Eisai Gains Positive CHMP Opinion for Fycompa^® (perampanel) First in a New Class of Treatment for Partial Onset Epilepsy

HATFIELD, United Kingdom--(BUSINESS WIRE)-- Eisai announced today that the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for the use of Fycompa^® (perampanel) as an adjunctive treatment of partial-onset seizures, with or without secondarily generalised seizures, in patients with epilepsy aged 12 years and older.

Perampanel has a different mechanism of action to current antiepileptic drugs (AEDs). As an AMPA receptor antagonist, perampanel is the first of a new class of AED.¹ The neurotransmitter glutamate plays a major role in the mediating seizures and perampanel is the only agent that selectively targets the transmission of seizures by blocking post synaptic glutamate AMPA receptors.^2,3 AMPA receptors are currently not selectively targeted by any other available AED.^2,3,4 Based on today's recommendation, EU approval of the new therapy is anticipated within three months.

In addition to the CHMP recommendation for the use of perampanel as an adjunctive treatment, Eisai received a positive CHMP opinion for Zonegran^® (zonisamide) as monotherapy for the treatment of partial seizures (with or without secondary generalisation) in adults with newly diagnosed epilepsy. Zonisamide is a second generation AED with multiple mechanisms of action and a chemical structure which is unrelated to any other AED^s.⁵

The successful treatment of partial-onset seizures (the most common type of epilepsy) remains a challenge in some patients. The incidence of uncontrolled epilepsy remains high despite many new AEDs and between 20 ? 40% of patients with newly diagnosed epilepsy will become refractory to treatment.⁶

Perampanel is a completely new option for the management of partial onset epilepsy as it is the first AED to exhibit clinical efficacy against partial-onset seizures by selectively (non-competitively) blocking AMPA receptor-mediated excitatory neurotransmission.^7,8

"Improving seizure control is one of the most pressing unmet needs in epilepsy patients. Perampanel will be a completely new option for the adjunctive treatment of patients with uncontrolled seizures," noted Professor Bernhard Steinhoff, Professor of Neurology, Medical Director and Executive, Epilepsy Center, Kehl-Kork, Germany. "The positive opinion announced today by the CHMP is a significant step in ensuring patients have access to this first-in-class treatment in Europe."

The CHMP based its decision on clinical data from three pivotal Phase III, global, randomised, double-blind, placebo-controlled, dose-escalation studies in 1,480 epilepsy patients. Each of the studies showed consistent results in the efficacy and tolerability of perampanel as an adjunctive therapy in patients with partial-onset seizures (with or without secondary generalisations).^8,9,10 Perampanel delivers the benefit of once-daily dosing, thereby helping to reduce the potential pill-burden a person with epilepsy may experience.¹¹ The most commonly reported adverse events were dizziness, headache, somnolence, irritability, fatigue, falls, and ataxia.^8,9,10

The development of perampanel and zonisamide 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 with epilepsy and their families. Eisai is proud to currently market more epilepsy products in EMEA than any other company.

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 306⁸ - Germany, Bulgaria, Portugal, Lithuania, India, and China

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=0.0132), and 8mg = 34.9% (p=0.0003) versus 17.9% with placebo.

• The median percent change in seizure frequency for the ITT population shown:
  2 mg = -13.6% (p=0.420), 4 mg = -23.3% (p=0.0026), 8 mg = -30.8% (p<0.0001) versus -10.7% with placebo

• The most frequent treatment-emergent adverse events were dizziness, headache and somnolence.

Study 305¹⁰- Europe, USA, South Africa, Israel, Russia, India, Australia

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=0.0008), 12mg = 33.9% (p=0.0006) versus 14.7% with placebo

• The median percent change in seizure frequency for the ITT population were:
  8mg = -30.5% (p=0.0008), 12mg = -17.6% (p=0.0105)) versus -9.7% with placebo

• The most reported adverse events were dizziness, fatigue, headache and somnolence

Study 304⁹- USA, Canada and South America

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, irritability, headache, falls, 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.¹² There are an estimated six million people living with epilepsy in Europe,¹³ and an estimated 50 million people with the condition worldwide.¹³ 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 the European market.

In Europe, Eisai currently has three marketed treatments including:

• Zonegran^® (zonisamide) as adjunctive therapy in adult patients with partial-onset seizures, with or without secondary generalisation
• Zebinix^® (eslicarbazepine acetate) as adjunctive therapy in adult patients with partial-onset seizures, with or without secondary generalisation
• 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 facility which now supports the company's growing European, Middle Eastern and African (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, Slovenia, the Netherlands, and Belgium.

For further information please visit our web site www.eisai.com

References

¹ Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics 2007;4:18?61.

² Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004;5:553-564.

³ Brodie MJ. Antiepileptic drug therapy: the story so far. Seizure 2010; 19: 650-655.

⁴ Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Currents 2011;11:56?63.

⁵ Eisai Ltd. (2005). Zonegran Summary of Product Characteristics

⁶ French JA. Refractory Epilepsy; Clinical Overview. Epilepsia 2007: 48 (Suppl1) 3 ? 7

⁷ Hanada T, Hashizume Y, Tokuhara N, Takenaka O, Kohmura N, Ogasawara A, Hatakeyama S, Ohgoh M, Ueno M, Nishizawa Y. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia. 2011 Jul;52(7):1331-40.

⁸ Krauss GM. Serratosa JM, Villanueva V et al. Randomized Phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012: Please visit: http://www.neurology.org/.

⁹ Perampanel Reduces Treatment-Resistant, Partial-Onset Seizures. Neurology Reviews 2011;19(6):1,26-29.

¹⁰ 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.

¹¹ Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed? A novel assessment technique. JAMA. 1989 Jun 9;261(22):3273-7.

¹² Pugliatti M et al. Estimating the cost of epilepsy in Europe: A review with economic modeling. Epilepsia 2007: 48(12) 2224 ? 2233.

¹³ 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].