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Epilepsy in check

Although there is no cure, there are promising treatments for this disorder's symptoms

frowning_with_hand_on_head Imagine walking to the park on a beautiful, crisp day listening to your favourite song. The next moment, you are on the ground feeling utterly exhausted and surrounded by a number of unfamiliar yet concerned faces; you have absolutely no recollection of what has happened. One of the strangers informs you that you have had a seizure, or more specifically, a generalised seizure. Sounds scary, doesn't it?

This is a very real risk for a person with epilepsy, a chronic neurological disorder, which affects approximately 50 million people worldwide. Epilepsy is characterised by recurrent unprovoked seizures; its diagnosis is typically made when a person experiences at least two seizures without any known cause, including alcohol withdrawal or extreme hypoglycaemia. Physiologically, seizures are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. Depending on the area of the brain affected, these translate to varying intensities of symptoms experienced by the patient, ranging from a momentary lapse in awareness or loss of motor control (simple partial seizures) to loss of consciousness and convulsions (generalised seizures).

Currently, no cure exists for epilepsy. All treatments are directed towards controlling the symptoms, namely, seizures. Anticonvulsants, of which 20 have been approved, are the mainstay treatment for epilepsy. These act to suppress the rapid and excessive firing of neurons characteristic of a seizure and offer protection against possible excitotoxic effects that may result in brain damage. While medication is effective for most, over 30 per cent of patients fail to achieve adequate seizure control. This is recognised in the pharmaceutical industry. A number of promising agents are in development.

Carisbamate (COMFYDE; Ortho-McNeil, a subsidiary of Johnson & Johnson) is a neuromodulator with antiepileptic properties that is being developed for the treatment of epilepsy. Its exact mechanism is unknown, although it appears to modulate neurotransmitters in a manner distinct from other antiepileptic drugs (AEDs). Preclinical studies indicated that the drug could be useful for tonic-clonic and complex partial seizures, as well as status epilepticus. Results from two phase III trials, evaluating 12 weeks of adjunctive carisbamate 200 and 400 mg/day, have been presented; efficacy and tolerability parameters were investigated in a combined total of over 1,000 patients with uncontrolled partial seizures. Only one of the trials demonstrated carisbamate at 400 mg/day reduced seizure frequency compared with placebo (27 per cent vs 15 per cent reduction; p<0.01). Both trials suggested that the drug was generally well tolerated. A new drug application (NDA) has been submitted to the US Food and Drug Administration (FDA) in the US for the adjunctive treatment of epilepsy and phase III development is ongoing in Europe and Asia.

Brivaracetam (Rikelta; UCB Pharma) is a pyrrolidone derivative from the same chemical family as levetiracetam. It is given orally and is being developed for the treatment of neurological conditions such as epilepsy and pain. The drug binds with high affinity to synaptic vesicle glycoprotein 2A (SV2A) in the brain, which is thought to play a considerable role in the release of neurotransmitters essential for normal neuronal activity in the brain and spinal cord. While the exact role of SV2A is unknown, there is a high correlation between binding affinity at SV2A and antiepileptic activity. Brivaracetam has also been shown to inhibit voltage-dependent sodium channels. The drug has been designed to be more efficacious than its predecessor, levetiracetam, which is UCB Pharma's existing antiepileptic agent, indicated as adjunctive therapy in the treatment of partial onset seizures in adult epileptic patients. Brivaracetam is currently being evaluated in numerous global, multi-centre, ongoing phase III trials in various indications associated with epilepsy and seizure disorders. Results from phase II trials showed that adjunctive brivaracetam significantly reduced weekly seizure frequency after seven weeks of treatment, compared with placebo in patients with refractory partial seizures.

Perampanel (Eisai) is an oral, AMPA-type glutamate receptor antagonist that is being developed for the treatment of epilepsy and neuropathic pain. Three global, randomised, phase III trials were initiated in May, June and September 2008 and are expected to be completed by March 2012, September 2010 and March 2012, respectively. These trials aim to investigate the efficacy and tolerability of adjunctive perampanel in patients with refractory partial seizures. Pending successful outcomes from these trials, regulatory submissions of perampanel in the US and EU are planned in 2012. An open-label, 14-month, follow-up of patients completing these trials is also ongoing. Results from a dose-ranging, double-blind, proof-of-concept, phase II trial conducted in 153 patients supported the use of perampanel for epileptic seizures. Patients completing this trial were permitted to enter a four-year open label extension. This extension trial began in September 2006 and is expected to conclude in May 2012.

An immediate-release formulation of retigabine (Valeant Pharmaceuticals International) is being developed for the adjunctive treatment of partial onset seizures in adult patients. It is a first-in-class, KCNQ potassium channel agonist with selectivity for neuronal cells and is believed to exhibit its therapeutic effects by positively modulating neurotransmission via the GABA pathway. GABA synthesis is also increased with minor effects on sodium and calcium channels. Two pivotal, placebo-controlled, double-blind, randomised, phase III trials that began patient enrolment in the second half of 2005 were completed in 2008. The trials, known as Retigabine Efficacy and Safety Trial for partial Onset Refractory seizures in Epilepsy (RESTORE) 1 and 2, were conducted in 301 and 539 patients with refractory disease, respectively. Results from both trials showed significant improvements in the percentage change in total partial seizure frequency and the proportion of responders, defined as the number of patients experiencing a reduction of ≥ 50 per cent in total partial seizure frequency from baseline (co-primary endpoints). Furthermore, retigabine 600 and 900mg doses (RESTORE-2) demonstrated highly statistically significant results on the primary efficacy endpoints important for regulatory review by the FDA and the European Medicines Agency (EMEA). An agreement between Valeant and GlaxoSmithKline (GSK) means that GSK receives worldwide development and commercialisation rights to retigabine, along with other back-up compounds from Valeant's potassium channel agonist research programme. Both companies intend to submit a NDA in the third quarter of 2009, with a Market Authorisation Application submission following a month later. More than 80 per cent of eligible patients have elected to take part in open-label extension studies directly after the completion of the RESTORE programme. In addition, Valeant is exploring a sustained-release formulation of retigabine for the treatment of partial onset seizures in the US.

Further investigations
While a significant proportion of epileptic patients may not achieve adequate seizure control, hope is not lost. Drugs with novel mechanisms of action, in addition to those that act via established efficacious pathways, are continually being discovered and investigated. Phase I testing has begun for HEPP and SPN 802 (Supernus Pharmaceuticals); the mechanisms of action for these agents are not yet known or defined. Other drugs in early clinical development include JZP 4 (Jazz Pharmaceuticals), which acts as an antagonist of type IIa sodium and calcium channels, and T 2000 (Taro Pharmaceutical Industries), which is an agonist for GABA A receptors. Tiprolisant, a histamine H3 agonist, is also being investigated for potential use in epilepsy. With continued success in this arena, patients are increasingly likely to receive therapies that will confer optimal seizure control.

The Author
Pipeline was written by David Young of Adis International (Wolters Kluwer Health), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Kuljeet Sohanpal on 0207 981 0714 or email:
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3rd September 2009


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