Antiepileptic Drug Market

 
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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.[1] Epilepsy affects approximately 2.5 million people in the United States, and results in an estimated annual cost of $15.5 billion in healthcare.[2] Epilepsy can be treated through both surgical and pharmaceutical intervention,[3] 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,[4] 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.[5]

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.

Players in the Antiepileptic Drug Market

2008 Revenue of Antiepileptic Drugs
2008 Revenue of Antiepileptic Drugs

Pfizer: Lyrica and Neurontin

Pfizer's antiepileptic franchise, consisting of Lyrica and Neurontin, eaned $2.96 billion in 2008, a growth of 31% from 2007.[6] Neurontin lost its patent exclusivity in 2003 and Lyrica is scheduled to retain its exclusivity until 2018.[7]

Neurontin, which lost exclusive patent rights in 2004,[8] once earned over $3 billion per year and was one of Pfizer's marquee drugs.[9] The precise mechanism of Neurontin is unknown.[10] However, Neurontin is structurally related to gamma-aminobutyric acid (GABA), a neurotransmitter known have a calming effect on neurons.[11]

Lyrica is the fastest growing antiepileptic in the market (41% growth in sales from 2007 to 2008)[12] and, as of 2008, was the most prescribed brand-name drug to treat epilepsy.[13] 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.[14]

Johnson & Johnson: Topamax

Topamax achieved sales of $2.7 billion in 2008, a growth of 11.3% from 2007.[15] While the primary product patent for Topamax expired in September 2008, the FDA granted Johnson & Johnson pediatric exclusivity for the drug into March 2009.[16] 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.[17]

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.[18]

UCB Pharma: Keppra

Keppra achieved sales of $1.74 billion in 2008[19], a growth of 23% from 2007.[20] UCB Pharma lost its market exclusivity for Keppra on July 2008,[21] and saw generic competition for the drug enter into the market in November of that year.[22]

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.[23]

Abbott Laboratories: Depakote

Depakote achieved sales of $1.3 billion in 2008, a decrease of 13% from 2007.[24] Abbott lost its market exclusivity for Depakote in July of 2008[25] 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.[26] All of these mechanisms can result in a calming effect on overactive neurons.

GlaxoSmithKline: Lamictal

Lamictal earned revenues of $1.27 billion[27] in 2008 for a decrease of 16% from 2007 to 2008.[28] Lamictal lost its exclusivity in July of 2008[29], and Taro Pharmaceutical's generic version was approved by the FDA in February of 2009.[30] 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.[31]

Others:

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.

Antiepileptics Market Share by Revenue, 2008
Rank Market Share Company Product Revenue ($ billion) Growth
1 26.1% Pfizer Lyrica, Neurontin 2.96 31%
2 23.8% Johnson & Johnson Topamax 2.7 11%
3 15.3% UCB Pharma Keppra 1.74 23%
4 11.5% Abbott Depakote 1.3 (-13%)
5 11.2% GSK Lamictal 1.27 (-16%)
6 6.9% Novartis Tegretol, Trileptal 0.78 (-29%)
7 4% Sanofi Aventis Depakine 0.45 4%
8 0.7% Shire Carbatrol 0.08 5%
9 0.5% Cephalon Gabitril 0.06 6%
Antiepileptic Market Share by Prescription
Antiepileptic Market Share by Prescription[32]

Major Drugs in the Pipeline

Vimpat (UCB Pharma): Vimpat (Lacosamide), a sodium channel modulator, was approved in October of 2008 as an adjunct therapy to treat epilepsy.[33] Vimpat became available in U.S. pharmacies in June of 2009.[34]

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.[35] 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.[36]

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.[37] 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.[38]

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.[39]

Trends and Forces

Patent Expirations Enable Significant Generic Competition

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.[40] Such a ban would benefit manufacturers of the branded antiepileptics and hurt generic manufacturers.

Risk of Suicide is a Concern for Users of Antiepileptics

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.[41] 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.[42] These warnings could decrease sales of antiepileptics on the market and discourage the development of new therapies.

New Antiepileptics are Predominately Approved as Adjunct Therapies

Since there are several epilepsy drugs currently on the market, and prognosis among treated patients is generally good,[43] 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.

References

  1. NINDS Epilepsy Information Page
  2. CDC: Epilepsy
  3. NINDS Epilepsy Information Page
  4. Drugs by generic name
  5. http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a9k3iDl4bTHo Seizure Threat Tied to Drug-Swap Laws May Hurt Teva, Mylan
  6. Pfizer 2008 10-K Annual Report, p. 66
  7. FDA Orange Book: Lyrica
  8. Pfizer `Spun' Neurontin Study Results, Experts Say
  9. The Neurontin Legacy — Marketing through Misinformation and Manipulation
  10. Neurontin Package Insert
  11. GABA: Your Brain's Own Anti-Anxiety Medication
  12. Pfizer 2008 10-K Annual Report, p. 63
  13. Cowen and Company. Therapeutic Categories Outlook. March 2008.
  14. Lyrica Proposed Mechanism of Action
  15. Johnson & Jonson 10-K Annual Report, p. 36
  16. FDA Orange Book: Topamax
  17. Johnson & Johnson Q2 2009 Earnings Call Transcript
  18. Help for Migranes (Topamax)
  19. Converted from £1.27 billion using a 1.37 pound to dollar conversation factor (British Pound Currency Exchange Forecast)
  20. UCB Pharma 10-K Annual Report, p. 8
  21. FDA Orange Book: Keppra
  22. UCB Pharma 10-K Annual Report, p. 16
  23. Keppra, a 'new class' of CNS drugs
  24. Abbott Laboratories 10-K Annual Report, p. 32
  25. FDA Orange Book: Depakote
  26. Mechanisms of action of Depakote: Professional
  27. Converted from £926 million using a 1.37 pound to dollar conversation factor (British Pound Currency Exchange Forecast)
  28. GlaxoSmithKline 2008 20-F Annual Report, p.35
  29. FDA Orange Book: Lamictal
  30. Taro's ANDA for seizure drug wins FDA approval
  31. Mechanisms of action of Lamictal
  32. Cowen and Company. Therapeutic Categories Outlook. March 2008.
  33. UCB Pharma 10-K Annual Report, p. 19
  34. UCB Launches Vimpat(R) In The U.S. For Add-on Treatment Of Epilepsy In Adults
  35. Retigabine A Promising New Antiepileptic Drug with a Novel Mechanism of Action
  36. Valeant Pharma shares fall following downgrade
  37. Carisbamate prevents the development and expression of spontaneous recurrent epileptiform discharges and is neuroprotective in cultured hippocampal neurons
  38. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Submits New Drug Application to FDA for Carisbamate
  39. Zebinix Shows Long-Term Reduction In Seizure Frequency
  40. http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a9k3iDl4bTHo Seizure Threat Tied to Drug-Swap Laws May Hurt Teva, Mylan
  41. http://www.forbes.com/feeds/hscout/2008/12/16/hscout622362.html
  42. AES 2008: Panel Disputes FDA Finding on Antiepileptics and Risk for Suicide
  43. WHO: Epilepsy
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