by Joyce Cramer, President, Epilepsy Therapy Project

The biennial conference devoted to clinical trials on antiepileptic drugs:"Antiepileptic Drugs-10," (held in Coral Gables, FL, on April 15-17, 2009) concluded with a full day of pipeline review. This was a fast-paced delivery of information about most of the drugs, biologics, and devices in development as epilepsy therapies, from preclinical to phase 3 developments. A separate article reviews the topics discussed during the first 2 days of the "Antiepileptic Drugs-10" biennial conference devoted to clinical trials on antiepileptic drugs (held in Coral Gables, FL, on April 15-17, 2009). See10th Antiepileptic Drug Trials Update: 2009.

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Epilepsy pipeline review

The pipeline review was divided into sections based on stage oh assessments, starting with the most advanced treatments (phase 3) concluding with those in preclinical testing. Extensive information is available elsewhere about the efficacy and adverse effect profiles for the following antiepileptic drugs now in phase 3 testing (preparation for submission to FDA):

Compound/Device Trade Name Company
Brivaracetam Rikelta UCB Pharma
Carisbamate Comfyde OrthoMcNeil Neurologics
Eslicarbazepine Stadesa (US), Zebinix (EU) Sepracor (US), Eisai (EU)
Retigabine   Valeant/GSK
Vigabatrin Sabril Lundbeck
Clobazam Frisium Lundbeck
Intranasal Midazolam   Ikano Therapeutics
Modified-release oxcarbazepine   Supernus Pharmaceuticals
Responsive Neurostimulation System   Neuropace
  • Brivaracetam is similar in structure and mechanism to levetiracetam (Keppra), binding to the synaptic vesicle protein 2A ligand with sodium-channel activity. Efficacy against partial-onset seizures and tolerability are good, and it may have fewer adverse effects than Keppra.
  • Carisbamate probably has multiple mechanisms of action. Its tolerability and adverse effect profile are good. Clinical trials are continuing to define efficacy against partial-onset seizures at the optimal dose.
  • Eslicarbazepine is similar in structure to carbamazepine and oxcarbazepine, as the enantiomer S-licarbazepine. It blocks voltage-gated sodium channels. Efficacy against partial-onset seizures and tolerability are good, likely without the safety concern of hyponatremia seen with related drugs. The drug has been approved for use in Europe.
  • Retigabine decreases neuronal excitability through action on the potassium channel M-current. Efficacy against partial-onset seizures and tolerability are good.
  • Vigabatrin, an irreversible inhibitor of GABA-transaminase, has been available in Europe for more than a decade, but little-used because of its potential to cause visual field restrictions. Recent testing in the USA defined its efficacy for infantile spasms as well as seizures associated with the Lennox Gastaut Syndrome.
  • Clobazam is a benzodiazepine with good efficacy against partial-onset seizures. It has been widely used in other countries for more than a decade.
  • Midazolam, a benzodiazepine, is being evaluated as a nasal spray for emergency treatment of acute repetitive seizures (ARS).
  • Oxcarbazepine has been available worldwide for several years. A modified-release formulation is being tested for improved tolerability.
  • Responsive Neuro Stimulation (RNS)

Antiepileptic drugs in Phase 2 testing are in the process of determining the optimum dose, titration schedule, patient type, etc. before initiating definitive phase 3 testing in larger populations. Information on some has been presented at earlier conferences, but others remain confidential. Following are the Phase 2 compounds described:

Compound Company
Ganaxolone* Marinus Pharmaceuticals*
ICA-105665 Icagen
Perampanel Eisai
T2000 Taro
YKP-3089 SK Life Science
VPA analogs** Hebrew University**
  • Marinus' ganaxolone is an Epilepsy Therapy Project success: our seed investment and introductions to investors led to their successful engagement of venture capital groups to provide the $30 million needed to reach this stage. Ganaxolone is a neurosteroid in development for efficacy against partial-onset seizures and infantile spasms.
  • ICA-105665 is a potassium-channel regulator. Clinical trials to evaluate efficacy against partial-onset seizures will begin soon.
  • Perampanel, an AMPA-antagonist, is in test for efficacy against partial-onset seizures.
  • T2000 is a novel barbiturate designed to reduce typical sedation associated with this class of drugs.
  • YKP-3089 is a novel compound expected to have a broad range of anticonvulsant activity.
  • Development of VPA analogs was supported by Epilepsy Therapy Project in collaboration with Jazz Pharmaceuticals. Unfortunately, the compound was not pursued because it was found to have some teratogenic potential.

Investor Panel

A panel of senior investment and business professionals, chaired by Frank Fisher (Neuropace), candidly discussed "Public, Private Equity & Industry Perspectives on Financing New Therapies in Epilepsy & CNS: Finding the Money in 2009." Each panelist described a perspective on the current state situation for start up companies in the biotech and device arenas. Overall group felt that there was no difference today in investing concepts but money is less available from limited partners. Investors need to know a lot about a program before taking the risk of putting a lot of money in that basket. Entrepreneurs need to show differentiation of their product from others and do you risk it in order to have credibility with investors.

Nicole Vitullo (Domain Associates) described financing concerns and the regulatory issues that plague drug development. Omar Amirana (Oxford Bioscience) noted the importance of the management team and meeting milestones as well as knowledge of the technology team. Nicole noted that business is a technology risk but the investors hoped to be paid for taking that risk. Regulatory risk is part of the value of change chain as much as other issues noted Marcus Goebel (Novartis Ventures). He reminded the group of the many failed to trials in CNS, although epilepsy has much better predictive animal models than other therapeutic areas. Nonetheless new treatments for epilepsy would meet some evidence of a potential secondary indication to show greater value beyond the epilepsy market. Of course, Omar responded that the company needs to prove its clinical outcomes in order for investors to get value from their early support. Tim Coan (Deerfield Management) invests in public companies that also must be careful with their capital. He said that companies can go public even in this environment might would have to settle for very low valuations the preferred approach would be merger and acquisition based on a strategic position rather than price. He wants to know what gaps exist as well as the reimbursement environment. Public companies that need cash flow are concerned about dilution for initial investors. Commenting from the perspective of a mid-size Pharma company looking for new entities, Nancy Santilli (Endo Pharmaceuticals) asked what the market will look like when the new product comes to market. This is a factor in determining the price to be paid for an acquisition. Nancy concluded the session by noting that early-stage companies can dream big because they don't know much; later stage companies cannot dream as much because they know the limits of their product. That's why she likes to consider secondary outcomes in clinical trials as support for pricing.

Phase 1 and Pre-Clinical

A series of drugs, biologics and devices were reviewed by their developers to showcase early findings that show promise for efficacy against seizures. Those being tested in humans (Phase 1) include:

Phase 1
Huperzine Harvard
NPY gene transfer Neurologix
Neural Plasticity: 2DG NeuroGenomeX
Drug Delivery Pump Sierra Neuropharmaceuticals
Drug Delivery System New York University
Seizure prevention NeuroVista
GAERS, MTLE models Synapcell
New molecular entity NeuroTherapeutics Pharma
Galanin NTX 5055 Neuroadjuvants
AMP-X-001, 026 AurimMed Pharma
Magnetonanoparticles Epinano
Toxin delivery to brain MedGenesis Therapeutix

Phase 1

  • Huperzine is a botanical compound used in China, and available as a health food supplement in the USA. It is effective against seizures in animals, but the Harvard group planning a clinical trial (supported by Epilepsy Therapy Project) has been hampered by the inconsistent amount available in typical capsules used in the USA.
  • NPY gene transfer (Neurologix) (supported by Epilepsy Therapy Project) has been hampered by FDA requirements for additional toxicity testing in primates.
  • A widely used tracer compound 2DG is in development by NeuroGenomeX (supported by Epilepsy Therapy Project) as a neuroprotectant that might stop seizures rapidly. The company is seeking additional investment to pursue clinical trials.
  • A system to detect seizures is being developed by NeuroVista. This device will stimulate the brain only when needed (before seizure inception) in order to abort the event.
  • Sierra Neuropharmaceuticals had a successful round of fundraising that allows them to pursue testing the efficacy of drugs delivered directly to the brain by an abdominal pump. This hybrid system will send tiny amount of drug into the CSF, avoiding first-pass metabolism and reducing potential toxicity.
  • Another hybrid system is being developed by New York University. They will implant electrodes that detect seizures before stimulating the device to deliver tiny amounts of drug to the brain tissue. They are seeking investment to raise funds needed for the next stage of testing in patients.


  • Pre-clinical testing in epilepsy always includes studies in small animals to learn whether the compound might be effective in standardized models of human epilepsy. Synapcell described 2 new models they have developed to simulate generalized epilepsy and localization-related epilepsy. These models are considered "platforms" that aid understanding of new compounds, in addition to the standard models available to researchers at no cost by the NIH Antiepileptic Drug Development Program.
  • NeuroTherapeutics Pharma used the Synapcell models to evaluate their new compound, active on chloride channels. The novel entity is based on bumetanide, a diuretic known to have antiepileptic properties.
  • Galanin, a peptide with antiepileptic effects, has been tested in animal models by Neuroadjuvants. Additional studies are needed to define dose and delivery to the brain.
  • AurimMed Pharma has developed 2 lead molecules using their Privileged Structure Platform to design compound for high efficacy and low toxicity. They are effective in animal models.
  • A series of toxins that can stop abnormal brain cells from firing are being tested in animals (supported by Epilepsy Therapy Project) at University of California/Davis. Micro amounts will be injected into the area surrounding abnormal cells by a convection-enhanced delivery system (MedGenesis Therapeutix).
  • Magnetonanoparticles can transform an MRI into a PET scan using technology developed by Epinano (supported by Epilepsy Therapy Project). These scans are very helpful in localizing the origin of seizures. This group will be supported by the National Cancer Institute to complete safety testing in hopes of using it to detect brain tumors.

The long day of pipeline presentations concluded with remarks by Warren Lammert, founder and chairman of Epilepsy Therapy Project. He is excited about the large number of drugs, biologics, and devices currently in development. He reminded us that more than one million people in the USA need better therapies to achieve seizure control and move forward with their lives.

A separate article reviews the topics discussed during first 2 days of the "Antiepileptic Drugs-10" biennial conference devoted to clinical trials on antiepileptic drugs (held in Coral Gables, FL, on April 15-17, 2009). See 10th Antiepileptic Drug Trials Update.

Please register for our newsletter to receive notices about the next epilepsy pipeline review and pipeline news.

Authored By: 
Joyce Cramer
Authored Date: