1 / 18

2DG – A Familiar Antiglycolytic Glucose-analog With Novel Anticonvulsant Properties

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.

demont
Download Presentation

2DG – A Familiar Antiglycolytic Glucose-analog With Novel Anticonvulsant Properties

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  2. 2DG: a glucose analog differing from glucose only by removal of Oxygen at the 2-position

  3. 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

  4. 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 into areas of neural circuitry with increased metabolic demands 2DG transiently inhibits glycolysis by blocking the isomerization step from glucose-6P to fructose-6P

  5. 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!

  6. 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! • 2DG reduces epileptic discharges • evoked by : • 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

  7. 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

  8. “Disease- modifying” actions of 2DG against progressive adverse effects of repeated seizures NUMBER OF SEIZURES SPONTANEOUS SEIZURES 1 5 30 90-100 + + + REDUCED INHIBITION HIPPOCAMPAL SCLEROSIS MEMORY LOSS APOPTOSIS NEUROGENESIS SPROUTING + 2DG NUMBER OF SEIZURES SPONTANEOUS SEIZURES 1 5 30 90-100 + + + REDUCED INHIBITION HIPPOCAMPAL SCLEROSIS MEMORY LOSS APOPTOSIS NEUROGENESIS SPROUTING

  9. “disease-modifying” antiepileptic actions with 2DG administration as long as 10 minute AFTER seizures

  10. “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

  11. 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

  12. 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

  13. TOXICITY PROFILE OF 2DG Previous 2DG experience 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 • 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

  14. TOXICITY PROFILE OF 2DG Previous 2DG experience 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 • 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 Based on this favorable prior history, we are hopeful for: FDA approval for an abbreviated pre-IND toxicology package FDA approval for combined Phase I/II studies in epilepsy patients

  15. Possible clinical trials/applications for 2DG Relevant 2DG Properties Clinical Trial Options • 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 Photosensitivity trial Conventional six month double blind add-on cross-over trial in refractory patients with partial complex and secondary generalized seizures Double blind trial in adult patients with Lennox-Gastaut syndrome (potential orphan drug indication) Administration at onset of seizures in patients experiencing seizure clusters Double blind add on trial in refractory status eplilepticus Implanted device - 2DG combination trials (stimulation-loading of 2DG into epileptogenic circuitry)

  16. 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

  17. 2DG in the drug development pipeline: approaching IND and Phase I/II 2DG

  18. 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

More Related