New Areas of R&D
fibrosis (PF) is a progressive interstitial lung disease with no known etiology.
There is no known cure for PF, and current treatment
modalities are minimally effective. PF
may be an autoimmune disorder, or
the after effects of a viral infection.
PF is characterized by excessive
deposition of intracellular matrix and collagen in the lung interstitium and
gradual replacement of the air sacs or "alveoli" of the lungs by scar
tissue as a result of inflammation and fibrosis. As the disease progresses the increase in scar tissue
interferes with the ability to transfer oxygen from the lungs to the
bloodstream. The act of breathing
becomes more difficult with the passage of time leading to a condition of
general breathlessness or dyspnea, and progressive hypoxemia.
PF patients eventually succumb to either heart or respiratory failure.
Even in the absence of a complicating disease,
the median survival after the diagnosis of biopsy-confirmed PF is less than
are five million people worldwide that are affected by PF
In the U.S. alone 200,000 suffer from this malady.
Of these more than 40,000 die annually.
The same number die from Breast Cancer, more than those who die from
Ovarian or Prostate Cancer and forty times more than those who die from Cystic
Fibrosis (CF). The debilitating impact of PF is equally severe as these types of
cancer or CF and is usually fatal.
WilVent is a proprietary agent of Pharmagenesis.
It is a prodrug of PG490 and PG490 is a natural product supplied by
Pharmagenesis. The unusual in vivo
effectiveness of WilVent in bleomycin-induced fibrosis holds promise for the
inhibition of further fibrosis and the attendant morbidity and mortality of the
disease of Pulmonary Fibrosis.
When incubated in human plasma, WilVent
reduces viability in Jurkat T lymphoid cells and suppresses IL-2 production by
stimulated Jurkat cells. PG490
suppresses T lymphocyte activation and proliferation by Jurkat cells and human
and mouse lymphocytes, and suppresses the production of proinflammatory
cytokines. In addition to effects upon immune cells, PG490 suppresses IL-8
expression by bronchial epithelial cells. The
inhibition by PG490 of cytokine gene expression by human lymphocytes and
bronchial epithelial cells supports the use of WilVent as an immunosuppressant
in inflammatory lung disease.
WilVent exerts an anti-fibrotic effect in a bleomycin model of
mouse lung fibrosis and prevents fibrosis if administered the same day or 5 days
after bleomycin. This treatment
also markedly reduces the number of lung myofibroblasts
of bleomycin-treated mice, the proliferation of which is thought to be a
hallmark of lung fibrosis. TGF-b
the most potent profibrotic cytokine, and plays a central role in the
pathogenesis of PF. WilVent
produces a significant decrease in the level of TGF-b in the bronchoalveolar
lavage fluid, and blocks the bleomycin-induced increase in TGF-b mRNA in
cultured normal human lung fibroblasts. WilVent
administered systemically has a demonstrated therapeutic effect in preventing
fibrosis development in the bleomycin model with the lung as a target organ. The inhibition of fibrosis by WilVent when treatment was
given late after bleomycin instillation supports the utility of WilVent in the
serious therapeutic area of PF.
PF is a chronic disease, whereas other diseases of current
significance involving the lung [e.g.,
Severe Acute Respiratory Syndrome (SARS) and acute respiratory distress syndrome
(ARDS)] are more acute. SARS is a serious, contagious, rapidly progressing viral
lung disease. A virus-induced hyperimmune response appears to lead to the
overproduction of proinflammatory cytokines. Immunopathological damage leads to
ARDS, early stages of PF, and a fatal outcome.
PG490 suppresses in vitro production of proinflammatory cytokines such as
IFN-g, TNF-a, IL-1b and IL-6 that are stimulated by viral infections and which
contribute to ARDS. PG490 has potent immunosuppressive and antiinflammatory
properties. The effectiveness of PG490 in suppressing proinflammatory
cytokines is consistent with the use of WilVent to prevent the morbidity and mortality of
The strategy for the development of WilVent will be an intravenous formulation for pulmonary fibrosis, with the possibility of an oral formulation at a later time. Pharmagenesis will seek a partner for later stages of development of WilVent in PF.
the most important excitatory neurotransmitter in the central nervous system
(CNS), plays an important role in
the pathophysiology of different neurological and psychiatric diseases.
Glutamate has a toxic action resulting from an activation of specific
glutamate receptors, which leads to acute or chronic death of nerve cells.
Glutamate neurotoxicity has been implicated in many neurological
disorders. Such mechanisms are
associated with acute neuronal death within the context of hypoxia, ischemia and
trauma, as well as in the chronic neurodegenerative diseases of
and Huntington's Diseases and others. A
compound that antagonizes the neurotoxic action of glutamates may constitute a
novel therapy for these diseases.
inflammation plays a role in the pathogenesis of chronic neurodegenerative
disorders like Alzheimer's and Parkinsonís Diseases.
Neurodegeneration caused by inflammation involves activation of the
brainís resident immune cells, the microglia, which produce large numbers of
proinflammatory factors. New
insights into the pathogenesis of neurodegeneration in several diseases suggest
potential utility of agents that can 1.) Suppress the production or activity of
cytokines and proinflammatory mediators in the CNS, 2.) Inhibit the response to
proinflammatory stimuli of neural cells and 3.) Exert neurotrophic effects upon
neural tissue to enhance outgrowth and survival.
Alzheimerís Disease (AD) is a progressive neurodegenerative
disease causing a gradual loss of cognitive function and characterized by beta-amyloid
deposition, senile plaques with intimately associated reactive microglial cells,
neurofibrillary tangles and dystrophic neurites.
Glutamate neurotransmission, an important process in learning and memory,
is severely disrupted in patients with AD.
Loss of glutamatergic function in AD may be related to the increase in
oxidative stress associated with the beta-amyloid peptide that is found in the
brains of individuals who have the disease.
The toxic cellular response to aggregates of beta-amyloid, oxidative
stress and energy metabolic disturbances promote neuronal sensitivity to
glutamate-induced excitotoxic injury to an extent that even normal amounts of
glutamate may become excitotoxic. Neurodegeneration
caused by inflammation involves microglia activated by the aberrant beta-amyloid
proteins to produce large numbers of proinflammatory factors mediated via the
Like AD, Parkinsonís Disease (PD) is a
progressive neurodegenerative disease. PD
is characterized by resting tremor, slowness of movement, rigidity and postural
instability as a result of progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)
region of the brain. The cause for
this loss of neurons is largely unknown, but considerable evidence supports the
suggestion that brain inflammation participates in the pathogenesis of PD. The striatal dopaminergic regions and spinal fluid of PD
patients show a marked increase in the level of proinflammatory cytokines.
Microglial-mediated inflammation has been implicated in this CNS
Other Neurodegenerative Diseases
Recent evidence from experimental models of multiple sclerosis
(MS) and studies with MS patients in relapse suggests an altered glutamate
homeostasis in the brain of patients with MS.
Neurotoxic events occur in MS, and they can be responsible for
oligodendrocyte and neuronal cell death in patients with this demyelinating
disease. Antagonizing glutamate
receptor-mediated excitotoxicity may have therapeutic implications in MS
Neurodegeneration can occur as a result of traumatic brain injury.
Acute brain insults are linked to inflammation that contributes to the
propagation of the neuropathological events, and also trigger increased
neurogenesis. Microglia activation associated with inflammation impairs
both the basal continuous formation of new neurons and the increased
neurogenesis in response to a brain insult.
The deleterious effects of microglia are most likely mediated by the
production of cytokines IL-1b or IL-6, TNF-a,
NO and reactive oxygen
species (ROS), which are neurotoxic.
Market Overview of Major Neurodegenative Diseases
Nearly five million Americans now have AD (),
which is predicted to affect 14 million Americans and 22 million persons totally
worldwide in just a few decades. One
in 10 people over 65 have AD and nearly half of those over 85 have AD.
AD is the seventh leading cause of death in Americans 65 years and older
Approximately 1 million people in the U.S.
suffer from PD, and 60,000 new cases are diagnosed each year ().
PD is more common in people age 60 and older ().
MS is an illness diagnosed in over 350,000 persons in the United States
Ninety percent of MS patients diagnosed are between the ages of 16 and
60; but MS can make its first appearance in early childhood or after age 60.
There were roughly 2 million cases of traumatic brain injury in 1990 in
the U.S, including over 50,000 deaths ().
Between 20 and 30% of the injuries that occur each year are severe enough
to result in lifelong disability.
is a proprietary agent of Pharmagenesis. It
is a prodrug of PG490, a natural product supplied by Pharmagenesis.
activity in the area of neuroprotection will focus on the AD and PD indications.
In vitro assays to be conducted include PC12 cells incubated with
glutamate or beta-amyloid, activation of microglia, and inflammatory effects
upon primary neuronal cultures. The
transgenic mouse models expressing mutant or truncated human beta-amyloid will
initially be employed to generate enabling pharmacology data with NeuroTriptin
relevant to AD. Unilateral
transection of the Medial Forebrain Bundle (MFB) of rats will serve as the basis for
an animal model of PD. This model produces a precisely defined lesion of dopaminergic afferents
resulting in degenerative changes in a subpopulation of dopaminergic cell bodies
in the SNpc with subsequent degeneration of the striatal dopaminergic nerve
Glutamate induces necrosis and apoptosis in the PC12
pheochromocytoma cell line, which is responsive to Nerve Growth Factor and has
been used as a cellular model of AD. PG490
inhibits glutamate-induced cell death, ROS formation and the decrease of
mitochondrial membrane potential. Glutamate
is thought to be instrumental in neuronal death in several neurological
diseases. The protection from
neuronal death induced by glutamate suggests that NeuroTriptin would be useful
in treating neurodegenerative disease such as AD.
Cerebral amyloid angiopathy due to beta-amyloid is one of the
specific pathological features of AD, and PC12 cells are extremely sensitive to
induction of neurotoxicity by mutant beta-amyloid protein aggregates.
PC12 cells treated with 50 mM beta-amyloid for 48 hours exhibit increased
intracellular accumulation of Ca(2+) and undergo apoptotic death.
PG490 at 10 pM markedly inhibits apoptosis induction by beta-amyloid and
the increase in intracellular Ca(2+). PG490
protects PC12 cells from the deleterious and pro-apoptotic effects of treatment
with beta-amyloid. This protection
from the neurotoxic effects of beta-amyloid suggests that NeuroTriptin would be
useful in treating AD.
PG490 exerts a powerful inhibitory influence
over microglia. Pretreatment with
PG490 dose-dependently reduces the lipopolysaccharide (LPS)-induced NO accumulation and TNF-a and IL-1b release from LPS-activated microglia.
PG490 reduces LPS-stimulated mRNA expression of
these inflammatory cytokines. These
results demonstrate that PG490 can inhibit inflammatory responses of microglia
to inflammatory stimulation via a mechanism involving the inhibition of the
synthesis and release of inflammatory factors.
Microglia inflammatory responses are mediated via the NF-kB pathway.
Treating AD with NeuroTriptin may also benefit by reducing inflammation
through PG490 suppression of NF-kB activation.
Tripchlorolide spares substantia nigra
(SN) neurons in rats with MFB
transection, a widely used animal model
of PD. This PG490 prodrug preserves
SN neurons and dendritic processes of domaminergic neurons and reduces dopamine
depletion in these
microglia may play an active role in the degeneration of dopaminergic neurons,
as massively activated microglia are found throughout the ventral mesencephalon
in this model, particularly in the most medial part of the SN.
inhibits the inflammatory and neurotoxic activity of
microglia, and shows potent in vivo activity in this model of SN domaminergic neuronal loss, suggesting that NeuroTriptin may be useful in the treatment of
LPS induces the degeneration of dopaminergic
neurons that mimics the process of inflammatory dopaminergic degeneration.
The density of
microglial cells is higher in the SN compared to other mid-brain areas, the
dopaminergic system is most susceptible to inflammation-mediated damage, and
microglial cells are implicated in this process. In primary mesencephalic neuron/glia mixed culture, PG490
blocks the activation of microglia and reduces the production of TNF-a and
NO induced by LPS. PG490
protects against the reduction in dopamine uptake, attenuates the loss of
dopaminergic neurons and ameliorates the reduction in dendrite number and
truncation of axons caused by LPS. PG490
treatment without LPS appears to produce more dopaminergic neurons with longer
neurites, indicating neurotrophic activity.
These results are relevant to PD, and further illustrate the potential
neuroprotective potential of NeuroTriptin.
Neurotrophic factors enhance the survival of CNS and peripheral
neurons under insult, and enhance the outgrowth of neurites after nerve injury.
Immunosuppressive agents like cyclosporin and FK506 possess neurotrophic
properties. PG490 and NeuroTriptin
are immunosuppressive, and PG490 has neuroprotective activity in vitro. Tripchlorolide promotes growth of long axon-like processes in primary
cultures of rat mesencephalic neurons, and stimulates mRNA production for brain
derived neurotrophic factor. This
nonproprietary PG490 prodrug was more potent than FK506 in this
neurotrophic activity. NeuroTriptin
may be useful in treating acute neurological insults as well as more chronic
neurodegenerative diseases, because of antiinflammatory and neuroprotective
activity, as well as neurotrophic
Clinical Development of NeuroTriptin
The strategy for the development of NeuroTriptin for AD and PD
will be an intravenous formulation, with the possibility of an oral formulation
for less intense, long-term administration subsequently.
Pharmagenesis will seek a partner for later stages of development of
NeuroTriptin in AD and PD.
 Deaths: Preliminary Data for 2001, National Statistics Reports vol. 51, No. 5, March 14, 2003, National Center for Disease Statistics, Centers for Disease Control.
 Family Caregiver Alliance (caregiver.org).
 Waxweiler, R.J. et. al. (1995). "Monitoring the Impact of Traumatic Brain Injury: A Review and Update." Journal of Neurotrauma. Vol. 12. No. 4. Mary Ann Leibert, Inc.