WOODCLIFF LAKE, N.J., May 30, 2018 /PRNewswire/ -- Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) has accepted its supplemental New Drug Application (sNDA) for Priority Review for its antiepileptic drug FYCOMPA^® (perampanel) CIII for monotherapy and adjunctive use for the treatment of partial-onset seizures (POS) with or without secondarily generalized seizures in pediatric patients (ages 2 to less than 12 years). The submission also proposes a pediatric indication for adjunctive use for primary generalized tonic-clonic (PGTC) seizures in patients with epilepsy (ages 2 to less than 12 years). The sNDA application includes both the FYCOMPA tablet and oral suspension formulations.

"The incidence of seizures in the pediatric age group has been steadily increasing in the U.S. where an estimated 470,000 children are living with epilepsy today. Approximately 30 percent of all patients have uncontrolled seizures, and it is crucial that we do whatever we can to help these patients achieve the ultimate goal of seizure freedom," said Trevor Resnick, MD, Pediatric Neurologist at Nicklaus Children's Hospital. "Approximately 71 percent of all people living with epilepsy miss at least one dose of their medication per month, and 45 percent of those missed doses result in a subsequent breakthrough seizure. FYCOMPA's long, 105 hour half-life may play an important role for patients who miss doses."

FYCOMPA is currently approved as therapy (adjunctive and monotherapy uses) for POS with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older, and as adjunctive therapy for PGTC seizures in patients with epilepsy 12 years of age and older. To date, more than 100,000 patients have been treated with FYCOMPA worldwide across all indications.

"The FDA's Priority Review designation for this sNDA underscores the urgent need for more treatment options like FYCOMPA in the pediatric population," said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. "We are committed to working with the FDA to bring forward more treatments for young patients to help physicians achieve seizure freedom, a critical goal in epilepsy care."

Eisai is seeking approval to expand the pediatric use for FYCOMPA based on a 2018 Draft Guidance noting the FDA's current thinking regarding clinical development programs that can support extrapolation of the effectiveness of drugs approved for the treatment of POS in adults to pediatric patients 4 years of age and older. This determination was based on the similarity of POS in adults and in pediatric patients four years of age and older, and on an analysis of multiple antiepileptic drugs, conducted by the FDA, that demonstrated a similar exposure-response relationship in pediatric and adult patients with POS.

In support of the extrapolation approach, the sNDA includes data from an ongoing global open-label, multicenter study (Study 311) with an extension phase that evaluated the safety, tolerability, and exposure-efficacy relationship of perampanel oral suspension when administered as an adjunctive therapy in children, ages 4 through 11, with inadequately controlled POS or PGTC seizures. The study enrolled 180 patients –149 with POS and 31 with PGTC seizures – with an overall mean daily dose of 6 mg.

The primary objective of Study 311 was safety and tolerability, evaluated based on incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), laboratory parameters, vital signs, and ECG parameters. Secondary endpoints included the efficacy of perampanel as measured by the median percent change per 28 days in seizure frequency, by the proportion of responders (≥25% , ≥50%, and ≥75%), and by the proportion of subjects who are seizure-free for POS, PGTC, and secondarily generalized tonic-clonic (SGTC) seizures as well as the effects of perampanel on cognition, behavior, visuomotor skills, and growth and development in children during short-term (23 weeks) and long-term (up to 52 weeks) treatment.

The sNDA also includes data from an open-label pilot study (Study 232) with an extension phase to evaluate the pharmacokinetics, and to generate preliminary data on safety, tolerability, and efficacy of FYCOMPA oral suspension when given as an adjunctive therapy in pediatric subjects from 2 to less than 12 years of age with epilepsy.

FYCOMPA, the first and only seizure medication that targets the AMPA receptor, was initially approved for adjunctive use in POS in 2012 and has treated over 100,000 patients worldwide in 55 countries across all indications. FYCOMPA was approved for adjunctive use in patients with PGTC seizures in 2015 and as monotherapy use for the treatment of POS in 2017. An oral suspension formulation was also approved in 2016.

About Epilepsy
Epilepsy is a medical condition that produces seizures affecting a variety of mental and physical functions. According to the Institute of Medicine, epilepsy is one of the most common neurological disorders, which affects about 3.4 million people in the United States, including 470,000 children. Partial-onset seizures are the most common type of seizure seen in people with epilepsy, accounting for 60 percent of all seizures. Generalized seizures account for approximately 40 percent of all epilepsy, with primary generalized tonic-clonic seizures being one of the most common and severe forms of generalized seizures.

Poor antiepileptic drug adherence is the number one cause of breakthrough seizures, including convulsive seizures that can cause significant injury to patients. Uncontrolled seizures and breakthrough seizures – including those stemming from poor treatment adherence – increase a patient's risk for sudden unexpected death in epilepsy (SUDEP).  Additionally, breakthrough seizures also increase a patient's risk of accidents, falls, fractures or head injuries, emergency room (ER) visits, and hospitalization, as well as an associated increase in healthcare costs.

About FYCOMPA
FYCOMPA is a prescription medicine used in people with epilepsy aged 12 and older alone or with other medicines to treat partial-onset seizures with or without secondarily generalized seizures and with other medicines to treat primary generalized tonic-clonic seizures.

FYCOMPA, a unique oral medication, is a selective, non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist. The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans is unknown. FYCOMPA has a long half-life of 105 hours with steady state reached in about 2 to 3 weeks. It has been demonstrated that because of the long 105 hour half-life of FYCOMPA a missed dose does not significantly impact plasma levels, a key risk factor for breakthrough seizures.

FYCOMPA is supplied as 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg film-coated tablets, and in an oral suspension formulation. FYCOMPA has been designated by the U.S. Drug Enforcement Administration as a federally-controlled substance (CIII).

Please visit www.FYCOMPA.com to learn more about the treatment.

IMPORTANT SAFETY INFORMATION

SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS
In the partial-onset seizures clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. These effects in FYCOMPA-treated patients led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. Homicidal ideation and/or threat have also been reported postmarketing in patients treated with FYCOMPA. The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Patients taking FYCOMPA should avoid the use of alcohol. Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Similar serious psychiatric and behavioral events were observed in the primary generalized tonic-clonic (PGTC) seizure clinical trial.

SUICIDAL BEHAVIOR AND IDEATION
Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients. Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, their caregivers, and families should be informed of the risk and advised to monitor and immediately report the emergence or worsening of depression, suicidal thoughts or behavior, thoughts about self-harm and/or any unusual changes in mood or behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

DIZZINESS AND GAIT DISTURBANCE
FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination. Dizziness and vertigo were reported in 35% and 47% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 10% of placebo-treated patients. Gait disturbance related events were reported in 12% and 16% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 2% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the PGTC seizure clinical trial.

SOMNOLENCE AND FATIGUE
FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events. Somnolence was reported in 16% and 18% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 7% of placebo-treated patients. Fatigue-related events were reported in 12% and 15% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 5% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the PGTC seizure clinical trial. Patients should be advised against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known.

FALLS
Falls were reported in 5% and 10% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 3% of placebo-treated patients.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
DRESS, also known as multiorgan hypersensitivity, has been reported in patients taking AEDs, including FYCOMPA. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement. If signs or symptoms are present, immediately evaluate the patient and discontinue FYCOMPA if an alternative etiology for signs or symptoms cannot be established. 

WITHDRAWAL OF AEDs
A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency, but if withdrawal is a response to adverse events, prompt withdrawal can be considered.

MOST COMMON ADVERSE REACTIONS
The most common adverse reactions in patients receiving FYCOMPA (≥5% and ≥1% higher than placebo) include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety.

DRUG INTERACTIONS
FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel. Plasma levels of FYCOMPA were decreased when administered with moderate and strong CYP3A4 inducers, including, carbamazepine, phenytoin, or oxcarbazepine. Multiple dosing of FYCOMPA 12 mg per day enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants.

PREGNANCY AND LACTATION
Physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Caution should be exercised when FYCOMPA is administered to pregnant or nursing women as there are no adequate data on the developmental risk associated with use in pregnant women, and no data on the presence of perampanel in human milk, the effects on the breastfed child, or the effects of the drug on milk production.

HEPATIC AND RENAL IMPAIRMENT
Use in patients with severe hepatic or severe renal impairment is not recommended. Dosage adjustments are recommended in patients with mild or moderate hepatic impairment. Use with caution in patients with moderate renal impairment.

DRUG ABUSE AND DEPENDENCE
FYCOMPA is a Schedule III controlled substance and has the potential to be abused and lead to drug dependence.

Please see accompanying Full Prescribing Information for FYCOMPA (perampanel), including Boxed WARNING.

About Eisai Inc.
At Eisai Inc., human health care (hhc) is our goal. We give our first thoughts to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to discover and develop innovative therapies to help address unmet medical needs.

Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Each group functions as an end-to-end global business with discovery, development, and marketing capabilities. Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Maryland and North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US. 

SOURCE Eisai Inc.