Eisai's Supplemental New Drug Application for FYCOMPA (Perampanel) as Monotherapy for Pediatric Partial-Onset Seizures Accepted in China

TOKYO, Oct. 30, 2020 /PRNewswire/ -- Eisai Co., Ltd. (Headquarters: Tokyo; CEO: Haruo Naito; "Eisai") recently announced that the National Medical Products Administration of China has accepted its self-developed antiepileptic drug (AED), Fycompa^®(Trade name: Vicks^®, generic name: perampanel) supplemental new drug application for the pediatric indication of monotherapy treatment of partial-onset seizures in patients aged 4 years and older.

The submission package for monotherapy in the treatment of partial-onset seizures is based on subgroup analyses evaluating the safety and efficacy of monotherapy from several global adjunctive therapy clinical studies (Studies 304, 305, 306, and 335), which were conducted in patients aged 12 years and older with partial-onset seizures (with or without secondary generalization) in the United States, Europe, and China. In addition, results from a Phase III clinical study (FREEDOM/Study 342) conducted in treatment-naïve patients aged 12 to 74 years with partial-onset seizures (with or without secondary generalization) in Japan and South Korea were submitted as supplementary safety and efficacy data.

The submission materials for pediatric patients with partial-onset seizures are based on the results of a Phase III clinical study of Fycompa (Study 311), which evaluated adjunctive therapy with Fycompa in pediatric patients (aged 4 to under 12 years) with inadequately controlled partial-onset seizures or primary generalized tonic-clonic seizures worldwide.

In ChinaThere are approximately 9 million patients with epilepsy. Although the disease can onset at any age, it is most common in children and adolescents aged 18 years and younger, as well as in the elderly. Since about 30% of patients with epilepsy cannot be controlled by current AEDs¹to control their epileptic seizures, a condition with significant unmet medical needs.

Fycompa is a novel antiepileptic drug developed by Eisai Tsukuba Research Laboratories, administered once daily. As a highly selective, non-competitive AMPA receptor antagonist, it reduces the hyperexcitability of neurons associated with seizures by targeting glutamate activity at AMPA receptors on the postsynaptic membrane. Fycompa has been approved in China as adjunctive therapy for partial-onset seizures (with or without secondary generalization) in patients aged 12 years and older with epilepsy.

Eisai considers neurology, including epilepsy, a key therapeutic area. With the acceptance of the supplemental application for Fycompa in China, Eisai continues to pursue its mission of providing effective epilepsy treatments to more patients worldwide. Eisai is committed to meeting the diverse needs of patients with epilepsy and their families, delivering greater benefits to them.

[Editor's Note]

1. AboutFycompa(Generic Name: Perampanel)

Fycompa is a novel antiepileptic drug exclusively developed by Eisai. Seizures are mediated by the neurotransmitter glutamate; Fycompa is a highly selective, non-competitive AMPA receptor antagonist that reduces seizure-related neuronal hyperexcitability by targeting glutamatergic activity at AMPA receptors on the postsynaptic membrane. Fycompa formulations are currently marketed for once-daily oral administration at bedtime. Tablet and fine granule formulations have been approved in Japan. The oral suspension and tablet formulations have been approved in the United States and Europe.

Currently, Fycompa is approved as adjunctive therapy for partial-onset seizures (with or without secondary generalization) in patients with epilepsy aged 12 years and older in more than 70 countries and regions, including Japan, the United States, China, and other countries in Europe and Asia. Furthermore, Fycompa has been approved in more than 65 countries, including the United States, Japan, Europe, and Asian nations, as adjunctive therapy for primary generalized tonic-clonic seizures in patients with epilepsy aged 12 years and older. In Japan and the United States, Fycompa is approved for both monotherapy and adjunctive therapy for partial-onset seizures (with or without secondary generalization) in patients with epilepsy aged 4 years and older. To date, Fycompa has been widely used to treat more than 300,000 patients worldwide across all indications. Eisai is currently conducting a global Phase III clinical study (Study 338) to evaluate the drug for the treatment of seizures associated with Lennox-Gastaut syndrome. Additionally, the development of an injectable formulation of Fycompa is underway.

2. Regarding the Submission in ChinaFycompaBasis for the Supplementary Submission of Monotherapy for Partial Epileptic SeizuresIIIPhase Clinical Study

The additional submission materials for Fycompa monotherapy in China are based on the Phase III clinical study (Study 335) conducted in Japan, China, and South Korea.^[2]) results, as well as three Phase III clinical studies conducted globally (including in the United States, Europe, and China) (Study 304^[3]、305^[4]and 306^[5]) results.

Study 335 primarily evaluates the efficacy and safety of Fycompa in patients in the Asian region. In addition, Studies 304 and 305 include three groups (placebo, Fycompa 8 mg, and 12 mg) and will evaluate an expanded dose range. The key objective of Study 306 is to determine the minimum effective dose, including four treatment groups (placebo group, Fycompa 2 mg, 4 mg, and 8 mg groups).

These studies were all multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. The subjects were patients aged 12 years and older diagnosed with partial-onset seizures, who were receiving one to up to three antiepileptic drugs. The primary endpoint of Study 335 was the percent change in seizure frequency. For Studies 304, 305, and 306, approved in Europe, the primary endpoint was the 50% responder rate (the percentage of patients experiencing a reduction in seizure frequency of 50% or more compared to pre-randomization), whereas the primary endpoint for US approval was the percent change in seizure frequency. Specifically, the results indicated:

1) Study 335

2) Study 304

3) Study 305

4) Study 306

3. AboutFREEDOM(Study342）^[6]

FREEDOM (Study 342) was an uncontrolled, open-label, Phase III clinical study conducted in Japan and South Korea to evaluate the efficacy and safety of Fycompa monotherapy in untreated patients aged 12–74 years with partial-onset seizures, with or without secondary generalization. Fycompa was administered orally once daily at bedtime at a maximum dose of 4 mg (titratable to 8 mg if convulsive seizures occurred). The study comprised a treatment period and an extension period; the treatment period included a 6-week titration phase and a 26-week maintenance phase (if the dose was up-titrated from 4 mg to 8 mg, the titration phase was 4 weeks and the maintenance phase was 26 weeks). In this study, 89 patients received Fycompa monotherapy. Among them, 73 patients receiving the 4 mg dose remained seizure-free during the treatment period, a proportion that exceeded the efficacy criterion* and met the primary endpoint. Furthermore, interim results indicated that the combined proportion of patients receiving 4 mg and 8 mg also exceeded the efficacy criterion. The most commonly observed adverse events (incidence ≥10%) in this study were dizziness, somnolence, nasopharyngitis, and headache, consistent with the safety profile of Fycompa established to date.

*The efficacy criterion for the 73 evaluable patients in this study was defined as a seizure-free rate of 52.1% or higher, which was primarily established based on results from other monotherapy studies with antiepileptic drugs (AEDs).

4. About the Study311^[7]

Study 311 is a global (United States, Europe, Japan, South Korea), open-label, Phase III clinical study evaluating the safety, tolerability, and exposure-efficacy relationship of Fycompa oral suspension as adjunctive therapy in 180 pediatric patients aged 4 to <12 years with poorly controlled partial-onset seizures or primary generalized tonic-clonic seizures. The study comprises a treatment period (including a titration phase of up to 11 weeks and a maintenance phase of up to 12 weeks) and an extension phase. In this study, Fycompa was administered orally once daily at bedtime at doses ranging from 2 to 16 mg. The primary endpoints were safety and tolerability. Efficacy was similar to that observed in patients aged 12 years and older. The most commonly reported adverse events (incidence ≥10%) in this study were somnolence, nasopharyngitis, pyrexia, vomiting, dizziness, influenza, and irritability, consistent with the known safety profile of Fycompa to date.

5. About Epilepsy

Epilepsy affects approximately 9 million people in China, 1 million in Japan, 3.4 million in the United States, 6 million in Europe, and around 60 million worldwide. Since approximately 30% of patients with epilepsy are not adequately controlled with current antiepileptic drugs (AEDs)^[1]to control their epileptic seizures, a condition with significant unmet medical needs.

Epilepsy is broadly classified by seizure type, with partial seizures accounting for approximately 60% of epilepsy cases and generalized seizures for approximately 40%. In partial seizures, abnormal electrical discharges are confined to a limited area of the brain and may subsequently spread to the entire brain, evolving into generalized seizures (termed secondary generalized seizures). In generalized seizures, abnormal electrical discharges involve the entire brain from the onset, often resulting in loss of consciousness or widespread somatic symptoms.

^[1]"Epilepsy and Seizures: Hope Through Research. What Is Epilepsy?" National Institute of Neurological Disorders and Stroke, accessed May 24, 2016,http://www.ninds.nih.gov/disorders/epilepsy/detail epilepsy.htm#230253109

^[2]Nishida T, et al. Perampanel as Adjunctive Therapy for Partial-Onset Seizures: A Randomized Phase III Study in the Asia-Pacific Region.Acta Neurol Scand. 2018; Issue 137, pp. 392-399.

^[3]French JA, et al. Perampanel as Adjunctive Therapy for Refractory Partial-Onset Seizures: Randomized Phase III Study 304.Neurology. 2012; Issue 79, pp. 589-596.

^[4]French JA, et al. Evaluation of Perampanel as Adjunctive Therapy in Patients with Refractory Partial-Onset Seizures: Results of the Global Randomized Phase III Study 305.Epilepsia. 2013; Issue 54, pp. 117-125.

^[5]Krauss GL, et al. Randomized Phase III Study 306: Adjunctive Perampanel for Refractory Partial-Onset Seizures.Neurology. 2012; Issue 78, pp. 1408-1415.

^[6]Yamamoto, Takamichi et al. Efficacy and Safety of Perampanel Monotherapy for Newly Diagnosed Focal Seizures or Epilepsy Relapse After Remission: Open-Label Study 342 (FREEDOM Study).Epilepsia. 2020; Issue 5, pp. 274-284.

^[7]Fogarasi, Andras et al. Open-Label Study to Evaluate the Safety and Efficacy of Perampanel as Adjunctive Therapy in Children (Aged 4 to <12 Years) with Focal Seizures or Generalized Tonic-Clonic SeizuresEpilepsia. 2020; Issue 61, pp. 125-137.