Eisai Presents New Seizure Freedom and Adherence Data Related to Anti-Epileptic Drug FYCOMPA® at the 2019 American Epilepsy Society Annual Meeting

WOODCLIFF LAKE, N.J., Dec. 9, 2019 /PRNewswire/ -- Eisai Inc. presented new seizure freedom and adherence data related to its antiepileptic drug (AED) FYCOMPA^® (perampanel) CIII at the 2019 American Epilepsy Society Annual Meeting in Baltimore. Of Eisai's 38 scientific posters about FYCOMPA, 23 included convulsive seizure freedom data underscoring Eisai's continued commitment to helping as many patients as possible achieve the ultimate goal of seizure freedom.

"The breadth of FYCOMPA data presented at the American Epilepsy Society Annual Meeting demonstrates Eisai's leadership and relentless commitment to researching advances in epilepsy care for a range of patients, including those with convulsive seizures and those who are newly diagnosed," said Lynn Kramer, M.D., Chief Clinical Officer, Neurology Business Group, Eisai. "This data provides important insights that we hope will help health care professionals as we work collectively toward the ultimate goal of seizure freedom."

Among the data presented were results from the FREEDOM Study, a Phase III open-label study conducted in Japan and South Korea that evaluated the efficacy and safety of FYCOMPA monotherapy in newly diagnosed patients with partial-onset seizures (POS). The primary endpoint was seizure freedom up to 26 weeks for patients with POS. A non-interventional, retrospective Phase IV study called PROVE assessed the retention rate, safety, efficacy, and dosing experience of FYCOMPA; and FAME, a post-hoc subgroup analysis of efficacy and safety data of FYCOMPA as first adjunctive therapy.

"I am excited to see additional encouraging results from the FYCOMPA FREEDOM Study," said James Wheless, MD, chair at the Division of Pediatric Neurology, Le Bonheur Children's Hospital, Memphis, Tennessee. "In this study, the majority of newly diagnosed patients taking FYCOMPA 4 and 8 mg per day were seizure free during the 26-week period."

Key Data:

• FREEDOM Study (Efficacy and Safety of Perampanel Monotherapy in Patients with Newly Diagnosed or Currently Untreated Recurrent Partial-Onset Seizures: Final Analysis of Study 342 (FREEDOM) 4 and 8 mg/day Core Data):
  Study 342 is a multicenter, uncontrolled, open-label, Phase III single-arm study conducted in Japan and South Korea. The study included 91 patients ≥12 years of age with newly diagnosed or untreated POS patients treated with FYCOMPA. Efficacy analyses were based on a modified intent-to-treat population of 73 patients that entered the maintenance period. The primary endpoint was seizure freedom rate for patients with partial-onset seizures at Week 26 maintenance period. During the 26-week maintenance period, seizure freedom rates were 64.6% (31/48; 95% CI: 49.5–77.8) and 77% (37/48; 95% CI: 62.7–88.0) of newly diagnosed POS patients with secondarily generalized seizures receiving FYCOMPA 4 mg/day and FYCOMPA 4 and 8 mg/day, respectively.
  
  
  The study consisted of a 4-week pre-treatment phase and a 32-week treatment phase (6-week titration period; 26-week maintenance period). The median baseline seizure frequency was two seizures per 12 weeks. During the titration period, patients were given FYCOMPA 2 mg/day for 2 weeks which was increased to 4 mg/day for 4 weeks. Patients who had no tolerability issues at the end of the titration period started the 4 mg/day maintenance period. Seizure freedom rates for POS was 63% in 46/73 patients (95% CI: 50.9–74.0) who received FYCOMPA 4 mg/day and 74% in 54/73 (95% CI: 62.4–83.5) patients who received FYCOMPA 4 and 8 mg/day combined. Of those patients who had secondarily generalized seizures, 31/48 (64.6%; 95% CI: 49.5–77.8) patients who received 4 mg/day and 37/48 (77.1%; 95% CI: 62.7–88.0) patients who received 4 and 8 mg/day combined were convulsive seizure free. Safety endpoints included monitoring treatment-emergent adverse events (TEAEs). The most common TEAEs in both the 4 mg/day and the 4 and 8 mg/day combined groups were dizziness (22.5% and 31.5%, respectively); nasopharyngitis (12.4% and 14.5%); somnolence (12.4% and 13.5%) and headache (11.2% and 11.2%). Limitations of this study include its open-label study design with no placebo control arm due to ethical concerns, no adjustment from multiplicity was included, and the data are descriptive.
  
  
• PROVE Study (Perampanel in Real-World Clinical Care of Patients with Epilepsy: Results from the Retrospective, Phase IV PROVE Study 506): 
  The PROVE study is a retrospective, multicenter, non-interventional Phase IV study assessing retention rate, safety, efficacy, and dosing experience of FYCOMPA administered to patients with epilepsy during routine clinical care. Following 24 months of FYCOMPA treatment during routine clinical care, 48% (501/1042) of patients remained on treatment; and 39.2% (20/51) of patients were seizure free during months 22–24.
  
  
  A total of 1703 patients were included in the Safety Analysis Set (SAS) and 328 were included in the Full Analysis Set (FAS). Of 1,703 patients in the SAS, 1,676 (98.4%) received perampanel as adjunctive therapy, 33 (1.9%) received perampanel as primary monotherapy, and 14 (0.8%) received perampanel as secondary monotherapy. The most common modal daily doses of perampanel received were 4 mg (n=332; 19.5%), 6 mg (n=299; 17.6%), 8 mg (n=272; 16.0%) and 2 mg (n=240; 14.1%). The primary endpoint was retention rate (percent of patients remaining on FYCOMPA at 3, 6, 12, 18, and 24 months following treatment initiation). Secondary efficacy endpoints assessed in the FAS, included median percent change in seizure frequency per 28 days from baseline; 50% and 75% responder rates and seizure-freedom rates (proportion of patients with a ≥50%, ≥75%, or 100% reduction, respectively, in seizure frequency per 28 days from baseline). At the end of the study, 868 (51.0%) patients were ongoing on FYCOMPA; 816 (47.9%) had discontinued. The most common reasons for discontinuation were adverse events (AEs; n=388 [22.8%]) and inadequate therapeutic effect (n=225; 13.2%). Following 24 months of FYCOMPA treatment during routine clinical care, 501/1042 (48.1%) patients remained on perampanel treatment. At months 22–24, median reduction in seizure frequency per 28 days from baseline was 89.4% (n=51); 50% responder rate was 76.5% (39/51), and 39.2% (20/51) of patients were seizure free. Treatment-emergent adverse events (TEAEs) were reported in 704 (41.3%) patients. Serious TEAEs were experienced by 79 (4.6%) patients, including 15 deaths. TEAEs leading to discontinuation of perampanel were reported in 414 (24.3%); the most common TEAES leading to discontinuation were aggression (n=53; 3.1%), irritability (n=52; 3.1%) and dizziness(n=45; 2.6%) The most common AEs were dizziness (n=125; 7.3%) and aggression (n=90; 5.3%); 704 (41.3%) patients had treatment emergent AEs (TEAEs) requiring dose adjustment. A limitation of this study was the low number of patients for efficacy outcomes at later time points, particularly during months 22 through 24 (n=21). In addition, selection bias due to the withdrawal for patients who do not respond well to perampanel, may result in increased responder rates and seizure freedom rates at later time points.
  
  
• FAME Study (Efficacy and Safety of Perampanel as First Adjunctive Therapy in Patients with Partial-Onset Seizures: Post Hoc Subgroup Analysis of the FAME Study by First-Line Antiepileptic Drug Use (Study 412): 
  Study 412, a multicenter, open-label, single-arm, Phase IV study conducted in South Korea, investigated the efficacy and safety of FYCOMPA as the first adjunctive therapy in patients ≥12 years with POS, with or without secondarily generalized seizures (SGS). The study consisted of an 8-week Screening Period (collection of informed consents and completion of baseline assessments), a 12-week Titration Period, and a 24-week Maintenance Period. 47% (40/85) of patients were seizure free requiring adjunctive therapy after failure to control POS with one AED. The 50% responder rate was 80% (68/85) and the 75% responder rate was 71.8% (61/85)
  
  
  A total of 106 patients were enrolled in the study. The FAS included 85 patients with POS, of whom 16 (18.8%) has SGS. The primary endpoint was the 50% responder rate (% of patients achieving a ≥50% reduction in seizure frequency from Baseline) during maintenance. Secondary endpoints included 75% responder rate (defined as the proportion of patients achieving a >75% reduction in seizure frequency from baseline), seizure-freedom rate (100% responder rate), and median percent change in seizure frequency per 28 days. All 85 patients received a concomitant AED, which may include levetiracetam, carbamazepine, oxcarbazepine, lamotrigine, valproic acid, topiramate and zonisamide. The safety analysis comprised all patients who received at least one dose of perampanel and were included in at least one safety assessment. Safety assessments included monitoring of TEAEs, adverse drug reactions, and serious AEs and TEAEs leading to discontinuation. Overall, 77 (75.5%) patients reported TEAEs, the majority of which were mild in severity. Regardless of baseline concomitant AED use, the most common TEAE was dizziness. Eight patients reported a serious adverse event (SAE); one SAE of suicidal ideation with FYCOMPA and levetiracetam was considered possibly related to treatment; all other SAEs were considered unrelated to treatment. Of 106 patients enrolled, the majority of patients completed the study (n=80/106; 75.5%). The primary reasons for discontinuation were AEs (n=14; 13.2%), patient's withdrawal of consent (n=4; 3.8%) major protocol violation (n=3; 2.8%), lost to follow up (n=2; 1.9%) and other (n=3; 2.8%).

This study is limited by the inclusion of only Korean patients, the open-label and non-randomized design, the absence of a comparator, and only a relatively small number of patients were included. However, this trial followed a comprehensive clinical development program that was conducted worldwide, with several other studies already indicating the efficacy and safety of perampanel in treatment-refractory patients.

In September 2018, FYCOMPA was approved for monotherapy and adjunctive use in pediatric patients four years and older for the treatment of POS with or without secondarily generalized seizures. FYCOMPA was first approved in 2012 for adjunctive use in partial-onset seizures (POS) in patients 12 years and older. In 2015, it was approved as adjunctive therapy for PGTC seizures in patients with epilepsy 12 years and older.

To date, FYCOMPA is approved in 55 countries and has been used to treat more than 200,000 patients worldwide across all indications.

INDICATION
FYCOMPA^® (perampanel) is indicated in patients with epilepsy aged 4 years and older for partial-onset seizures (POS) with or without secondarily generalized seizures and adjunctive therapy for patients aged 12 years and older for primary generalized tonic-clonic (PGTC) seizures.

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 aged 12 years and older 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. Adverse reactions in patients aged 4 to <12 years were generally similar to patients aged 12 years and older.

DRUG INTERACTIONS
FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel. Plasma levels of perampanel were decreased when administered with known 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 and withdrawal symptoms including anxiety, nervousness, irritability, fatigue, asthenia, mood swings, and insomnia.

Please see Prescribing Information for FYCOMPA.

About FYCOMPA 
FYCOMPA is a prescription medicine used in people with epilepsy aged 4 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 for people with epilepsy aged 12 and older.

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. In a pharmacokinetic study, it has been demonstrated that because of its long half-life, a missed dose of FYCOMPA does not significantly impact plasma levels.

FYCOMPA is supplied as 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg film-coated tablets, and as a 0.5 mg/mL 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.

About Epilepsy
Epilepsy is a medical condition that produces seizures affecting a variety of mental and physical functions. Epilepsy is one of the most common neurological disorders, which affects about 3.4 million people in the United States, including 470,000 children. Children with uncontrolled seizures are at greater risk for sudden unexpected death in epilepsy (SUDEP), which is relatively uncommon in childhood, but the risk increases if epilepsy persists into adulthood.

Partial-onset seizures are the most common type of seizure seen in people with epilepsy, accounting for 60 percent of all seizures. Convulsive seizures account for up to 25 percent of all epilepsy, with primary generalized tonic-clonic seizures being one of the most common and severe forms of seizures.

Missed medication doses are the number one cause of breakthrough seizures, which can cause significant injury to patients. People who experience breakthrough seizures have an increased risk of fractures or head injuries, emergency room (ER) visits, and hospitalization, as well as an associated increase in healthcare costs.

About Eisai Inc.

Eisai is a leading global research and development-based pharmaceutical company headquartered in Japan, with approximately 10,000 employees worldwide. We define our corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call our human health care (hhc) philosophy. We strive to realize our hhc philosophy by delivering innovative products in therapeutic areas with high unmet medical needs, including Oncology and Neurology. In the spirit of hhc, we take that commitment even further by applying our scientific expertise, clinical capabilities and patient insights to discover and develop innovative solutions that help address society's toughest unmet needs, including neglected tropical diseases and the Sustainable Development Goals.

For more information about Eisai, please visit www.eisai.com (for global), us.eisai.com (for U.S.) or www.eisai.co.uk (for U.K.), and connect with us on Twitter (U.S. and global) and LinkedIn (for U.S.).

Contact:
Media Inquiries
James Merse
Eisai Inc.
551-502-2710
James_Merse@eisai.com

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