A randomized, double-blind, three-way crossover study to compare the pharmacokinetics, pharmacodynamics and safety of a single 6 mg subcutaneous administration of the
proposed biosimilar product LA-EP2006, Neulasta® US and Neulasta® EU in healthy subjects

LA-EP2006 is an investigational compound that is being developed as a proposed
biosimilar to Neulasta® (the originator*s product). A biosimilar is a compound
that is similar to the originator for which the patent has expired. The
biosimilar aims to be similar to the originator*s product in terms of activity,
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. Neulasta® is on the market in the US as Neulasta®US and in Europe
as Neulasta®EU. The aim for LA-EP2006 is to be approved for the treatment of
the same shortage of white blood cells as Neulasta®US and Neulasta®EU.

The active compound of LA-EP2006, Neulasta®US and Neulasta®EU is called
pegfilgrastim. This is a protein which is very similar to the human protein
called *granulocyte colony stimulating factor* (also known as G-CSF or
filgrastim). G-CSF is naturally present in the human body. Therefore,
pegfilgrastim is called a *biological*. The difference between naturally
occurring G-CSF and pegfilgrastim is the attachment of a large chain of
molecules (a polymer called polyethylene glycol) 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®US and Neulasta®EU. These 3 compounds are produced with the help of
bacteria which have received a small piece of human DNA which makes them able
to produce the active protein. LA-EP2006 has not been approved 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®US and
Neulasta®EU 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 the volunteers blood. Finally it will be investigated to what
extent the compounds are safe and tolerated.

This is a randomized double-blind single-dose, three treatments, six sequence
crossover, PK/PD study with three Treatment Periods (Treatment Periods I, II
and III) in 576 healthy male and female subjects. The study duration for an
individual subject will be approximately 25 weeks (up to 5 weeks of screening
followed by at least 20 weeks of treatment, assessment and washout periods).
Dosing in Treatment Period I and II will be followed by at least 8 week washout
period, including a 4 week assessment period. Dosing in Treatment Period III
will be followed by a 4 week assessment period only.

The volunteer will receive one single injection of 6 mg LA-EP2006 diluted in
0.6 mL solution during one period, one single injection of 6 mg Neulasta®US
diluted in 0.6 mL solution during other period and one single injection of 6 mg
Neulasta®EU diluted in 0.6 mL solution during another period.

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® (US and EU). The volunteers should be
aware that the aforementioned adverse effects and possibly other, still unknown
adverse effects, may occur during the study. If this is the case, the
volunteers will be given all new information that may affect their willingness
to start or continue in the study. However, with the doses used in this study
serious adverse effects are uncommon.

Neulasta® has been used now for 14 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®US and Neulasta®EU), 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 (painkillers will be
offered as needed, as judged by the responsible doctor).
• Nausea and headaches.

Common side effects (may affect up to 1 in 10 people, but in more than 1 in 100
people):
• Pain and redness at the site of the injection.
• Musculoskeletal pain
• Some changes may occur in the blood, but these will be detected by routine
blood tests. The volunteer's white blood cell count may become high for a short
period of time. Their platelet count may become low which might result in
bruising.

Uncommon (may affect up to 1 in 100 people, but in more than 1 in 1000 people):
• Allergic-type reactions, including redness and flushing, skin rash, and
raised areas of the skin that itch.
• Injection site reaction.
• Sickle cell crisis in patients with sickle cell anemia.
• An increase in various laboratory markers as uric acid, liver enzymes,
lactate dehydrogenase and alkaline phosphatase.
• Serious allergic reactions, including anaphylaxis (weakness, drop in blood
pressure, difficulty breathing, swelling of the face).
• Increased spleen size or rupture. Some cases of splenic rupture were fatal.
• A serious lung problem called Acute Respiratory Distress Syndrome (ARDS).
• Sweet*s syndrome (plum-colored, 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).
• Kidney injury (glomerulonephritis).
• Capillary Leak Syndrome; the study compound can cause fluid to leak from
blood vessels into your body*s tissues. This condition is called *Capillary
Leak Syndrome*.

Vomiting, nausea, oropharyngeal pain, feeling hot, malaise, palpitations, ear
pain, tooth ache, hot flushes, ocular erythema and nasopharyngitis were also
experienced in several other studies. In patients with breast cancer the
following adverse events were reported: vomiting, nausea, stomatitis, anemia,
decreased appetite, abdominal pain, alopecia, fatigue, myalgia, arthralgia,
pyrexia, weakness (asthenia), leukopenia (a decrease of white blood cells),
thrombocytopenia (a decrease in platelet counts), cough, pain in the extremity,
bone pain and headache.

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

LA-EP2006 and Neulasta® (US and EU) 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 chance is very small, as antibody development to
(peg)filgrastim occurs in only 3% of the cases. In addition, there is no
scientific evidence that these antibodies will block the effect of the study
compound.
However, theoretically this means that if antibody development occurs and you
should need filgrastim or pegfilgrastim 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. This chance however is very small.
Filgrastim and pegfilgrastim are in clinical use extensively for more than 10
years. According to current knowledge, there seems to be no reason to believe
that administration of pegfilgrastim or its biosimilars hampers the possible
future use of these agents.