Epilepsy, one of the oldest conditions known to mankind, is a neurological disorder characterised by recurrent, transient seizures caused by a disturbance in the electrical activity of the central nervous system. According to the World Health Organisation, up to 50 million people worldwide, equating to a prevalence of at least 50 per 100,000 of the general population will have epilepsy at any one time.

Characterised by a tendency to recurrent seizures and defined by two or more unprovoked seizures, the clinical manifestations of seizures will vary depending on where in the brain the disturbance first starts and how far it spreads. Transient symptoms can occur, such as loss of consciousness and disturbances of movement, sensation, mood or mental function. While the condition can develop at any age, it is most often diagnosed before the age of 20 and after the age of 60, and can be due to any one of several conditions, including:

• genetic
• hippocampal sclerosis
• congenital disorders
• cerebrovascular disorders
• alcohol/drugs and metabolic disorders
• cerebral infection
• brain tumours

Electro-encephalograms (EEGs) are used to diagnose epilepsy along with additional tests/techniques, while magnetic resonance imaging (MRI) scanning can determine the cause. As a result of the wide range of symptoms that can occur, epilepsy is generally classified by seizure type - partial (simple or complex) or generalised - and treatment, which involves regular long-term drug therapy, is commenced once the patient displays more than one seizure.

History of treatment
The first drug to be used to treat epilepsy was phenobarbitone in 1912, and there are now around 17 drugs available, many of which, especially the older first-line therapies, are already off-patent. First-line therapies use carbamazepine (Novartis' Tegretol), sodium valproate (Abbott's Depakote/Valcote), phenytoin (Pfizer's Dilantin) or ethosuximide as monotherapy or in combination, and these treat approximately 80% of cases.

If unsuccessful, newer second-line anticonvulsant therapy is employed, using drugs such as Pfizer's Neurontin (gabapentin), GlaxoSmithKline's Lamictal (lamotrigine), UCB's Keppra (levetiracetam), Johnson & Johnson's Topamax (topiramate), Novartis' Trileptal (oxcarbazepine) and Sanofi-Aventis' Sabril (vigabatrin). Other drugs occasionally used in treatment include benzodiazepines and barbiturates. With the appropriate treatment, up to 80% of people are seizure free, and surgery may help a small number of people whose seizures do not respond to medication.

Leading 10 anti-epileptics worldwide
12 months to June 2004

Source IMS MIDAS

Five pharmaceutical giants (Pfizer, Johnson & Johnson, Abbott, GSK and Novartis) together dominate approximately 75% of the global anti-epileptic market (N3A therapy class), with Pfizer alone generating around one-third of total sales with Neurontin, first launched in 1994, up to June 2004. Other important players in this market include UCB, Sanofi-Aventis and Roche.

Generic defeat…
Pfizer's dominance in the market, however, is under threat. In 2004, several generic companies challenged Neurontin’s US patents in the courts. Pfizer believes its patents extend to 2017, but in October 2004, Alpharma and Teva carried out an 'at risk' launch of generic gabapentin capsules, which received final FDA approval later in the month as a generic equivalent of Neurontin. Pfizer then launched its own generic gabapentin product. In August 2004, Ivax launched gabapentin tablets in the US, but these are not directly substitutable for Neurontin, which had US sales of $2.4 billion in 2003. Generic gabapentin had previously been launched in several other markets, including Canada, Germany and the UK.

…but Pfizer fights back with Lyrica
Despite losses to generic manufacturers, Pfizer looks set to maintain a leading position within the epilepsy market, however, with Lyrica (pregabalin), its follow-up compound to Neurontin. European approval was granted in July 2004 as an adjunctive therapy for epilepsy in adults with partial seizures as well as for the treatment of adult peripheral neuropathic pain; Lyrica was launched in the UK immediately. In September 2004, the US FDA followed suit and deemed three indications approvable (neuropathic pain, post-herpetic neuralgia, and epilepsy). Pfizer also plans to seek a monotherapy indication for Lyrica in epilepsy, and analysts have forecast sales of more than $2 billion by 2008.

Most neurologists in the USA considered pregabalin to be useful but not revolutionary, and opinion leaders interviewed by IMS Health believed that pregabalin has fewer side-effects than its predecessor. They also perceived its anti-anxiety effects and twice-daily dosing as advantageous (gabapentin is often taken three times per day). IMS believes that pregabalin will be successfully marketed in the USA, although a significant proportion of drive may come from the indication in pain rather than in epilepsy.

Global* sales of anti-epileptics

Source: IMS Therapy Forecaster

The global epilepsy market had grown by five times in size (in terms of dollar sales) from 1994, with a historical compound annual growth rate (CAGR) of 21.4%: combined sales in the nine countries covered by IMS Therapy Forecaster topped $8 billion in 2003. With a forecasted CAGR of 6.8%, sales are expected to double over the next decade, beginning to level off after 2008. Significant events depressing market growth will be the potential dominance of generics as unbranded gabapentin, topiramate and lamotrigine become available, each capturing around 70% of brand volume in the US.

The approval of anti-epileptic drugs for new indications, use as monotherapy, and in children, will potentially provide growth however, along with the availability of already marketed anti-epileptic drugs in countries such as Japan.

Novel launch imminent
A launch may be imminent of the structurally novel compound (unrelated to currently marketed anti-epilepsy drugs) rufinamide, a broad-spectrum anticonvulsant, discovered and developed by Novartis and then in-licensed by Eisai in February 2004. Novartis had discontinued development in 2000 despite positive Phase III results that showed efficacy as an adjunctive therapy in the treatment of inadequately controlled partial seizures in adults, as well as seizures associated with severe generalised epilepsy (Lennox-Gastaut syndrome).

With Phase III trials now complete, Eisai is hoping to file the drug in the USA and EU in the near future, and possibly before the end of 2004. Many opinion leaders interviewed by IMS did not foresee great potential for this drug, although they did think it would be useful as an additional treatment option, especially in Lennox-Gastaut syndrome, and as an adjunct for refractory patients.

Major epilepsy therapies in development

Source: IMS LifeCycle R&D focus

A number of early stage pipeline products, as revealed by IMS Lifecycle R&D focus, are in development for the treatment of epilepsy, are outlined in the table above, set to provide further options for patients in the future.

This article was written by Angie Fraser, Deputy Managing Editor of IMS Company Profiles, and Lara Holt, IMS Therapy Forecaster Manager.

Find out more

Relevant reports on this topic:
Global and regional sales information:

• N3A
• Abbott
• GSK
• Johnson & Johnson
• Novartis
• Pfizer

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