Epilepsy is one of the most common neurological disorders. More than 2 million people in the United States live with the disease, and an estimated 150,000 new cases are diagnosed each year. The disease stems from problems in the brain and is typified by recurring seizures caused when a group of brain cells begins to fire in an abnormal, synchronized way. Epilepsy is treated with a type of drug called an anticonvulsant, a variety of which are currently in use. Despite these drugs’ availability, as many as 50 percent of patients continue to have seizures and about 15 percent do not respond to any currently available anticonvulsants. These researchers are developing a new anticonvulsant drug that acts by stopping the bursts of brain cell activity that trigger seizures. It may also modify the disease so that more patients are amenable to treatment.
Scientific Synopsis
This proposal is for a preclinical program of pharmacokinetic, toxicological and CMC studies to complete an Investigational New Drug (IND) application that will advance the glucose analog 2DG into human clinical trials as a novel therapy for epilepsy. 2DG has been used for decades as a tracer in autoradiographic and PET imaging and unexpectedly was discovered to have novel anticonvulsant actions in acute and chronic experimental animal models of epilepsy. 2DG has a broad spectrum of action against a variety of cellular and network mechanisms underlying seizures and also impairs the progression of kindled seizures, implying that it may have “disease-modifying” actions against chronic consequences of seizures, which include susceptibility to intractability as well as cognitive and memory dysfunction. In addition to acute anticonvulsant actions, 2DG has novel “disease-modifying” effects when administered as long as 10 minutes after a seizure as a consequence of “activity-dependent” loading of 2DG into epileptogenic brain regions with high energy demands. These novel anticonvulsant, “disease-modifying” antiepileptic and “activity-dependent” actions distinguish 2DG from all currently marketed anticonvulsants. Preclinical toxicity studies of 2DG and human Phase I/II clinical trials of 2DG for treatment of cancer have demonstrated that doses effective against seizures are well-tolerated. Despite introduction of 11 new drugs for epilepsy since 1990, approximately 50 percent of patients have recurring seizures and approximately 15 percent are medically intractable.
The pharmacokinetic, toxicological and CMC studies proposed in this RAID application build on already completed preclinical studies conducted at the University of Wisconsin and NeuroGenomeX, Inc., and will enable submission of an IND application to advance 2DG into human clinical trials as a novel promising treatment for epilepsy, with potential to increase the number of patients who achieve control and favorably modify adverse consequences in patients in whom complete control is not achieved.
Lead Collaborator
University of Wisconsin–Madison
Thomas Sutula, M.D., Ph.D.
Public Health Impact
There is a need to develop anticonvulsants with novel mechanisms of action that increase the number of patients achieving complete seizure control and for antiepileptic disease-modifying therapies that treat the progressive adverse effects of repeated seizures on neural circuits. 2DG, with its anti-glycolytic action and novel mechanism of metabolic regulation of gene transcription contributing to seizure-induced plasticity, represents an entirely new therapeutic approach for treatment of seizures and for reducing the consequences of epilepsy.
Outcomes
Approved studies are ongoing.
Project Details
- Synthesis of Good Manufacturing Practice (GMP) and non-GMP material
- Formulation development, manufacture of clinical dosage form
- Pharmacokinetic studies
- IND-directed toxicology
Publication
2-Deoxy-d-Glucose (2-DG)-Induced Cardiac Toxicity in Rat: NT-proBNP and BNP as Potential Early Cardiac Safety Biomarkers • International Journal of Toxicology • Feb. 2, 2016