Pivotal Study of Eisai's Partial Epilepsy Treatment Fycompa® (perampanel) Published in Neurology®

HATFIELD, England, July 26, 2012 /PRNewswire/ --

Eisai today announces the publication of results from a pivotal Phase III study[1] of Fycompa® (perampanel), the first in a new class of adjunctive treatment in people with partial-onset seizures, with or without secondary generalised seizures, aged 12 years and older.

According to research published in the August 2012 issue of Neurology®, the medical journal of the American Academy of Neurology, the Study 304 data, published online today show that once-daily, adjunctive perampanel at doses of 8 or 12mg improved seizure control in people with uncontrolled partial-onset seizures, and that both doses had an acceptable safety and tolerability profile. Study 304 is one of three pivotal Phase III studies in the EXPLORE (EXamining Perampanel Observations from Research Experience) clinical trial programme.

The successful treatment of partial-onset seizures (the most common type of epilepsy) remains a challenge in some people. The incidence of uncontrolled epilepsy remains high despite many new anti-epileptic drugs (AEDs) and it is estimated that the proportion of people diagnosed with epilepsy who, are or will become, refractory to treatment range from 20% to as high as 40%.[2]

Perampanel selectively (non-competitively) blocks postsynaptic AMPA receptor-mediated excitatory neurotransmission.[3,4] Epileptic seizures are primarily mediated by the neurotransmitter glutamate. As an AMPA receptor antagonist, perampanel selectively targets the transmission of seizures by blocking the effects of glutamate.[5,6] This mechanism of action, which is different to that of current AEDs, means that once approved perampanel will be the first approved AED in this new class of treatment.

In May 2012, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for the use of perampanel as an adjunctive treatment of partial-onset seizures, with or without secondarily generalised seizures, in people with epilepsy aged 12 years and older. EU approval of the new therapy is anticipated in Q3 of 2012. The drug is also currently under review with the US Food and Drug Administration (FDA).

The development of perampanel underscores Eisai's human health care mission, the company's commitment to innovative solutions in disease prevention, cure and care for the health and well being of people worldwide.  Eisai is committed to the therapeutic area of epilepsy and addressing the unmet medical needs of patients and their families.

Notes to Editors

About perampanel

Eisai has developed perampanel for the adjunctive treatment of partial-onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older. Perampanel is a highly selective, non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptor antagonist that has demonstrated seizure reduction in Phase II and III studies. AMPA receptors, widely present in almost all excitatory neurons, transmit signals stimulated by the excitatory neurotransmitter glutamate within the brain and are believed to play a role in central nervous system diseases, characterised by excess neuroexcitatory signalling including epilepsy, neurodegenerative disorders, movement disorders, pain and psychiatric disorders. If approved, perampanel will be the first product in this class for the adjunctive treatment of partial-onset seizures with or without secondarily generalised seizures in patients with epilepsy aged 12 years and older.

About the perampanel Phase III studies (Study 306, 305 and 304)

The clinical development plan for perampanel consisted of three global Phase III studies: Studies 306, 305 and 304 in which a total of 1,480 patients participated. The key goal of Study 306 was to identify the minimal effective dose and included four treatment arms (placebo, 2mg, 4mg, and 8mg). Studies 304 and 305 included three arms (placebo, 8mg, and 12mg) and were to evaluate a more extended dose range.

The studies were similar in design: global, randomised, double-blind, placebo-controlled, dose-escalation, parallel-group studies. The primary and secondary endpoints were the same in all the studies: percentage change in seizure frequency, 50% responder rate, percentage reduction of complex partial plus secondarily generalized seizures, and evaluation for dose response. The primary endpoint for the EMA is 50% responder rate and the FDA is median percent change in seizure frequency.

Study 306[4] - Australia, Bulgaria, China, Czech Republic, Germany, Spain, Estonia, Hong Kong, Hungary, India, Italy, South Korea, Lithuania, Latvia, Malaysia, Philippines Poland, Portugal, Romania, Russia, Serbia & Montenegro, Thailand, Taiwan and the Ukraine

Study 306 showed that perampanel was well-tolerated and effective in reducing median seizure frequency and increasing responder rates. Specifically the results showed:

       -   The 50% responder rates compared to placebo for the ITT (intention-to-treat) population were:
           2mg = 20.6% (p=ns), 4mg = 28.5% (p=0.013), and 8mg = 34.9% (p<0.001) versus 17.9% with placebo. 
       -   The median percent change in seizure frequency for the ITT population shown:
           2mg = -13.6% (p=0.4197), 4mg = -23.3% (p=0.003), 8mg = -30.8% (p<0.0001) versus -10.7% with placebo
       -   The most frequent treatment-emergent adverse events were dizziness, somnolence and headache.

Study 305[7] - Austria, Finland, Australia, Belgium, Germany, France, Great Britain, Greece, India, Israel, Netherlands, Italy, Russia, Sweden, USA and South Africa

The was a significant difference in median percent change in seizure frequency with perampanel 8mg and 12mg. Specifically the preliminary results for Study 305 showed:

       -   The 50% responder rates compared to placebo for the ITT population were:
           8mg = 33.3% (p=0.0018), 12mg = 33.9% (p < 0.001) versus 14.7% with placebo 
       -   The median percent change in seizure frequency for the ITT population were:
           8mg = -30.5% (p< 0.001), 12mg = -17.6% (p=0.011) versus -9.7% with placebo
       -   The most reported adverse events were dizziness, somnolence, fatigue and headache.

Study 304[1] - USA, Canada, Mexico, Chile, Argentina

Study 304 showed consistent results in the efficacy and tolerability of perampanel given as a treatment for patients with partial-onset seizures. Specifically:

       -   The 50% responder rates compared to placebo for the ITT population were:
           8mg = 37.6% (p=0.0760), 12mg = 36.1% (0.0914) versus 26.4% with placebo.
       -   The median percent change in seizure frequency for the ITT population were:
           8mg = -26.3% (0.0261), 12mg = -34.5% (p=0.0158) versus -21.0% with placebo.
       -   The most common side effects were dizziness, somnolence, headache, falls, irritability and ataxia

About Epilepsy

Epilepsy is one of the most common neurological conditions in the world, affecting approximately eight in 1,000 people in Europe.[8] There are an estimated six million people living with epilepsy in Europe,[9] and an estimated 50 million people with the condition worldwide.[9] Epilepsy is a chronic disorder of the brain that affects people of all ages. It is characterised by abnormal discharges of neuronal activity causing seizures. Seizures can vary in severity, from brief lapses of attention or jerking of muscles, to severe and prolonged convulsions. Depending on the seizure type, seizures may be limited to one part of the body, or may involve the whole body. Seizures can also vary in frequency from less than one per year, to several per day. Epilepsy has many possible causes but often the cause is unknown.

About Eisai Europe in Epilepsy

Eisai is committed to developing and delivering highly beneficial new treatments to help improve the lives of people with epilepsy. The development of AEDs is a major strategic area for Eisai in Europe, the Middle East, Africa and Russia (EMEA). Eisai currently has three marketed treatments including:

       -   Zonegran® (zonisamide) as monotherapy and adjunctive therapy in adult patients with partial-onset seizures, with or without secondary generalisation. (Zonegran is under license from the originator Dainippon Sumitomo Pharma)
       -   Zebinix® (eslicarbazepine acetate) as adjunctive therapy in adult patients with partial-onset seizures, with or without secondary generalisation (Zebinix is under license from BIAL)
       -   Inovelon® (rufinamide) for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients >4 years

About Eisai

Eisai is one of the world's leading R&D-based pharmaceutical companies and has defined its corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call human health care (hhc). Eisai recently expanded their UK Hatfield commercial, research and manufacturing facility which now supports the company’s growing EMEA business. Eisai concentrates its R&D activities in three key areas:

       -   Neuroscience, including: Alzheimer's disease, multiple sclerosis, neuropathic pain, epilepsy, depression
       -   Oncology including: anticancer therapies; tumour regression, tumour suppression, antibodies, etc and supportive cancer therapies; pain relief, nausea
       -   Vascular/Immunological reaction including: acute coronary syndrome, atherothrombotic disease, rheumatoid arthritis, psoriasis, Crohn's disease

With operations in the U.S., Asia, Europe and its domestic home market of Japan, Eisai employs more than 11,000 people worldwide. In Europe, Eisai undertakes sales and marketing operations in over 20 markets, including the United Kingdom, France, Germany, Italy, Spain, Switzerland, Sweden, Ireland, Austria, Denmark, Finland, Norway, Portugal, Iceland, Czech Republic, Slovakia, the Netherlands, Belgium, Luxembourg, the Middle East and Russia.

References

1. French J, et al. Neurology 2012;79:1-1

2. French JA. Epilepsia 2007: 48 (Suppl1) 3-7

3. Hanada T, et al. Epilepsia. 2011 Jul;52(7):1331-40.

4. Krauss GM, et al. Neurology 2012: Please visit: http://www.neurology.org/.

5. Rogawski MA, et al. Nat Rev Neurosci 2004; 5:553-564.

6. Brodie MJ. Seizure 2010; 19: 650–655.

7. French J et al. Use of perampanel, a selective, non-competitive AMPA receptor antagonist, as adjunctive therapy in patients with refractory partial-onset seizures: results of a global phase III study. Presented at 29th International Epilepsy Congress, 28th August until 1st September, 2011, Rome. Abstract# 122/ Ref 020

8. Pugliatti M et al. Epilepsia 2007: 48(12) 2224–2233.

9. Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe. http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf [Accessed 10 April 2012].

Date of preparation: July 2012
Job code: Perampanel-UK2028