A randomized, double-blind, two-way crossover study to compare the pharmacokinetics, pharmacodynamics and safety of a single subcutaneous administration of LA-EP2006 and a single subcutaneous administration of Neulasta® (EU-authorized) in healthy subjects

LA-EP2006 is an investigational compound that is being developed as a proposed
biosimilar to pegfilgrastim (Neulasta®; the originator*s product). A biosimilar
is a compound which aims to be similar to the originator*s product in terms of
ability to treat the disease, safety profile and overall quality. Neulasta® is
an approved drug for the treatment of a shortage of white blood cells in order
to prevent infections. It is used mostly for patients with cancer to treat the
side effects of chemotherapy. The aim for LA-EP2006 is to be approved for the
treatment of the same shortage of white blood cells as Neulasta®. The active
compound of LA-EP2006 and Neulasta® is called pegfilgrastim. This is a protein
which is very similar to the human version *granulocyte colony stimulating
factor* (also known as GCSF or filgrastim). GCSF is naturally present in the
human body. Therefore, Neulasta® is called a *biological*. The difference
between naturally occurring GCSF and pegfilgrastim is the attachment of a large
chain of molecules (a polymer called polyethylene glycol [PEG]) to the protein.
This makes the protein stay longer in the body so patients need to receive drug
less often to achieve the same effect. LA-EP2006 is a new pegfilgrastim
strongly resembling Neulasta®. Both Neulasta® and LA-EP2006 are produced with
the help of bacteria which have received a human gene which makes them able to
produce this protein. LA-EP2006 has not been registered as a drug, but has been
given to humans before in other studies.

The purpose of the study is to compare LA-EP2006 and Neulasta® with respect to
how quickly and to what extent the compounds are absorbed and eliminated from
the body after injection under the skin of the abdomen (this is called
pharmacokinetics). It will also investigate the effect of the compounds on the
amounts of certain types of white blood cells (this is called pharmacodynamics)
and the possible development of antibodies against pegfilgrastim in your blood.
Finally it will be investigated to what extent the compounds are safe and
tolerated.

The study will consist of 2 periods. You will receive one single injection of 6
mg LA-EP2006 diluted in 0.6 mL solution during one period and one single
injection of 6 mg Neulasta® diluted in 0.6 mL solution during the other period.

The dosing sequence (i.e., whether you will first receive LA-EP2006 and then
Neulasta® or in reverse order) will be determined by chance, like a coin flip.
Neither you, nor the responsible doctor will know the dosing sequence of
LA-EP2006 and Neulasta®; we call this *the study is blinded*. However,
information on the administration sequence of the study compound will be
present in the clinical research center, in sealed envelopes, which can be
opened in case of emergency.

The actual study will consist of 2 periods during which you will stay in the
clinical research center in Zuidlaren for 7 days (6 nights). You will leave the
clinical research center on Day 6 (Day 1 is the day of administration of the
study compound).
After each stay you will return to the clinical research center for 7
ambulatory visits (Days 7, 8, 9, 10, 12, 15 and 28,). The time interval between
the last visit of the first period and the administration of the study compound
in the second period is at least 28 days.

You are expected at the clinical research center in the afternoon prior to the
day of administration of the study compound in each period. You will be
required not to have consumed any food or drinks (with the exception of water)
during the 4 hours prior to arrival in the clinical research center at the
pre-study screening and on Day -1, Day 7 and Day 28 of each period.

A post-study screening will take place on Day 28 of each period.

The study will consist of 2 periods. You will receive one single injection of 6
mg LA-EP2006 diluted in 0.6 mL solution during one period and one single
injection of 6 mg Neulasta® diluted in 0.6 mL solution during the other period.

All potential drugs cause adverse effects; the extent to which this occurs
differs. LA-EP2006 has been studied before in research similar to the current
study. The most frequently observed adverse effects in man were similar to the
side effects described below for Neulasta®. You should be aware that the
aforementioned adverse effects and possibly other, still unknown adverse
effects, may occur during the study. However, with the doses used in this study
no serious adverse effects are expected.

Neulasta® has been used now for 13 years and is registered as a drug in over
100 countries worldwide. The following list represents most of the side effects
known for pegfilgrastim, reported by cancer patients who received multiple
doses of pegfilgrastim to treat the side effects of chemotherapy. Because this
study includes only healthy volunteers who will receive single doses of
LA-EP2006 and Neulasta®, the probability of any of the following events to
happen is considered low in this study.

Very common side effects (may affect more than 1 in 10 people):
* bone pain, and general aches and pains in the joints and muscles.
* nausea and headaches.

Common side effects (may affect up to 1 in 10 people):
* pain and redness at the site of the injection.

Uncommon (may affect up to 1 in 100 people):
* allergic-type reactions, including redness and flushing, skin rash, and
raised areas of the skin that itch.
* serious allergic reactions, including anaphylaxis (weakness, drop in blood
pressure, difficulty breathing, swelling of the face).
* increased spleen size.
* spleen rupture. Some cases of splenic rupture were fatal. It is important
that you contact your doctor immediately if you experience pain in the upper
left side of the abdomen or left shoulder pain since this may relate to a
problem with your spleen.
* breathing problems. If you have a cough, fever and difficulty breathing
please tell your doctor.
* some changes may occur in your blood, but these will be detected by routine
blood tests. Your white blood cell count may become high for a short period of
time. Your platelet count may become low which might result in bruising.
* Sweet*s syndrome (plum-coloured, raised, painful lesions on the limbs and
sometimes the face and neck with fever) has occurred but other factors may play
a role.
* cutaneous vasculitis (inflammation of the blood vessels in the skin).

It should be emphasized that the most common side effects could still be
present or may appear on the day you leave the clinical research center.

LA-EP2006 and Neulasta® are so-called *biologicals*; given the properties of
these drugs, there is a chance that your body will develop antibodies against
filgrastim, pegfilgrastim and PEG or that a hypersensitivity reaction will be
induced. This means that should you need filgrastim as therapy in the future,
your response to treatment by this drug may be reduced or absent, and/or you
may get a hypersensitivity reaction.