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Perampanel: a weapon against epilepsy

By Gareth Malson and Lin-Nam Wang

Who it is for

New drugs are often described as a “welcome addition to the armoury” against whichever disease they are intended to treat. But in the case of perampanel (Fycompa), this cliché is apt: while working on the molecule researchers nicknamed it shuriken (ninja star) because of its flat propeller-type shape (see Image).

Perampanel is an addition to our armoury against epilepsy, specifically partial-onset seizures with or without secondary generalised seizures in patients aged 12 years or over. This is a standard starting point for new antiepileptics, said Hannah Cock, honorary consultant neurologist for St George’s Healthcare NHS Trust. “Over half of epilepsies are focal [partial] seizures and all new antiepileptics have started out being licensed for this indication,” she explained.

 

Types of epilepsy

There are two main types of seizure, simple partial-onset (only a defined part of the brain is affected) and generalised (all or most of the brain is affected). Partial-onset seizures are most common, often the result of brain damage. There are several types:

  • Simple partial — only a localised part of the brain is affected, the patient is conscious and usually aware of the seizure
  • Complex partial — a larger part of the brain is affected, patients can experience altered consciousness along with abnormal or repetitive movements
  • Secondary generalised — a partial-onset seizure that develops into a generalised seizure, causing the patient to lose consciousness

 

 

How it works

Perampanel is a selective, non-competitive, AMPA-type glutamate receptor antagonist. Speaking at the launch of Fycompa last month, Martin Brodie, professor and clinical research director of the epilepsy unit at the University of Glasgow, explained that glutamate is the most excitatory neurotransmitter in the central nervous system, playing a key role in the initiation and spread of seizures. Glutamate, for example, opens AMPA receptors to allow the influx of sodium ions. Although exactly how perampanel exerts an antiepileptic action remains unclear, Professor Brodie said that its high selectivity for the non-competitive binding site on AMPA receptors represents a unique mechanism of action.

Research

Several phase III trials have compared perampanel with placebo. One double-blind, placebo-controlled trial involved 388 epilepsy patients being randomised to perampanel 8mg, 12mg or placebo (Neurology 2012;79:589). The primary endpoint was percentage change in seizure frequency. The median change was –21.0 per cent for placebo, –26.3 per cent for 8mg and –34.5 per cent for 12mg but differences were not statistically significant.

A second, similarly designed study compared the responder rates (proportion of patients who experienced a reduction in seizure frequency of at least 50 per cent) of perampanel 8mg and 12mg against placebo. (Epilepsia 20 August 2012). Among the 321 patients who completed the study, these were 14.7, 33.3 and 33.9 per cent for the placebo, 8mg and 12mg groups, respectively. Compared with placebo, the results for 8mg (P=0.002) and 12mg (P=0.001) were significantly different.

A third study (Neurology 2012;78:1408) compared 2mg, 4mg and 8mg perampanel with placebo in terms of responder rates and percentage reduction in seizure frequency. Statistical significance versus placebo was shown on both parameters for the 4mg and 8mg groups, but not 2mg. The 4mg group had a responder rate of 28.5 per cent (P=0.132) and a 23.3 per cent median reduction (P=0.0026) in seizure frequency. The 8mg group had a responder rate of 34.9 per cent (P=0.0003) and a 30.8 per cent median reduction (P<0.0001) in seizure frequency. “Trials have shown perampanel to be effective when compared with placebo,” concluded Annett Blochberger, lead pharmacist in neurosciences at St George’s NHS Healthcare Trust. “However, its ability to make patients seizure free is not groundbreaking, so it’s unlikely to be the silver bullet for epilepsy.”

Administration

Perampanel is taken once a day, at bedtime. Tablets should be swallowed whole. “The dose will be increased slowly [usually increasing by 2mg at a minimum of every two weeks] with the aim of reaching the lowest dose that works — ie, at which seizure frequency reduces — or the highest dose the patient can tolerate before side effects become an issue,” Dr Cock said.

Safety

Fergus Rugg-Gunn, consultant neurologist at University College London Hospital, also spoke at the Fycompa launch. “What patients really want to know about is side effects. Perampanel has a relatively clean bill of health in that respect… . I’d be telling patients about three things in particular: dizziness, somnolence and fatigue,” he said.

Cost

Perampanel will cost £140 per month (excluding VAT). “All strengths of perampanel cost the same,” Mrs Blochberger pointed out. “Clinicians and dispensing chemists need to be made aware that when they double the dose, they need to prescribe the higher strength of the tablet rather than just increasing the number of tablets to take.”

Place in therapy

Perampanel’s place in therapy has yet to be established, Mrs Blochberger reckons, but it is expected that it will be used as third-line therapy in otherwise refractory patients.

“[Perampanel] represents another option for treating epilepsy,” Dr Cock adds. “We won’t know how good [it is] until head-to-head trials are published and clinicians get clinical experience with its use. Many patients have refractory epilepsy so are not seizure free despite treatment. This drug might be the perfect treatment for any of those patients.”

As with any other new medicine in the UK, gaining inclusion in local formularies remains a hurdle. Nonetheless, Mrs Blochberger believes that perampanel’s novel mode of action will make it a useful alternative to existing treatments. “Unfortunately, whether or not this drug is included in local formularies might well vary between trusts,” she concedes. “Local formulary committees ought to understand that the full armamentarium for treating epilepsy should be made available and governed appropriately by strict prescribing guidelines.” Dr Cock agreed: “This should be an option available to all patients referred to epilepsy specialists.”

Fycompa is currently only licensed for adjunctive treatment. However, research into the uses for perampanel is continuing, including phase III trials on its use as monotherapy in partial-onset seizures.

The authors

Gareth Malson is a pharmacist and freelance writer. Lin-Nam Wang is senior contributions editor at The Pharmaceutical Journal. She attended the launch of Fycompa in London in September 2012.

Citation: The Pharmaceutical Journal URI: 11108387

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