillance by sponsors and regulators.

The use of MabThera and Rituxan has been shown to be associated with an
increased risk of progressve multifocal leukoencephalopathy (PML). On the basis
of limited experience with MabThera and Rituxan in RA patients the present data
do not suggest an increased risk of malignancy, however, the possible risk for
the development of solid tumors cannot be excluded.

BI695500, as a proposed biosimilar product, may be seen to provide comparable
PK, efficiacy, safety and tolerability in patients with RA and may present an
opportunity to improve healthcare.