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Antiepileptics are therapies approved to treat patients with epilepsy, a brain disorder in which clusters of nerve cells signal abnormally, which can lead to seizures. Epilepsy affects approximately 2.5 million people in the United States, and results in an estimated annual cost of $15.5 billion in healthcare. Epilepsy can be treated through both surgical and pharmaceutical intervention, and the market for pharmaceutical treatment of epilepsy generated $12 billion in 2008.
The major players in the antiepileptic market include Abbott Laboratories, Cephalon, GlaxoSmithKline, Johnson & Johnson, Novartis AG, Pfizer, Sanofi-Aventis SA, Shire, and UCB Pharma. Pfizer maintains the largest market share in the antiepileptics market with 26% for its two products, Lyrica and Neurontin ($2.96 billion combined sales in 2008). Pfizer's antiepileptic products are also growing at the fastest rate among major competitors, with a sales growth of 31% from 2007 to 2008.
The antiepileptic drug market is threatened by generic competition, which has risen dramatically in the face of patent expirations among several of the major branded antiepileptics. Generic competition, which is usually 40-60% cheaper than branded drugs, can drive down prices and decrease sales achievable by branded antiepileptics. However, there have been cases of generic antiepileptics not being as efficacious as their branded counterparts. This has led patient advocacy organizations to press for bans on pharmacies switching to generic antiepileptics without notification of the patient.
In 2008, the FDA issued a black-box warning that several antiepileptics increase the risk of suicidal thoughts and behavior among users. These warnings could hurt the sale of antiepileptics with warnings on their labels.
Pfizer's antiepileptic franchise, consisting of Lyrica and Neurontin, eaned $2.96 billion in 2008, a growth of 31% from 2007. Neurontin lost its patent exclusivity in 2003 and Lyrica is scheduled to retain its exclusivity until 2018.
Neurontin, which lost exclusive patent rights in 2004, once earned over $3 billion per year and was one of Pfizer's marquee drugs. The precise mechanism of Neurontin is unknown. However, Neurontin is structurally related to gamma-aminobutyric acid (GABA), a neurotransmitter known have a calming effect on neurons.
Lyrica is the fastest growing antiepileptic in the market (41% growth in sales from 2007 to 2008) and, as of 2008, was the most prescribed brand-name drug to treat epilepsy. Lyrica works by binding to the α2−δ subunit of calcium channels in neurons. This binding has an inhibitory effect on hyper-excited neurons, which lead to epileptic events.
Topamax achieved sales of $2.7 billion in 2008, a growth of 11.3% from 2007. While the primary product patent for Topamax expired in September 2008, the FDA granted Johnson & Johnson pediatric exclusivity for the drug into March 2009. Since Johnson & Johnson's loss of market exclusivity for Topamax, generic competition has entered the market, leading to a decrease in sales for Topamax in the first two quarters of 2009.
The exact mechanism of action for Topamax is not clearly understood. However, studies indicate that Topamax blocks sodium channels in neurons and may augment the effects of the neurotransmitter, GABA, in the brain. Both of these mechanisms are known to have a calming effect on neurons.
Keppra achieved sales of $1.74 billion in 2008, a growth of 23% from 2007. UCB Pharma lost its market exclusivity for Keppra on July 2008, and saw generic competition for the drug enter into the market in November of that year.
Keppra represents a unique class of antiepileptic, binding to and inhibiting a protein that facilitates the release of neurotransmitters from neurons. Keppra's unique mechanism enables it to be effective as an adjunct therapy for patients who are already taking a different class of drug, such as Topamax or Lyrica. In fact, Keppra has been shown to significantly improve rates of seizures when added to another first-line therapy.
Depakote achieved sales of $1.3 billion in 2008, a decrease of 13% from 2007. Abbott lost its market exclusivity for Depakote in July of 2008 and began to see generic competition in the second half of 2008.
While the mechanism of action for Depakote is not fully understood, it probably blocks sodium channels in neurons, which inhibits overactivity. In addition, it is known to augment the activity of a GABA-synthesizing protein, GAD, and restrict a GABA-degrading protein, GABA-T. All of these mechanisms can result in a calming effect on overactive neurons.
Lamictal earned revenues of $1.27 billion in 2008 for a decrease of 16% from 2007 to 2008. Lamictal lost its exclusivity in July of 2008, and Taro Pharmaceutical's generic version was approved by the FDA in February of 2009. The increased competition has led to decreased sales of Lamictal.
Lamictal is known to inactivate sodium channels in neurons. However, this mechanism alone does not fully explain Lamictal's therapeutic effects. The mechanism of action for Lamictal has yet to be fully elucidated.
Other antiepileptics on the market include Tegretol and Trileptal (Novartis AG (NVS)), Depakine (Sanofi-Aventis SA (SNY)), Carbatrol (Shire (SHPGY)), and Gabitril (Cephalon (CEPH)). Together, these drugs achieved $1.37 billion in sales in 2008, accounting for 12% of the antiepileptics market.
|Rank||Market Share||Company||Product||Revenue ($ billion)||Growth|
|2||23.8%||Johnson & Johnson||Topamax||2.7||11%|
Vimpat (UCB Pharma): Vimpat (Lacosamide), a sodium channel modulator, was approved in October of 2008 as an adjunct therapy to treat epilepsy. Vimpat became available in U.S. pharmacies in June of 2009.
Retigabine (Valeant Pharmaceuticals International (VRX)): Retigabine is an antiepileptic that works by prolonging the opening of potassium channels in neurons, producing effects similar to those produced by GABA in the brain. Retigabine would represent a new class of antiepileptics, and is being pursued as an adjunct therapy for epilepsy. Valeant Pharmaceuticals has completed Phase III trials for Retigabine and plans to request FDA approval for the drug in the third quarter of 2009.
Comfyde (Johnson & Johnson (JNJ)): Comfyde (Carisbamate) is a drug being developed by Johnson & Johnson to treat epilepsy. The mechanism of action for Comfyde is unknown and currently under investigation. Phase III trials have been completed, and on October 2008, Johnson & Johnson submitted an NDA to seek approval for Comfyde for use as an antiepileptic.
Zebinix (Sepracor (SEPR)): Zebinix (Eslicarbazepine) is a sodium channel blocker being developed by BIAL - Portela & Cª, S.A. and licensed to Sunovion and Eisai Co. Ltd. (ESALY). Phase III trials have been completed, and results indicate that Zebinix results in a sustained decrease in seizure frequency over the long-term.
Among the major antiepileptics currently in the market, all but Lyrica have lost their patent exclusivity (the Lyrica patent expires in 2018). Loss of patent exclusivity opens the opportunity for generic drug makers, such as Teva Pharmaceutical Industries (TEVA), Mylan Laboratories (MYL), and Watson Pharmaceuticals (WPI) to introduce competition. This competition forces prices down and lowers the number of prescriptions going to the branded pharmaceutical. As stated in the above sections, generic competition has already begun for many of these antiepileptics, resulting in decreases in sales numbers for the manufacturers of the drugs.
However, recent cases in which patients switched onto generic antiepileptics experienced returns in seizures are causing concern that there are differences between the generics and the branded antiepileptics. Patient advocacy groups are now petitioning lawmakers to stop pharmacies from substituting generics for branded antiepileptics without alerting the patients. Such a ban would benefit manufacturers of the branded antiepileptics and hurt generic manufacturers.
On December of 2008, the FDA added a warning to several antiepileptics that usage could result in a heightened risk of suicidal thoughts and behaviors. This warning was added after a review of 199 studies comparing the safety and effectiveness of antiepileptics showed that usage of the drugs doubled the risk of suicidal behaviors compared with placebos. However, there have been disputes that the results of the study were inconsistent and may not be significant across all of the drugs implicated. These warnings could decrease sales of antiepileptics on the market and discourage the development of new therapies.
Since there are several epilepsy drugs currently on the market, and prognosis among treated patients is generally good, New therapies are typically approved as adjunct therapies. An adjunct therapy is used in patients in combination with a first-line treatment to improve outcomes. The emergence of more adjunct therapies will lead to more epilepsy patients taking more than one medication, increasing the size of the epilepsy market.