Transcript A Neurobiology Drug Development Company

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2DG – A Familiar Antiglycolytic Glucose-analog
With Novel Anticonvulsant Properties
Thomas Sutula, MD, PhD
Detling Professor and Chair
Department of Neurology
University of Wisconsin
Chief Scientific Officer
NeuroGenomeX, Inc.
Madison, WI
2DG: a glucose analog differing from glucose only by
removal of Oxygen at the 2-position
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2DG: a glucose analog differing from glucose only by
removal of Oxygen at the 2-position
glycolytic inhibitor
2DG transiently inhibits glycolysis
by blocking the isomerization step
from glucose-6P to fructose-6P
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2DG: a glucose analog differing from glucose only by
removal of Oxygen at the 2-position
focal brain delivery
during seizures
(18F-2DG PET scan
Israel & Fishman 1999)
focal brain delivery
by stimulation
(3H-2DG autoradiogram
Sutula et al.)
glycolytic inhibitor
Activity-dependent uptake loads
2DG transiently inhibits glycolysis
2DG into areas of neural circuitry
by blocking the isomerization step
with increased metabolic
from glucose-6P to fructose-6P
demands
Completed Preclinical efficacy studies
In vivo studies in acute and chronic
models of epilepsy
Acute anticonvulsant action
•
protection against seizures evoked
acutely by 6Hz stimulation
(ED50 = 79.5 mg/kg)
•
protection against audiogenic seizures
in Fring’s mice
(ED50 = 206 mg/kg)
•
2-fold slowing of latency to status
epilepticus onset by pilocarpine
Chronic antiepileptic action
•
2-fold slowing of kindled seizure
induction and progression from
different brain sites (37.5 mg/kg)
•
Effective against seizure progression
when administered as long as 10 min
AFTER a seizure!
Completed Preclinical efficacy studies
In vivo studies in acute and chronic
models of epilepsy
In vitro studies in
hippocampal slices
Acute anticonvulsant action
•
protection against seizures evoked
acutely by 6Hz stimulation
(ED50 = 79.5 mg/kg)
2DG reduces epileptic discharges
evoked by :
•
protection against audiogenic seizures
in Fring’s mice
(ED50 = 206 mg/kg)
•
2-fold slowing of latency to status
epilepticus onset by kainic acid
•
•
•
•
Chronic antiepileptic action
•
2-fold slowing of kindled seizure
induction and progression from
different brain sites (37.5 mg/kg)
•
Effective against seizure progression
when administered as long as 10 min
AFTER a seizure!
7.5 mM K+ (ictal and interictal)
bicuculline (GABAa antagonist)
4AP (K+ channel antagonist)
DHPG (metabotropic glutamate agonist)
Implies that actions of 2DG at the cellular
level are potentially “broad-spectrum”
against different mechanisms of network
synchronization
2DG slows progression of kindled seizures by 2-fold
also at 37.5 mg/kg
2DG has “disease-modifying” effects against progression of seizures
and long-term consequences of poorly controlled epilepsy
“Disease- modifying” actions of 2DG against
progressive adverse effects of repeated seizures
NUMBER OF SEIZURES
1
5
30
APOPTOSIS + SPROUTING
NEUROGENESIS
90-100
+
HIPPOCAMPAL
SCLEROSIS
MEMORY LOSS
+
SPONTANEOUS
SEIZURES
REDUCED
INHIBITION
+ 2DG
NUMBER OF SEIZURES
1
5
30
APOPTOSIS + SPROUTING
NEUROGENESIS
+
90-100
HIPPOCAMPAL
SCLEROSIS
MEMORY LOSS
+
REDUCED
INHIBITION
SPONTANEOUS
SEIZURES
“disease-modifying” antiepileptic actions with 2DG
administration as long as 10 minute AFTER seizures
“disease-modifying” antiepileptic actions with 2DG
administration as long as 10 minute AFTER seizures
implications for novel applications including status epilepticus,
seizure clusters, Lennox-Gastaut syndrome
Chronic “disease-modifying” antiepileptic effects
of 2DG are associated with alterations of
seizure-induced gene expression by novel
mechanisms of metabolic
transcriptional regulation
required for kindling
progression
TOXICITY PROFILE OF 2DG
Previous 2DG experience
• Used since 1979 in humans
as PET imager (18F-2DG)
• >20 investigator-initiated
clinical trials in man (~700
normal controls and patients)
with no systematic side
effects
• FDA Approved IND tox
packages from U.Iowa and
Kettering available to NGX as
“right of reference” letters
• 2004 completed Phase I
clinical trial for adjuvant
cancer chemotherapy at
doses up to 200 mg/kg was
without adverse toxicity
(Threshold Pharma)
• Hundreds of published
animal studies
TOXICITY PROFILE OF 2DG
Previous 2DG experience
• Used since 1979 in humans
as PET imager (18F-2DG)
• >20 investigator-initiated
clinical trials in man (~700
normal controls and patients)
with no systematic side
effects
• FDA Approved IND tox
packages from U.Iowa and
Kettering available to NGX as
“right of reference” letters
• 2004 completed Phase I
clinical trial for adjuvant
cancer chemotherapy at
doses up to 200 mg/kg was
without adverse toxicity
(Threshold Pharma)
• Hundreds of published
animal studies
Tox Observations
• No overt systemic toxicity
in rats treated for 6
months at 500 mg/kg/day
• No effect on spatial
memory in rats after 2
weeks at 1 gm/kg/day
• No effect on open field
activity at minimal
effective dose of 37.5
mg/kg
TOXICITY PROFILE OF 2DG
Previous 2DG experience
• Used since 1979 in humans
as PET imager (18F-2DG)
• >20 investigator-initiated
clinical trials in man (~700
normal controls and patients)
with no systematic side
effects
• FDA Approved IND tox
packages from U.Iowa and
Kettering available to NGX as
“right of reference” letters
Tox Observations
• No overt systemic toxicity
in rats treated for 6
months at 500 mg/kg/day
• No effect on spatial
memory in rats after 2
weeks at 1 gm/kg/day
• No effect on open field
activity at minimal
effective dose of 37.5
mg/kg
• 2004 completed Phase I
clinical trial for adjuvant
cancer chemotherapy at
doses up to 200 mg/kg was
without adverse toxicity
(Threshold Pharma)
Based on this favorable prior
history, we are hopeful for:
• Hundreds of published
animal studies
2. FDA approval for combined
Phase I/II studies in epilepsy
patients
1. FDA approval for an abbreviated
pre-IND toxicology package
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Possible clinical trials/applications for 2DG
Relevant 2DG Properties
• Efficacy against focal
seizures and secondary
generalized seizures in
preclinical models
Clinical Trial Options
1.
Photosensitivity trial
2.
Conventional six month double blind addon cross-over trial in refractory patients
with partial complex and secondary
generalized seizures
3.
Double blind trial in adult patients with
Lennox-Gastaut syndrome (potential
orphan drug indication)
4.
Administration at onset of seizures in
patients experiencing seizure clusters
5.
Double blind add on trial in refractory
status eplilepticus
6.
Implanted device - 2DG combination trials
(stimulation-loading of 2DG into
epileptogenic circuitry)
• Relatively short t1/2 of ~ 40
minutes
• Rapid absorption by both
oral and parenteral routes
• Enhanced activitydependent focal loading in
epileptogenic brain regions
maximized around the time
of seizure
INTELLECTUAL PROPERTY
Licensed from Wisconsin Alumni Research Foundation (WARF) to
NeuroGenomeX
•
license agreement* includes all WARF “therapeutic use” patents of 2DG
1) “Metabolic-Based Methods for Modulating Gene Expression” P05137US (Priority date- 2/14/2005)
claims: USE of 2DG for prevention of cancer metastasis and treatment of other systemic conditions
status: patent issued
2) “Compounds and Methods for Treating Seizure and Paroxysmal Disorders”
P04134US (Priority date- 6/17/2004)
claims: USE of 2DG for treatment of seizures and neuropathic pain
status: pending
Freedom-to-operate: favorable opinion provided in 2005
3) “Methods and Compounds for Treating Seizure Disorders” P05095US (Priority date - 3/25/2005)
claims: Another metabolic-based method for therapeutic development
status: awaiting office action
* License includes all US and foreign related patent applications
2DG in the drug development pipeline:
approaching IND and Phase I/II
2DG
2DG in the drug development pipeline:
approaching IND and Phase I/II
• novel acute and chronic anticonvulsant mechanisms based on
metabolic regulation and long-term alterations
in seizure-related gene expression
• broad spectrum of action at the cellular level
against mechanisms of network synchronization
• distinctive spectrum of activity against
preclinical screening models
• disease-modifying actions against progressive effects of seizures
• activity-dependent delivery to regions of epileptic activity
• potentially novel methods of delivery:
post-seizure, with device therapies
• favorable preclinical toxicity and human use toxicity profile