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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. - PowerPoint PPT Presentation
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2DG – A Familiar Antiglycolytic Glucose-analog With Novel Anticonvulsant Properties
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Thomas Sutula, MD, PhDDetling Professor and ChairDepartment of Neurology University of Wisconsin
Chief Scientific OfficerNeuroGenomeX, Inc.Madison, WI
2DG: a glucose analog differing from glucose only by removal of Oxygen at the 2-position
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glycolytic inhibitorglycolytic inhibitor
2DG: a glucose analog differing from glucose only by removal of Oxygen at the 2-position
2DG transiently inhibits glycolysis by blocking the isomerization step from glucose-6P to fructose-6P
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focal brain deliveryfocal brain deliveryduring seizuresduring seizures
(18F-2DG PET scan(18F-2DG PET scanIsrael & Fishman 1999)Israel & Fishman 1999)
focal brain deliveryfocal brain deliveryby stimulation by stimulation
(3H-2DG autoradiogram(3H-2DG autoradiogramSutula et al.)Sutula et al.)
glycolytic inhibitorglycolytic inhibitor
2DG: a glucose analog differing from glucose only by removal of Oxygen at the 2-position
2DG transiently inhibits glycolysis by blocking the isomerization step from glucose-6P to fructose-6P
Activity-dependent uptake loads 2DG into areas of neural circuitry with increased metabolic 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)
• 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!
Implies that actions of 2DG at the cellular level are potentially “broad-spectrum”
against different mechanisms of network synchronization
2DG reduces epileptic discharges evoked by :
• 7.5 mM K+ (ictal and interictal)• bicuculline (GABAa antagonist)• 4AP (K+ channel antagonist)• DHPG (metabotropic glutamate agonist)
2DG has “disease-modifying” effects against progression of seizures and long-term consequences of poorly controlled epilepsy
2DG slows progression of kindled seizures by 2-fold 2DG slows progression of kindled seizures by 2-fold
also at 37.5 mg/kgalso at 37.5 mg/kg
NUMBER OF SEIZURES
1 5 30 90-100
APOPTOSISNEUROGENESIS
SPROUTING HIPPOCAMPAL SCLEROSISMEMORY LOSS
REDUCEDINHIBITION
+ + +
SPONTANEOUSSPONTANEOUS SEIZURES SEIZURES
“Disease- modifying” actions of 2DG against progressive adverse effects of repeated seizures
NUMBER OF SEIZURES
1 5 30 90-100
APOPTOSISNEUROGENESIS
SPROUTING HIPPOCAMPAL SCLEROSISMEMORY LOSS
REDUCEDINHIBITION
+ + +
SPONTANEOUSSPONTANEOUS SEIZURES SEIZURES
+ 2DG
“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
• 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 2004 completed Phase I clinical trial for adjuvant clinical trial for adjuvant cancer chemotherapy at cancer chemotherapy at doses up to doses up to 200 mg/kg200 mg/kg was was without adverse toxicity without adverse toxicity (Threshold Pharma)(Threshold Pharma)
• Hundreds of published Hundreds of published animal studiesanimal studies
Previous 2DG experience
TOXICITY PROFILE OF 2DG
• 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 2004 completed Phase I clinical trial for adjuvant clinical trial for adjuvant cancer chemotherapy at cancer chemotherapy at doses up to doses up to 200 mg/kg200 mg/kg was was without adverse toxicity without adverse toxicity (Threshold Pharma)(Threshold Pharma)
• Hundreds of published Hundreds of published animal studiesanimal studies
Previous 2DG experience
• 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
Tox Observations
TOXICITY PROFILE OF 2DG
• 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 2004 completed Phase I clinical trial for adjuvant clinical trial for adjuvant cancer chemotherapy at cancer chemotherapy at doses up to doses up to 200 mg/kg200 mg/kg was was without adverse toxicity without adverse toxicity (Threshold Pharma)(Threshold Pharma)
• Hundreds of published Hundreds of published animal studiesanimal studies
Previous 2DG experience
• 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
Tox Observations
Based on this favorable prior history, we are hopeful for:
1. FDA approval for an abbreviated pre-IND toxicology package
2. FDA approval for combined Phase I/II studies in epilepsy patients
TOXICITY PROFILE OF 2DG
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Possible clinical trials/applications for 2DG
1. Photosensitivity trial
2. Conventional six month double blind add-on 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)
• Efficacy against focal seizures and secondary generalized seizures in preclinical models
• Relatively short t1/2 of ~ 40 minutes
• Rapid absorption by both oral and parenteral routes
• Enhanced activity-dependent focal loading in epileptogenic brain regions maximized around the time of seizure
Relevant 2DG Properties Clinical Trial Options
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 developmentstatus: awaiting office action
INTELLECTUAL PROPERTY
* 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