Introduction to Neuren.
Neuren Pharmaceuticals is a biopharmaceutical
company, developing new medicines for
diseases and disorders of the central
nervous system or "CNS".
We have four ongoing clinical development programs
on acute conditions : traumatic brain injury
and concussion, and chronic disorders :
Rett syndrome and Fragile X syndrome,
as well as preclinical R&D programs
in a range of other CNS conditions.
Our expert team in Australia,
the US and the UK, includes people with
many years of experience in all aspects of
pharmaceutical development and commercialization.
Neuren shares are traded on the Australian Securities Exchange,
under the code NEU.
What is Trofinetide ?
Trofinetide is the name proposed by the
World Health Organization for our lead
clinical-stage drug candidate.
It is an analog of a molecule, which is derived
from IGF-1 and occurs naturally in the brain.
IGF-1 is a growth factor
stimulated by growth hormone.
In the central nervous system, IGF-1 is produced
by both of the major types of brain
cells : neurons and glia.
IGF-1 in the brain is critical, both
for neural development and for responding
to injury and disease.
In the brain, IGF-1 gets broken down in two separate
molecules : one often referred to as
glypromate - or GPE - comprises the last
three peptides of IGF-1.
GPE affects glial cells, astrocytes and microglia,
while IGF-1 itself mostly affects neurons.
One of the effects of GPE is that
it actually increases production of IGF-1
by neurons and glial cells.
Trofinetide is Neuren's chemically modified
form of GPE, that can mimic GPE's natural
function in the brain.
The small modification results in the drug having
an increased half-life in the circulation,
better stability for easier storage and shipping,
and suitability for use as an oral medication,
whereas GPE itself and
IGF-1 can only be administered by injection.
In the brain, the role of IGF-1 and GPE
is to facilitate the brain's development
and maintain the biological balance
required for normal functioning.
These processes have evolved over millions of years
and are still being extensively
researched by scientists.
During development, the brain and the cells that
make it up change rapidly and in complex ways.
IGF-1 and GPE play a significant
role in regulating these changes.
In the mature brain, IGF-1 and GPE play
an equally important role in responding
to disease, stress and injury.
Whereas most drugs typically exert a
specific effect on a specific target,
Trofinetide exerts diverse effects which
can help to control or normalize
abnormal biological processes in the brain.
Common Pathology Among CNS Disorders
All the different CNS conditions, brain injury,
neurodevelopmental disorders and
neurodegenerative diseases can result in
very different symptoms and outcomes,
many share common underlying
pathological features.
These include : inflammation, overactivation of microglia
(a type of glial cell),
dysfunction of synapses
(the connections between neurons
through which information is transmitted)
and reduced levels of IGF-1.
In other words, diseases and conditions caused by
different mechanisms often result in the
same pathology, at the cellular and
molecular level.
Let's look at these four features.
Inflammation.
Inflammation in the brain,
often referred to as neuroinflammation,
is perhaps the most common pathological
feature of CNS disorders.
Much of it is the result of excess production of
molecules called inflammatory cytokines.
These are prominent in brain injuries,
neurodevelopmental disorders such as
Rett and Fragile X syndromes, as well as
autism, neurodegenerative diseases like
Alzheimer's and Parkinson's and even
so-called normal aging.
Neuroinflammation places significant stress on brain cells.
Stress can disrupt normal cellular processes,
such as information signaling,
increase energy requirements beyond the
ability of the cells to meet their
metabolic needs,
disturb electrical functions which can lead to seizures
and other abnormalities, and even result in
premature cell death.
In animal models, ranging from brain injury and stroke
to Fragile X syndrome to age-associated
cognitive impairment, Trotinetide has
showed an ability to significantly reduce
the levels of inflammatory cytokines.
This has resulted in an improvement in a wide
range of symptoms including
post-traumatic seizures, anxiety,
memory impairment and hyperactivity.
Microglial activation.
Microglia are the resident immune cells in the brain.
Once thought to serve primarily a
sentinel function, responding to
infection and damaged cells by
surrounding and removing them from the
CNS, it is now known that they play a
central role in maintaining synapses
during development and in mature brains
by pruning dendrites (the many small
extensions of neurons that form synapses).
Microglia are also a key source of IGF-1.
Due to this wide-ranging maintenance function,
they have appropriately been
referred to as the "constant gardeners" of
the brain.
Microglia are not only activated in response to
infection and injury.
They are also activated by
inflammation that accompanies acute
brain injury and chronic CNS conditions.
In this activated state, they not only
lose their ability to effectively
perform their normal function in
synaptic maintenance, but also produce
more inflammatory cytokines which can
further compound and damage neurons
and other brain cells.
Trofinetide has been shown to normalize microglial biology
and function, in both acute and chronic conditions.
Restoring normal microglial activity has resulted in
improved synaptic structure as well as correction
of imbalance and synaptic signaling and
cell-to-cell communication.
This has led to reversal of symptoms such as
impaired memory, anxiety, hyperactivity and
compromised social behavior.
Synaptic dysfunction.
Neurons communicate with each other by chemical and
electrical signals transmitted via synapses.
Normal synaptic function is essential for healthy brain function
and underlies memory, cognition, behavior
and other brain activities.
Normal synaptic function requires that
the dendrites (part of the neurons which
form synapses) are appropriately formed
as well as that excitatory and
inhibitory signals are kept in balance.
When dendritic structure and synaptic
signaling are abnormal, virtually all
brain activities can be negatively impacted.
Synaptic dysfunction is then
identified as a core feature of many CNS conditions,
including acute brain injury,
neurodevelopmental disorders and
neurodegenerative diseases.
For example, in Rett syndrome,
dendrites are sparse and immature,
while in Fragile X syndrome,
dendritic branching is excessive
although the dendrites are also immature.
Trofinetide increases the length
and branching of dendrites
in the model of Rett syndrome
while increasing pruning of
excess branching in Fragile X syndrome.
In the Fragile X animal model, aberrant
synaptic signaling was normalized within
15 minutes of the first dose.
IGF-1 dysregulation.
As previously mentioned,
IGF-1 levels in the brain have been
reported to be depressed in a number of
CNS conditions, particularly in Rett and
Fragile X syndromes and brain injury.
In these conditions, the critical role of
IGF-1 and GPE in maintaining and
repairing brain cells and synapses is impaired.
In the Fragile X model, in which
the IGF-1 level is depressed,
Trofinetide increases the amount of IGF-1 to
normal levels.
This was accompanied by normalized synaptic signaling
and complete reversal of cognitive and
behavior abnormalities.
In the model of Rett syndrome,
increasing IGF 1-levels has been
reported to correct deficits in dendritic spines,
and in isolated cells
from human Rett syndrome patients, both
IGF-1 and GPE are able to partially
reverse the deficits in cellular function.
Summarizing, Trofinetide helps to
correct four of the hallmark pathological
features of many CNS disorders :
inflammation, abnormal microglial function,
impared synaptic signaling and
disrupted IGF-1 expression.
By simultaneously targeting multiple
processes, Trofinetide works to restore
the natural balance of brain function.
For more information, please visit our website.
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