(Laurie Barclay, MD, February 2004)

Epilepsy, or seizure disorder, is a neurological condition characterized by recurrent seizures, or "fits." These episodic disturbances in brain function caused by abnormal electrical excitation are associated with changes in attention, level of consciousness, and/or behavior.

Epilepsy affects between 0.5% - 1.0% of the population, or approximately 2.5 million Americans and 40 million people worldwide. However, 1.5% to 5.0% of the population may have at least one seizure during their lifetime.

Although effective medications and other treatments are available, many individuals with epilepsy still suffer from uncontrolled seizures or from adverse effects of treatment. In the U.S., the annual healthcare cost of epilepsy is about $12.5 billion, according to a study by the Epilepsy Foundation.

Many seizure disorders are idiopathic and chronic, whereas others of metabolic origin may be caused by a temporary condition such as drug toxicity or withdrawal, abnormal electrolyte levels, or hypoglycemia. Brain injury related to stroke, head trauma, or mass lesion such as tumor may cause epilepsy if neurons in the damaged area become abnormally excitable.

Other causes include inherited conditions, degenerative disorders such as Alzheimer’s disease, brain infections like meningitis and encephalitis, and complications of AIDS or other immune disorders. Epilepsy can affect individuals at any age.

Symptoms of epilepsy vary depending on the seizure type and the brain region involved. Some seizures, especially those originating from the temporal lobe, may be preceded by an aura, or unusual sensory experience such as tingling in an extremity, an unpleasant smell, or a feeling of deja vu.

Generalized seizures, which include petit mal and grand mal seizures, affect most of the brain. Petit mal seizures consist mostly of staring spells and lapses in consciousness lasting only for a few seconds, with eye blinking and minimal or no movement.

Grand mal, or tonic-clonic seizures, affect the whole body with rigidity and stiffness, followed by jerking muscle contractions of the limbs. During the tonic-clonic seizure, there is loss of consciousness, temporary cessation of breathing, and often incontinence and tongue or cheek biting. After the tonic-clonic seizure, the post-ictal state may include confusion, weakness known as Todd's paralysis, and lethargy.

Because partial seizures affect only a localized region of the brain, they vary in symptomatology depending on where they originate. There may be muscle contractions or tingling of a specific body part, olfactory or gustatory hallucinations, nausea, sweating, skin flushing, and automatisms, or automatic performance of complex, stereotyped behaviors.

Complications of epilepsy may include serious injury, vocational disability, aspiration pneumonia, or even permanent brain damage or death from prolonged or repeated seizures (status epilepticus).

Epilepsy is typically diagnosed by history of recurrent seizures and confirmed by abnormal electrical activity on electroencephalography. Neurological examination and brain imaging studies such as CT and MRI may be normal, or they may reveal abnormalities underlying the seizure disorder. Analysis of cerebrospinal fluid and blood tests may be helpful in diagnosing infectious or metabolic causes.

Treatment begins with correcting any underlying cause for recurrent seizures, but the mainstay of treatment, especially for idiopathic epilepsy, is antiepileptic drugs. Most of the currently available anticonvulsants, such as phenytoin, carbamazepine, valproate (VPA), primadone and phenobarbital, act on five molecular targets involved in neurotransmission.

None of the available agents controls all seizure types, and all have adverse effects which may include liver damage, impaired coordination, speech disturbances, anemia and neutropenia, nausea and vomiting, lethargy, irritability, confusion, and teratogenicity. Other problems associated with currently available agents include the need for monitoring with frequent blood work, and the refractory nature of some seizure disorders even to combination therapy.

Potential new therapies include stem cell transplants, stimulation of controlled neurogenesis in the brain, and gene replacement, although much research is still needed before these treatments bridge the gap from laboratory bench to clinic.

CenterWatch has identified a pipeline of 12 drugs for epilepsy in various stages of development. These include gap junction blockers, amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonists, and calcium channel modulators.

Pfizer has submitted a new drug application (NDA) for pregabalin, a calcium channel modulator touted as a major advance in the treatment of epilepsy, neuropathic pain, and anxiety disorders. In Phase III trials, this drug has been effective for all three indications, with good safety and tolerability, rapid onset of action, and a simple dosing schedule.

Although one mouse study raised safety issues, additional studies have alleviated these concerns and allowed Pfizer to file its NDA for pregabalin for epilepsy add-on therapy. Between 2004 and 2006, a filing is also anticipated for epilepsy monotherapy.

In Phase II development by D-Pharm and Shire Pharmaceuticals is DP-VPA, a D-RAP derivative of valproic acid (VPA), linked to a lipid vector. Data are being analyzed from the first European Phase II trial of DP-VPA as add-on therapy for complex partial seizures, and additional trials have been scheduled.

Although VPA is known to be effective and is widely used for complex partial seizures, chronic use is still limited by serious adverse effects including liver toxicity, teratogenicity, gynecological complications, and arrested cognitive development in children.

To circumvent these problems, DP-VPA was developed as a prodrug which acts only at the epileptogenic focus. It remains as an inert prodrug in unaffected tissues, and it is activated only by an enzyme with supranormal activity in affected brain tissue, allowing lower doses and reduced toxicity. In animal models, DP-VPA had an effective dose range about 80 times lower than that of VPA without significant toxicity.

In a Phase I safety study of 56 healthy male volunteers, DP-VPA has minimal systemic effects; no dizziness, somnolence or other neurological adverse effects, and good oral absorption.

Talampanel is a potent and selective AMPA receptor antagonist which IVAX is testing for epilepsy in expanded, multicenter Phase II trials involving more than 260 patients.

In a safety study of 14 patients with intractable epilepsy, oral talampanel was rapidly absorbed and achieved maximal plasma concentrations within one to three hours. However, talampanel concentrations in patients taking enzyme-inducing antiepileptic drugs were 50% lower than those achieved in healthy volunteers. On the other hand, talampanel and VPA each inhibited the metabolism of the other. There were no serious adverse events, but some patients reported dizziness, ataxia, drowsiness, and headaches at lower doses compared with those in healthy subjects.

Another AMPA receptor antagonist is NS1209 (SPD 502), in Phase II testing by NeuroSearch A/S. In preclinical models of status epilepticus and other forms of epilepsy, NS1209 was shown to be more effective than known antiepileptic drugs, and it may also be useful in acute neuronal damage associated with stroke, transient cardiac arrest, head trauma and spinal cord injury. One treatment with NS1209 appears to prevent the development of spontaneous seizures occurring eight to 12 weeks after the episode of status epilepticus.

In Phase I studies of 70 volunteers, NS1209 was safe and well tolerated at plasma levels higher than those needed for neuroprotection. In February 2003, NeuroSearch began a dose-finding, double-blind, placebo-controlled Phase II study with patients suffering from chronic epilepsy.

Novartis’ version of the AMPA receptor antagonist is AMP397, also in Phase II testing. This drus is said to be the first competitive AMPA antagonist with high receptor affinity, good in vivo potency, and oral activity. In vitro and animal models suggested that AMP397 has no genotoxic potential in vivo and therefore allowed further clinical development.

Safinamide (NW-1015), in Phase II development for epilepsy by Newron Pharmaceuticals, has multiple mechanisms of action. As might be expected from a dopamine uptake inhibitor, it is in Phase III trials for the treatment of Parkinson’s disease.

However, safinamide is also a potent, selective and reversible inhibitor of monoamine oxidase (MAO) B, without affecting MAO-A, and it has potent sodium (Na+) channel blocking activity and calcium (Ca2+) channel modulation. By selectively affecting only those neurons with abnormal firing patterns, the Na+ channel blockade does not disrupt normal neuronal activity.

Based on animal models, safinamide is thought to have both anticonvulsant and neuroprotective effects, with a broad spectrum of activity in different seizure types with potency comparable to or better than that of known antiepileptic drugs. Unlike other potential anticonvulsants, safinamide does not appear to have any proconvulsant effects, and it is effective in models of intractable complex partial seizures and status epilepticus.

Clinical trials thus far have suggested excellent tolerability and bioavailability for safinamide. Potential advantages of this drug include a broad spectrum of antiepileptic activity, low toxicity, favorable pharmacokinetic profile, preferential brain uptake reducing systemic toxicity, water solubility allowing emergency intravenous use, and 24-hour half-life permitting once-daily dosing.

Like safinamide, rufinamide (RUF 331) is a sodium-dependent action potential inhibitor in Phase II development by Novartis. Initial studies suggested satisfactory efficacy and acceptable toxicity.

In a double-blind, proof of principle trial of rufinamide in 50 patients with partial or primary generalized tonic-clonic seizures, seizure frequency decreased by 41% in the rufinamide group and increased by 52% in the placebo group (P = .04). Reduction in seizure frequency of at least 50% relative to baseline occurred in 39% of rufinamide-treated and in 16% of placebo-treated patients, but this difference was not statistically significant.

At steady state, peak plasma concentration occurred at a mean time of 3.4 hours, and mean half-life was 7.3 hours. There was no autoinduction of rufinamide metabolism, and rufinamide did not affect the plasma concentration of carbamazepine, phenytoin or VPA when used as adjunctive therapy with these agents. Adverse events were primarily those neurologic signs and symptoms typically seen with antiepileptic drugs.

A Phase III, multicenter randomized trial is planned to test rufinamide as add-on therapy for intractable partial seizures in children. After the double-blind, placebo-controlled, parallel-group phase of this trial, all entered children will be eligible for a long-term extension.

Harkoseride (SPM 927) is a novel central nervous system drug undergoing testing by Schwarz Pharma. In a Phase II open label tolerance study as adjunctive therapy in 86 patients with refractory partial seizures, 33% of patients had a reduction of seizures by at least half.

Harkoseride was generally well-tolerated in this study, and initial safety studies in healthy human subjects showed no serious adverse effects at single intravenous doses up to 300 mg, single oral doses up to 600 mg or multiple oral doses up to 400 mg daily for seven days.

Teva Pharmaceutical Industries is in Phase II development of
valrocemide (TVP-1901), a potent, broad-spectrum, antiepileptic compound thought to have a novel mechanism of action. In animals, it has shown efficacy in a wide range of clinically relevant epilepsy models.

Results are pending from a 13-week Phase II European study of valrocemide as add-on therapy in patients with refractory epilepsy. In September 2003, Teva entered into a strategic collaboration with Acorda Therapeutics, Inc. to develop and promote valrocemide for epilepsy and related indications.

Isovaleramide (NPS 1776) is a small, orally active organic molecule in Phase I testing by NPS Pharmaceuticals for epilepsy and other neurological and psychiatric conditions. Potential advantages of this drug in preclinical trials include a high margin of safety, rapid onset and a broad spectrum of antiepileptic activity.

While awaiting new developments from molecular biology and gene therapy, clinicians treating epilepsy can look forward to new agents targeting receptors and channels different from those affected by currently marketed antiepileptic drugs. By limiting activity to the epileptogenic focus, some of these agents may allow lower toxicity and fewer adverse effects than those associated with the armamentarium now available.