by Robert S. Fisher, M.D., Ph.D., Editor-in-Chief

This is the second part of a report on the 2010 Pipeline Conference held in San Francisco 2/25-2/26/2010 highlighting new medicines for epilepsy. Last month’s column summarized new devices for epilepsy. The conference was sponsored by the Epilepsy Therapy Project with unrestricted educational support from Eisai, Sepracor, UCB, Lundbeck, Pfizer, Upsher-Smith, Cyberonics, Medtronic and an anonymous donor. Webcasts of the conference can be found at http://www.epilepsy.com/etp/pipeline2010_webcasts.

Don't be confounded by the alphabet soup of drug names below. Early in development, drugs are designated by an abbreviation of the original company developing them plus a number. As they proceed into development, they assume a more memorable generic, and if successful, brand name.

Drugs at a Clinical Testing Stage of Development

Eslicarbazepine: This drug, sponsored by Sepracor®, Inc and Bial-Portela & Co®, SA. is a chemical relative of carbamazepine (Tegretol®). It has some potential advantages over carbamazepine, including fewer drug interactions, less tendency to induce its own metabolism and clearance from the body inadvertently, and less tendency to raise blood cholesterol and lipids. Three double-blind, placebo-controlled trials have been conducted in 1049 patients with partial-onset seizures. At daily doses of 800 or 1200 mg per day, seizures were significantly reduced. The most common adverse events were dizziness, sleepiness, headache, nausea, double vision and incoordination. This drug will be considered for availability and for testing in pediatric and other populations of people with epilepsy.

Retigabine: Valeant Pharmaceutics®, Inc. has sponsored a novel antiepileptic drug called retigabine. This is the only seizure medication so far invented that works on potassium ion channels in nerve cells. Many existing drugs work on the sodium channel in nerve cells, but both channels have a role in regulating the excitability of brain cells. Retigabine has shown activity in a wide variety of experimental seizure models. Three large clinical trials have been completed in patients showing safety and efficacy against seizures. The drug is under review by the FDA and other regulatory authorities.

Brivaracetam: This drug is chemically related to levetiracetam (Keppra®), and it also is made by UCB Pharma®, Inc. Keppra® was discovered to work by binding to a presynaptic site called the SV2A site. Brivaracetam binds even more strongly to this site. It has been effective in a wide variety of epilepsy models and has been tested in approximately 1000 patients with epilepsy. Its safety profile was good. There is hope, although not yet proof, that brivaracetam might show fewer psychiatric side effects than does Keppra®. Effectiveness of brivaracetam was shown in two out of three clinical trials, but not in all three, so consideration is under way as to the next development steps for the medication.

Carisbamate: This drug, sponsored by Ortho-McNeil, arose from the NIH Antiepileptic Drug Screening Project. Although early results were promising, large clinical studies of efficacy and adverse events did not lead to a favorable decision to move forward with development of the drug.

Diazepam auto-injector: King Pharmaceuticals, Inc. is developing a new delivery device for injecting diazepam (Valium®). The Vanquix® auto-injector has a prepackaged amount of diazepam for injecting, 5, 10 or 15 mg doses. It can be delivered into muscle by non-professional individuals. It has been in use in the Army since 1991. Testing is being considered for home use, with injections into the thigh during times of acute seizures.

Perampanel: Eisai, Inc. is developing this drug as a representative of so-called glutamate antagonists. Glutamate is the brain’s main excitatory neurotransmitter. Glutamate interacts with nerve cells at one of three types of receptors, and perampanel blocks glutamate's effect at the AMPA type receptor. Considerable clinical experience derives from previous trials of perampanel for Parkinson's disease. It appears to be generally safe and well tolerated. It is related to a drug called talampanel, which previously was tested for epilepsy, but did not reach release.

Clobazam: Lundbeck®, Inc. is sponsoring clobazam as a treatment for epilepsy. This drug is a benzodiazepine, in the general category of diazepam, clonazepam, lorazepam, but with a variation on the chemical formula. Clobazam has been used for epilepsy around the world for many years and is considered to be safe and effective. Lundbeck® has completed a phase 2 randomized, double-blind study of atonic drop seizures in patients with Lennox-Gastaut syndrome. Seizures were cut in half or better for 83% of patients taking 1 mg per kilogram per day to a maximum of 40 mg. Sleepiness and lethargy were the main side effects, but one patient had respiratory distress and another aspiration of saliva. The drug is now being tested in a phase 3 large controlled trial as treatment of seizures associated with Lennox-Gastaut syndrome.

Ganaxolone: Ganaxolone, sponsored by Marinus® Pharmaceuticals, Inc. is a drug in the category of neuro-steroids. Such drugs are not related to steroids used by athletes or those injected into joints, but rather to the hormone steroids such as progesterone and its metabolic products. Certain female hormones, including this drug, can modify the brain's response to its main inhibitory neurotransmitter, GABA. Ganaxolone completed a randomized clinical trial in 146 patients with partial seizures. The trial showed that ganaxolone was safe, well tolerated, and able to reduce seizures significantly more than did placebo. Ganaxolone may have some special benefits for seizures relating to female hormonal cycles. Development of ganaxolone has been supported by the Epilepsy Therapy Project.

Drugs at an Early Stage of Development

Possible epilepsy medications at an early stage of development may have completed animal toxicology studies and tests in laboratory models of epilepsy, but not have completed trials in patients.

Galanin NAX 5055: Galanin is a neuropeptide that can be found in brain. Increased amounts are able in laboratory studies to reduce brain excitability. Several novel molecules are under study to manipulate the galanin system in brain. Screening in epilepsy model systems at the University of Utah suggests effectiveness in preclinical animal studies. One of the compounds, NAX 5055, maybe targeted for clinical development.

Galanin gene transfer: Asklepios BioPharmaceutical®, Inc. is developing a method to increase galanin in temporal lobes of people with uncontrolled epilepsy. A "friendly" virus would be used to deliver genes for producing galanin to the brain’s temporal lobe by injection. This would result in more regional brain galanin, which would reduce brain excitability and hopefully result in fewer seizures. Plans are being made for human trials of this technology. This is an example of one of many likely future studies using the gene therapy approach.

MPP-021: The compound MPP-021, identified by MediProPharma®, Inc. is a drug being tested to improve thinking in people with dementia and neurodegenerative disorders. Analysis of the mechanism of action of this compound suggested that it might be useful also against seizures. The suggestion was validated by testing in the NIH Anticonvulsant Screening Program. Many compounds already known to be relatively safe might have activity against seizures.

NTP-2014: Neurotherapeutics Pharma®, Inc. received support from the Epilepsy Therapy Project to develop a compound currently designated as NTP-2014. This compound enhances inhibition in the brain by a unique mechanism of action that may not produce sedation. It has shown effectiveness in several laboratory models of epilepsy, and also for treatment of pain in laboratory models. It is developing plans for clinical testing.

Vigabatrin analog, CPP-115: The recently released drug, Sabril® (vigabatrin) is effective for treating partial and secondarily generalized seizures, but it can produce troublesome loss of peripheral vision. Catalyst Pharmaceutical Partners®, Inc. has developed an analog drug called CPP-115 that inhibits the same enzyme that vigabatrin inhibits. The result is increasing levels of GABA, the brain’s main inhibitory neurotransmitter. The hope is that CPP-115 will not show the vision loss side effects, and if not, it will go on to further development.

P529, Palomid: Great excitement exists within the tuberous sclerosis community about clarification of the genetic and molecular pathway that leads to the benign tumors (tubers) and seizures in tuberous sclerosis. Paloma Pharmaceuticals®, Inc. is developing potential medications to influence that pathway. One such drug, labeled P529, has completed toxicology testing and is soon to be tested in laboratory models of epilepsy. The compound is at an early stage but may provide hope for treating infantile spasms and other seizure types associated with tuberous sclerosis.

Dynamin Inhibitors: This class of drugs represents a new strategy for treating epilepsy. During a seizure, brain cells influence other brain cells by releasing an excitatory neurotransmitter at the synapse between neurons. These neurotransmitters are then taken up and repackaged for subsequent use. The process for doing so involves a chemical called dynamin. Blocking dynamin causes the excitation to run down, which might be a valuable method to stop seizures. One caution is whether beneficial inhibitory neurotransmission also would be affected. Preliminary evidence of effectiveness and safety has been obtained in screening laboratory models for epilepsy.

2-Deoxy-glucose: 2-DG has long been used as a test drug during brain PET scanning. Now Thomas Sutula, M.D., PhD, a former president of the American Epilepsy Society, has developed a project in conjunction with NeuroGenomex®, Inc. to develop 2-DG as an epilepsy medication. 2-DG is a chemical analog of sugar, but it cannot undergo metabolism after being taken up into brain cells. It accumulates preferentially in regions of brain consuming a lot of glucose during seizures. Laboratory studies have shown 2-DG to suppress seizures. Efforts are underway to take the agent from the laboratory to the clinic.

YKP3089: SK Life Science®, Inc. is developing YKP3089 for many possible uses including epilepsy, nerve pain, anxiety and bipolar depression. So far, the drug has shown a good safety margin in toxicological studies and a half-life in the blood that should allow single daily dosing. Patients with light-sensitive epilepsy showed beneficial EEG changes when given the medication. Further clinical development is in planning.

Other topics: Several general medication topics were considered at the Pipeline conference. The process of innovation and financing for new drug development received considerable attention. The need for new seizure medication formulations that last longer in the bloodstream or can be delivered by alternate routes were considered. Benzodiazepine drugs such as diazepam (Valium®) or midazolam (Versed®) were discussed in terms of a nasal spray administration. The Orphan Drug Act assists development of medicines for rare disorders: as of 12/31/09, 353 orphan drugs were in use.

Conclusion:

The antiepileptic drug pipeline remains rich and creative. Despite having many existing drugs to treat seizures, the number of people who remain uncontrolled is still very large. It therefore is exciting to see so much interest in producing better seizure medicines. Not all drugs listed in this report will find their way to the clinic. Conversely, numerous other drugs not mentioned here are in various stages of development. The important point is that the pipeline continues, that industry remains a key component of the Epilepsy Community, and that collectively we will not give up until we have treatments that stop seizures with acceptable levels of tolerability. The Epilepsy Therapy Project has contributed in a real way to several of these new therapies, and it remains committed to that goal.