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AEDs: New Approaches to Discovery and New Challenges to Commercialization
Washington, DC-In a meeting room literally overflowing with enthusiastic attendees, four speakers elaborated their visions of ‘translating’ basic research into useful treatments for people with epilepsy. Orrin Devinsky, MD, New York University Comprehensive Epilepsy Center, New York, NY, and Warren Lammert, Co-Founder and Director of The Epilepsy Therapy Development Project and Epilepsy.com, coordinated the session.
Steven Schachter, MD, Professor of Neurology, Harvard Medical School Osher Institute, Boston, Massachusetts, and two-time recipient of the Epilepsy Research Foundation (ERF) New Therapy Grant Award was the first speaker. In December, 2005, Dr. Schachter and colleagues were awarded an ERF New Therapy Grant to explore herbal extracts and extract-derived compounds for the treatment of epilepsy. During his presentation he emphasized the importance of studying botanicals as a rich potential source for new antiepileptic drugs.
“In the Far East, 135 herbal medicines have been studied as treatment for epilepsy and results published in 71 publications. However, these studies are often difficult to interpret as Eastern clinical trial design varies significantly from familiar Western randomized, double blind, placebo controlled trials”, said Schachter. In an effort to scientifically examine the effects of herbal medicines for epilepsy, Dr. Schachter submitted 11 herbal extracts used for epilepsy to the anticonvulsant screening program, a government sponsored effort to identify new AEDs directed by James Stables, MS, RPh. Nine of the 11 compounds demonstrated significant efficacy in MES, PTZ, and 6-Hz, and amygdala kindling models. Additional studies are underway.
Challenges of Commercialization of Herbal Therapies
According to Schachter, herbal medications are widely available and generally inexpensive, presenting a potential boon to the therapy of epilepsy in developing countries where drug costs often limit treatment. Of the estimated 50 million people with epilepsy in developing countries, 85% remain untreated. However, commercialization of herbal therapies faces many challenges. Issues include intellectual property rights, authentication, intra-species variability and seasonal variation in potency, soil contaminants, uncertainty regarding active ingredients (herbal extracts may have hundreds of potentially active compounds), and insufficient federal standards for manufacturing and quality control.
Herbal products are classified by the government as dietary supplements, not pharmaceuticals. Consequently, herbal products are not rigorously evaluated by the FDA as are conventional prescription medications. Consumer products, such as the commonly used St. John’s Wort, may be contaminated or contain suboptimal amounts of the active ingredient. At present, there are no herbal products of proven benefit to people with epilepsy.
Dr. Schachter concluded that herbal medicines are a potential source of new epilepsy therapies, “The challenges of commercialization can be overcome with appropriate business models, FDA approval, and more research to understand and standardize the active ingredients of botanicals.”
Overview of Botanicals
Thinking Outside the Box: Antiepileptogenesis
Frances Jensen, MD, Senior Associate in Medicine at Children’s Hospital and Associate Professor of Neurology at Harvard Medical School, Boston, MA, ERF New Therapy Grant recipient in May 2005, was the second presenter. She was awarded a New Therapy Grant to explore the efficacy of Talampanel in neonatal seizures and brain injury. During her presentation, Jensen discussed the interactions between epileptogenesis, brain plasticity and excitotoxicity. “Because epilepsy develops over time, multiple opportunities for treatment exist; at the onset of an episode of status epilepticus, during the latent period before epilepsy begins, and once chronic epilepsy occurs,” Jensen said.
She further explained that during the course of epileptogenesis, ion channels and ligand-gated receptors are activated, posttranslational modifications of receptors occur, followed by transcriptional events, neuronal death, inflammatory cascades, neurogenesis, mossy fiber sprouting, and network reorganization. All of these changes in the central nervous system represent targets for treatment. Drugs with theoretical effectiveness include bumetanide, transporter inhibitors, kinase and phosphatase inhibitors, gene therapy, protein synthesis inhibitors, neuroprotectants, NSAIDs, COX-2 inhibitors, and minocycline. Treatment would be time-sensitive, with specific drugs active only at certain stages of epileptogenesis.
Best Formulation Strategies
Stephen Collins, MD, PhD, Chief Scientific Officer and VP Clinical Affairs, Ovation Pharmaceuticals, Inc, Deerfield, Illinois, directed his comments to the practical issues facing the development new drugs. An essential component of a business plan, he advised, is exclusivity, a period of time of protected ownership of the drug, in order to obtain the necessary resources for development and distribution. Exclusivity of a new chemical patent lasts 17 years. “Unfortunately, the very nature of academic world works against exclusivity, because researchers race to publish their results rather than conceal them”, said Collins.
Another route to exclusivity, according to Collins, is the Orphan Drug Law, which provides for granting special status to a product to treat a rare disease (<200,000 population) or condition upon request of a sponsor. This special status is granted to developers of ‘orphan drugs’ because the potential marketplace (and profitability) is relatively limited. The product to treat the rare disease or condition must meet certain criteria. Orphan designation qualifies the sponsor for tax credits, marketing exclusivity for 7 years, and other incentives. AEDs currently being considered for orphan drug development include vigabatrin and clobazam.
Another approach is to qualify for pediatric exclusivity. Development of a medication for the pediatric population may qualify for an additional 6 months of patent protection.
Collins concluded, “A small company, using orphan or pediatric exclusivity, can line up the money and develop drugs for people who need them.”
Gregory Went, PhD, CEO and Chairman of NeuroMolecular Pharmaceuticals, Emeryville, CA, declared, “It is critically important that academics who care about translational research understand the patent process.”
Went explained that his company has been evaluating memantine (Namenda), a drug approved for the treatment of moderate-severe Alzheimer’s disease, as a potential vehicle to deliver other medications to the brain. Modified to memantine nitrate, the new drug could inhibit NMDA receptor activity and deliver nitrous oxide to excitotoxic brain regions, improving regional blood flow, scavenging free radicals, and protecting the cell from death. Development of memantine nitrate may take 11-15 years and cost $200-$800 million. The company hopes to file a new drug application in 2006.
Alternatives Approaches to Drug Development
Went also discussed several alternative approaches to drug development. “An alternative approach to drug development is ‘combination therapy’, which can result in faster drug approval by the FDA. One proposal is to combine memantine with an AED into a once a day pill. Projected development of such a product would take from 3-5 years and cost $20-40 million”, he said.
Other approaches to marketing include controlled release technologies, such as Type I-Matrix (hydrophilic or hydrophobic, mini-tablets, pellets), Type II-membrane controlled (tablets, beads, mini-tablets, capsules), or Type III-osmotic pumps.
Went concluded, “Synergies between academic enterprises (medical, basic research) are not well exploited. It is critical to understand the rigors of product development, the high cost of safety, and the concept of intellectual property. Translating new drugs into products is a very challenging project.”
For more information about translational research in epilepsy go to:www.epilepsytdp.org/sec/support_translational
Topic Editor: Steve C. Schachter, MD
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