WOODCLIFF LAKE, N.J., Dec. 7, 2021 /PRNewswire/ -- Eisai Inc. presented analyses of the ELEVATE study of its antiepileptic drug (AED) FYCOMPA® (perampanel) CIII at the 2021 American Epilepsy Society (AES) Annual Meeting. ELEVATE was a multicenter, open-label, Phase IV study of FYCOMPA as monotherapy or first adjunctive therapy in patients aged four years and older with focal- onset seizures (FOS) or generalized tonic-clonic seizures (GTCS). Retention rates (primary endpoint) were approximately 63% (n=34/54) for the overall patient population at 12 months, seizure freedom (secondary endpoint) was achieved in >30% of patients following 12 months of treatment, and a median percent reduction in seizure frequency (exploratory endpoint) was 77.9% (n=47) per 28 days.
A total of 48 (88.9%) patients experienced at least one treatment-emergent adverse event (TEAE) in the overall group, 8 (80.0%) patients experienced at least one TEAE in the monotherapy group, and 40 (90.9%) patients experienced at least one TEAE in the first adjunctive therapy group. Four (7.4%) patients had serious TEAEs (monotherapy group, n=1; first adjunctive therapy group, n=3). The most common TEAEs were dizziness (27.8% [n=15/54] in the overall population; 10.0% [n=1/10] in the FYCOMPA monotherapy group; 31.8% [n=14/44] in the FYCOMPA first adjunctive therapy group) and fatigue (16.7% [n=9/54] in the overall population; 30.0% [n=3/10] in the FYCOMPA monotherapy group; 13.6% [n=6/44] in the FYCOMPA first adjunctive therapy group).
An exploratory assessment of ELEVATE (study 410) included 54 patients treated with FYCOMPA as monotherapy or first add-on therapy in patients aged four years and older with epilepsy assessing quality of life, sleep quality, cognition, and severity of depression.
In the final analysis, 54 patients were included in the Safety Analysis Set, 32 (59.3%) patients completed the study and 22 (40.7%) of patients discontinued; the primary reasons were adverse events (n=10/54), other (n=5/54), lost to follow-up (n=3/54), and patient choice (n=3/54).
"Results from these analyses show the efficacy and tolerability of FYCOMPA monotherapy as an early add-on therapy and explore quality of life considerations which can present significant challenges for people living with epilepsy," said Manoj Malhotra, Vice President, Head of Medical Affairs for the Neurology Business Group at Eisai Inc. and the lead study investigator. "These data give us more insight into how FYCOMPA may be associated with higher rates of adherence and reductions in the number of seizures."
"Our commitment to human health care is well represented in the breadth of data shared at the 2021 American Epilepsy Society Meeting," said Ivan Cheung, Chairman, Eisai Inc. and Global President, Neurology Business Group, Eisai Co., Ltd. "We're excited to not only further our understanding of the patient experience with FYCOMPA, but to also see encouraging results across a diverse set of patients that can impact overall care."
Key data presented:
This study is prospective, has an open-label and non-randomized design, an absence of a comparator, and only a relatively small number of patients were included.
Poster presentation number: # 3.270
Poster session: Monday, December 6, 12:00 p.m. to 1:45 p.m. CST
ELEVATE Study 410: Phase IV Study of Perampanel as Monotherapy or First Adjunctive Therapy in Patients Aged ≥ 4 Years with Focal-Onset Seizures (FOS) or Generalized Tonic-Clonic Seizures (GTCS)
Summary: The open-label, multicenter study consisted of screening, titration (≤ 13 weeks), maintenance (39 weeks), and follow-up (4 weeks) periods. During titration patients received FYCOMPA 2 mg/day, which was titrated to 4 mg/day (further dose increases of 2 mg were administered based on response and tolerability up to a maximum of 12 mg/day). Dose increases were ≥ 2 weeks for patients taking a non- enzyme-inducing anti-seizure medication (EIASM) and weekly for those taking an EIASM. The primary endpoint was retention rate at 3, 6, 9, and 12 months. A secondary endpoint included seizure freedom rate (during the maintenance period). Exploratory endpoints (maintenance period) included median percent reduction in seizure frequency at 28 days relative to baseline, and 50% and 75% responder rates.
Retention rates were approximately 63% for the overall population at 12 months with a median percent reduction in FOS frequency of 76.1%, and GTCS frequency of 100% per 28 days from baseline. The total retention rate in the overall population was 85.2% (n=46/54) at 3 months, 68.5% (n=37/54) at 6 months, 63.0% (n=34/54) at 9 months, and 63.0% (n=34/54) at 12 months (or study completion). In the overall patient population, seizure freedom was achieved by 32.7% (n=17/52) of patients. Reductions in seizure frequency were observed in the overall population, as well as in patients receiving FYCOMPA as monotherapy or as first adjunctive therapy. Seizure freedom rates in three patients with FOS in the FYCOMPA monotherapy group were 37.5% (observed), and a ≥ 50% reduction in seizure frequency for all four evaluable patients with FOS (100.0%) were shown in the last observation carried forward (LOCF).
In the final analysis, 54 patients were included in the Safety Analysis Set (FOS, n=38 [including the subset with focal to bilateral tonic-clonic seizures (FBTCS), n=9]; GTCS, n=11; FOS+GTCS, n=5) and 52 were included in the Full Analysis Set (FOS, n=37 [including the subset with FBTCS, n=9]; GTCS, n=11; FOS+GTCS, n=4). Of these, 32 (59.3%) patients completed the study and 22 (40.7%) discontinued. The primary reasons for discontinuation included adverse events (AEs; 18.5% [n=10/54]), other (9.3% [n=5/54]), lost to follow-up (5.6% [n=3/54]), and patient choice (5.6% [n=3/54]).
A total of 48 (88.9%) patients experienced at least one TEAE in the overall group, 8 (80.0%) patients experienced at least one TEAE in the monotherapy group, and 40 (90.9%) patients experienced at least one TEAE in the first adjunctive therapy group. Four (7.4%) patients had serious TEAEs (monotherapy group, n=1; first adjunctive therapy group, n=3). The most common TEAEs were dizziness (27.8% [n=15/54] in the overall population; 10.0% [n=1/10] in the FYCOMPA monotherapy group; 31.8% [n=14/44] in the FYCOMPA first adjunctive therapy group) and fatigue (16.7% [n=9/54] in the overall population; 30.0% [n=3/10] in the FYCOMPA monotherapy group; 13.6% [n=6/44] in the FYCOMPA first adjunctive therapy group).
Poster presentation number: # V.065
Poster session: Thursday, December 9, 4:00 p.m. to 5:00 p.m. CST
ELEVATE Study 410: Phase IV Study of Perampanel as Monotherapy or First Adjunctive Therapy in Patients Aged ≥ 4 Years with Epilepsy: Quality of Life and Sleep Results
Summary: This analysis of the 12-month, multicenter, open-label ELEVATE study consisted of a screening period, a titration period (≤ 13 weeks), a maintenance period (39 weeks), and a 4-week follow- up. During titration, patients received FYCOMPA 2 mg/day, which was titrated to 4 mg/day, with further dose increases of 2 mg allowed based on response and tolerability, up to a maximum of 12 mg/day. Dose increases were ≥ 2 weeks for patients taking a non-enzyme-inducing anti-seizure medication (EIASM) and weekly for those taking an EIASM. The primary endpoint was retention rate at 3, 6, 9, and 12 months.
Exploratory endpoints included change in patient-reported quality of life via the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) and change in subjective sleep quality via the Pittsburgh Sleep Quality Index (PSQI) at the end of the maintenance period (12 months) relative to baseline.
The mean (standard deviation) change from baseline in overall QOLIE-31 score at the end of maintenance (12 months) was +1.7 (10) for patients with FOS and +7.0 (6.4) for patients with GTCS. Across the seven QOLIE-31 subdomains, a minimum clinically important change at group level (>11.8) from baseline was only seen in patients with GTCS (in this case all changes were an improvement) for overall quality of life. The mean (SD) change was +18.1 (18.2), medication effects +32.0 (25.4), and social function +14.3 (24.5). The mean (SD) change in the Pittsburgh Sleep Quality Index (PSQI) global score was -0.3 (3.9) for patients with FOS (n=23) and -0.2 (4.2) for patients with GTCS (n=6).
Overall, in this final analysis, 54 patients were included in the Safety Analysis Set (FOS, n=38 [including the subset with FBTCS, n=9]; GTCS, n=11; FOS+GTCS, n=5). Of these, 32 (59.3%) patients completed the study and 22 (40.7%) discontinued. The primary reasons for discontinuation included adverse events (AEs; 18.5% [n=10/54]), other (9.3% [n=5/54]), lost to follow-up (5.6% [n=3/54]), and patient choice (5.6% [n=3/54]).
Poster presentation number: # 2.208
Poster session: Thursday, December 9, 10:00 a.m. to 11:00 a.m. CST
Assessment of Cognition (EpiTrack®) and Depression (Beck Depression Inventory-II) Following Perampanel (Monotherapy/First Adjunctive) in Patients with Epilepsy Enrolled in the ELEVATE Phase IV Study
Summary: This analysis of the 12-month, multicenter, open-label ELEVATE study consisted of a screening period, a titration period (≤ 13 weeks), a maintenance period (39 weeks), and a 4-week follow- up. Patients received FYCOMPA 2 mg/day, which was titrated to 4 mg/day, with further dose increases (of 2 mg) allowed based on response and tolerability, up to a maximum of 12 mg/day. Dose increases were ≥ 2 weeks apart for patients taking a non-enzyme-inducing anti-seizure medication (EIASM) and weekly for those taking an EIASM. Cognition and depression were exploratory objectives − cognition was assessed using EpiTrack® for patients >/= 16 years or EpiTrack Junior screening tool (6 to <16 years) and depression using the BDI-II (patients ≥ 16 years of age who had completed EpiTrack® assessment) at baseline, and 3 and 12 months. BDI-II was used to aid interpretation of cognition score.
The mean (standard deviation [SD]) change from baseline in EpiTrack® report total score at 12 month (n=12) was -0.4 (3.3), and then list by seizure types: FOS and GTCS was -0.6 (3.3) for FOS patients and +1.6 (1.7) for GTCS patients (increase = improvement). Five patients with FOS had an improved shift and two a worsening shift from their baseline EpiTrack® category at 12 months (improved: average to excellent, n=1; mildly impaired to average, n=3; significantly impaired to mildly impaired, n=1; worsening: excellent to mildly impaired, n=1; average to mildly impaired, n=5). No shifts for patients with GTCS were observed. The mean (SD) change from baseline in BDI-II total score at 12 months was -1.8 (8.0) for FOS patients and +2.8 (8.3) for GTCS patients (increase = worsening). Overall, five patients (all FOS [with FBTCS, n=1]) had an improved shift and two patients (all FOS; improved: moderate to minimal, n=2 (both FOS); and mild to minimal, n=2 (FOS) and n=1 (FOS+GTCS) had a worsening shift in depression severity category from their baseline BDI-II score following 12 months of FYCOMPA treatment (improved: average to excellent, n=1 (FOS); mildly impaired to average, n=3 (all FOS [with FBTCS, n=1]); and significantly impaired to mildly impaired, n=1 (FOS); worsening: excellent to mildly impaired, n=1 (FOS); and average to mildly impaired, n=5 (all FOS).
Among the 54 patients included in the Safety Analysis Set, 32 (59.3%) patients completed the study and 22 (40.7%) discontinued. The primary reasons for discontinuation included adverse events (18.5%), other (9.3%), lost to follow-up (5.6%), and patient choice (5.6%).
Overall, in this final analysis, 54 patients were included in the Safety Analysis Set (FOS, n=38 [including the subset with FBTCS, n=9]; GTCS, n=11; FOS+GTCS, n=5). Of these, 32 (59.3%) patients completed the study and 22 (40.7%) discontinued. The primary reasons for discontinuation included adverse events (AEs; 18.5% [n=10/54]), other (9.3% [n=5/54]), lost to follow-up (5.6% [n=3/54]), and patient choice (5.6% [n=3/54]).
INDICATION FOR FYCOMPA
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 FOR FYCOMPA
WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS |
• Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA |
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. Patients should be carefully observed for signs of central nervous system (CNS) depression when FYCOMPA is used with other drugs with sedative properties because of potential additive effects.
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. 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 full Prescribing Information, including Boxed WARNING.
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). To date, FYCOMPA has been approved in more than 70 countries and territories and has been used to treat more than 410,000 patients worldwide across all indications.
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 47,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
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.).
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