Perampanel – Treatment for Epilepsy, Japan

Perampanel (E2007) is an AMPA-type glutamate receptor antagonist indicated for the treatment of epilepsy. It is also being investigated for the treatment of neuropathic pain, multiple sclerosis and migraines.

Perampanel is being developed by Japan-based healthcare company Eisai and is currently in Phase III of development.

Eisai submitted a new drug application to the US Food and Drug Administration (FDA) in May 2011, to use Perampanel for the treatment of partial onset seizures in patients with epilepsy.

The application was rejected in August 2011 and the company was asked to conduct a reanalysis of the data to support the approval.

Eisai also submitted Marketing Authorisation Application to the European Medicines Agency in May 2011. This application was accepted, and the drug is currently under review.

Epilepsy

Epilepsy is a chronic neurological ailment which affects about 45m people worldwide. It may be hereditary or caused by an illness or brain injury. In 70% of the cases, however, the exact cause is not known. The disease is characterised by frequent seizures caused by abnormal activity in the brain.

Communication between brain cells takes place through electrical signals, which are released in an orderly manner. In epilepsy these electrical signals are sent abnormally causing a surge in electrical activity in the brain.

This activity causes partial or generalised seizures leading to loss of awareness, black outs and convulsions.

There is no cure available for epilepsy. Existing treatment methodologies target just the symptoms of the disease, such as seizures. These treatments are effective in most epilepsy patients but more than 30% patients fail to achieve sufficient seizure control.

Perampanel - AMPA-type glutamate receptor antagonist

Clinical evidence suggests that alpha amino-3-hydroxy-5-mrthyl-4-isoxazolepropionic acid (AMPA) receptors play a key role in several neurodegenerative disorders.

AMPA receptor is a type of receptor for glutamate (a primary molecule in cellular metabolism) that plays a key role in neurotransmission and synaptic transmission.

Excessive activation of AMPA receptors damages brain cells by increasing the flow of calcium into the brain. This condition leads to seizures in patients.

Perampanel works by inhibiting the excess activity of AMPA receptors. Its action reduces the excitatory-inhibitory nerve imbalance caused in the brains of epilepsy patients. Consequently perampanel helps in reducing damage to brain cells and preventing seizures.

Clinical trials

Perampanel was effective in all the five animal seizure models developed in preclinical trials. The drug was initially tested in patients with Parkinson's Disease but failed in phase III clinical trials. In 2008, Eisai discontinued clinical trials of Perampanel for Parkinson's Disease.

Three phase II studies were conducted for refractory partial seizures in epilepsy patients. The studies indicated that Perampanel was well-tolerated and effective in treating refractory partial seizures.

The drug is currently being investigated in three global phase III clinical trials, studies 304, 305 and 306. A total of 1,430 patients have been recruited for the trials. Study 306 is the first of the three studies.

In August 2010, Eisai announced positive results from study 306. The randomised, double-blind, parallel-group study was conducted in Europe and Asia in 706 patients.

The study indicated that Perampanel was well-tolerated and was able to reduce the median seizure frequency in subjects.

The results of study 304 and 305 were presented in April and September 2011, respectively.

An open-label, follow-up study in patients who have completed phase III trials is also being carried out.

Patients who have completed phase II trials were enrolled in a four-year open label extension trial which started in September 2006. The extension trial is expected to be completed by May 2012.

Marketing commentary

Only 60-70% of epilepsy patients respond to medication. The remaining may not respond to any type of epilepsy drug. Treatment options for these patients include behavioural modification, neurostimulation and diet modification.

Newer drugs to treat epileptic seizures, therefore, have good market potential. The market for epileptic drugs was valued at $3.5bn in 2009 across the US, Japan, France, Germany, Italy, Spain and the UK. Although newer drugs do not offer more benefits than older drugs, they are easier to use and have fewer adverse side affects.

The efficacy of Perampanel, however, is in question due to the lack of publicly available information on its safety profile. Glutamate receptor antagonists are known to have several side effects. The success of Perampanel, therefore, is expected to rely on its safety and tolerability profile.