Final Pivotal Phase III Fycompa® (perampanel) Study Results Published Ahead of First European Launch

HATFIELD, England, August 22, 2012 /PRNewswire/ --

Results of longer term safety and efficacy study also released

Results from the final pivotal Phase III study and long term Phase III extension study Fycompa^® (perampanel), were published online today in Epilepsia^®. Findings from Study 305, one of three pivotal global studies, and the extension study for perampanel add further weight to the growing body of clinical evidence supporting the efficacy and safety of the new treatment.^[1,2]

Perampanel is the only licensed anti-epileptic drug in Europe that selectively targets AMPA receptors, which are thought to play a central role in seizure generation and spread.^[3]  This first in class treatment selectively targets the transmission of seizures by blocking the effects of glutamate, which can trigger and maintain seizures.

The 305 study demonstrated that once-daily, adjunctive perampanel improved seizure control and was acceptably-tolerated in subjects 12 years and older with refractory partial-onset seizures. Study 305 is one of three pivotal Phase III studies in the EXPLORE (EXamining PerampaneL Observations from Research Experience) clinical trial programme.^[1]

Showing consistency with other results from the Phase III clinical trial programmes, the 307 interim results showed that perampanel had an acceptable tolerability profile in patients with refractory partial-onset seizures over the longer term. Furthermore, reduced seizure frequency and improved responder rates were consistent and maintained during 1 - 2 years of continued perampanel therapy.^[2] Study 307 is an open-label extension study for people with epilepsy completing the double-blind phase of three pivotal Phase III trials (studies 304, 305, and 306).

"The publication of these encouraging new data comes at an important time for perampanel. They follow the publication of pivotal data from the therapy's clinical development programme published in this month's Neurology journal, and its European Commission approval on 23 July 2012," noted Dr Antonio Laurenza, Executive Director and Head of Epilepsy, Neuroscience Product Creation Unit, Eisai. "In combination these results reinforce perampanel's tolerability profile and demonstrate seizure control over the longer term."

Study 305

In the 305 study 386 patients were randomised and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent-to-treat analysis) were 14.7%, 33.3% (p = 0.002), and 33.9% (p < 0.001) respectively, for placebo, perampanel 8mg, and perampanel 12mg, with significant improvements over placebo for both perampanel 8mg and 12mg The median percent change from baseline in seizure frequency/28 days (intent-to-treat [ITT] analysis) was -9.7%, -30.5%, and -17.6% for placebo, 8mg (p < 0.001), and 12mg (p = 0.011), respectively, with significant reductions compared with placebo for both 8mg and 12mg. For complex partial seizures plus partial seizures that secondarily generalised, the median percent change in frequency was -32.7% (8mg), -21.9 (12mg), and -8.1% (placebo), with significant reductions for both 8mg (p < 0.001) and 12mg (p = 0.005). The most frequent (occurring in ≥10% of patients in any treatment group) treatment-emergent adverse events (AEs) were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache.^[1]

Study 307

In total, 1218 patients were enrolled in the 307 study. At the interim cut-off date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks' exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years' exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n=1,084 [91%]) were titrated to 10 mg or 12mg/day. Median (range) duration of exposure was 51.4 (1.1-128.1) weeks. Treatment-emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients.^[2]

In the ITT analysis set (n=1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks' exposure to perampanel (n=1006 [83.3%]); this reduction was maintained in patients with at least one year of exposure (n=588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13-week interval of perampanel treatment were -39.2% for weeks 14-26 (n=1114), -46.5% for weeks 40-52 (n=731), and 58.1% for weeks 92-104 (n=59). Overall responder rates in patients included in each 13-week interval of perampanel treatment were 41.4% for weeks 14-26 (n=1114), 46.9% for weeks 40-52 (n=731) and 62.7% for weeks 92-104 n=59).  During the blinded conversion period, the reduction in seizure frequency in patients previously randomised to placebo (-42.4%, n=369) was similar to that in patients previously randomised to perampanel (-41.5%, n=817).^[2]

Perampanel is licensed in Europe Union as an adjunctive treatment for people aged 12 years and older with partial-onset seizures, with or without secondarily generalised seizures.^[4] Discovered and developed by Eisai in Europe and Japan, perampanel is the first licensed treatment to exhibit clinical efficacy in Phase III clinical trials against partial-onset seizures by selectively (non-competitively) blocking postsynaptic AMPA receptor-mediated excitatory neurotransmission.^[5,6]

The worldwide supply of perampanel will be packaged and manufactured at Eisai's EMEA (Europe, the Middle East, Africa and Russia) headquarters in Hatfield, UK. The worldwide supply of perampanel will be packaged and manufactured at Eisai's EMEA headquarters in Hatfield, UK.

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 305

The 305 study sought to assess the efficacy and safety of once-daily doses of perampanel 8 mg and 12 mg when added to 1-3 concomitantly administered, approved AEDs in patients with uncontrolled partial-onset seizures. It was a multicenter, double-blind, placebo-controlled trial in patients aged 12 years and above with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving one to three AEDs. Equal randomisation to once-daily oral perampanel 8 mg, 12 mg, or placebo was performed. Patients entered a 19-week double-blind treatment phase comprising a 6-week titration period, with weekly 2 mg dose increments, followed by a 13 week maintenance period.^[1]

Primary efficacy endpoints were the responder rate (proportion of patients who had a ≥50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre-perampanel baseline. The secondary endpoint was percent change in the frequency of complex partial plus secondarily generalized seizures. AEs were monitored throughout the study.^[1]

About 307

The 307 study was designed to evaluate safety, tolerability, and seizure outcome data during long-term treatment with once-daily adjunctive perampanel (up to 12mg/day) in patients with refractory partial-onset seizures. It was an open-label extension (OLE) study for patients completing the double-blind phase of three pivotal Phase III trials (studies 304, 305, and 306).^[2]  

The study consisted of two phases: an open-label treatment phase (including a 16-week conversion period and a planned 256-week maintenance period) and a 4-week follow-up phase. Patients were blindly titrated during the Conversion Period to their individual maximum tolerated dose (maximum 12mg/day).  AEs were monitored throughout the study and seizure frequency recorded. The interim data cut-off date for analyses was 1 December 1 2010.^[2]

About Perampanel

Eisai 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. Perampanel is the first licensed product in this new class for the adjunctive treatment of partial-onset seizures with or without secondarily generalised seizures in patients with epilepsy aged 12 years and older.

Further information for healthcare professionals can be found at http://www.fycompa.eu

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^[6]- 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^[1]-Austria, Finland, Australia, Belgium, Germany, France, Great Britain, Greece, India, Israel, Netherlands, Italy, Russia, Sweden, USA and South Africa.

There 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^[7]- USA, Canada, Mexico, Chile and, 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, and an estimated 50 million people with the condition worldwide.^[8,9] 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).

In the EMEA region, 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.

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

Job code: Perampanel-UK2045

References

[1] French JA et al. Epilepsia 2012. In press online

[2] Krauss GM et al. Epilepsia 2012. In press online

[3] Rogawski MA. Epilepsy Currents 2011;11:56-63

[4] Fycompa Summary of Product Characteristics. 2012

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

[6] Krauss GM. et al. Neurology 2012 May 1;78(18):1408-15

[7] French JA. Neurology 2012;79:589-596.

[8] 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].

[9] Pugliatti M, et al. Epilepsia 2007: 48(12) 2224 - 2233.

Date of preparation: August 2012

Job code: Perampanel-UK2045