Exploring Convulsive Seizure Freedom and Other Endpoints with an Antiseizure Medication: A Focus on Early Use

 

[Music] 

 

Hello, I’m Dr Matthew Holtzman, a neurologist in private practice in Michigan. I’ve been treating patients with epilepsy for many years. 

 

Today I’m going to review some data for FYCOMPA with respect to convulsive seizure freedom and other important clinical endpoints, with a focus on how early use of FYCOMPA may help give patients the seizure control they need. 

 

First let’s look at some of the risk factors for and consequences of uncontrolled convulsive seizures. 

 

There are a number of risk factors associated with the development of uncontrolled convulsive seizures in patients with epilepsy. 

 

Some risk factors are potentially modifiable. They include: 

 

Nonadherence to antiseizure medicine (or ASM).1 Importantly, the most common cause of breakthrough seizures is noncompliance. 

 

And side effects with any ASM. 

 

Other risk factors are not modifiable. They include age at onset <13 years, history of status epilepticus, and generalized epileptiform activity. 

 

Uncontrolled convulsive seizures may have significant clinical consequences for these patients, such as: 

 

SUDEP, sudden unexpected death in epilepsy: A systemic review of the risk factors for epilepsy found that the presence of generalized tonic-clonic (or GTC) seizures results in a 10 times greater risk for SUDEP. 

 

Cognition: In a retrospective analysis of 136 patients, significant correlations were found between the average annual frequency of GTC seizures during the interest interval and declines in verbal and performance intelligence quotient (or IQ). Significant associations also were found between GTC seizure frequency and verbal learning, delayed verbal recall, naming, and semantic fluency. 

 

Injury: 306 consecutive patients with epilepsy were systemically assessed for seizure-related injuries; tonic-clonic seizures were associated with a 3.2 times greater risk for seizure-related injuries. 

 

Mortality: A study of 1,091 patients in the United Kingdom found that tonic-clonic seizures significantly increased risk for mortality associated with idiopathic causes. 

 

Now let’s turn the discussion to FYCOMPA. 

 

FYCOMPA is indicated in patients with epilepsy aged 4 years and older for partial-onset seizures with or without secondarily generalized seizures. 

 

FYCOMPA is also indicated as adjunctive therapy for patients aged 12 years and older for primary generalized tonic-clonic seizures. 

 

Please see Important Safety Information within and full Prescribing Information, including Boxed WARNING. 

 

Let’s take a look at that Boxed WARNING. 

FYCOMPA has a Boxed WARNING for 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, irrespective of prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression 

 

Monitor patients for these reactions as well as for changes in mood, behavior, or personality that are not typical for the patient, particularly during the titration period and at higher doses 

 

FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening. 

 

The objectives for today’s presentation are to: 

Understand FYCOMPA’s use across convulsive and nonconvulsive partial-onset seizures and primary generalized tonic-clonic seizures 

 

Review seizure frequency reduction and convulsive seizure freedom data for FYCOMPA in patients with partial-onset seizures, including convulsive seizures, as: 

• Adjunctive therapy in patients whose epilepsy was uncontrolled despite treatment with 1 to 3 antiseizure medications (which we will refer to here as ASMs) 

• First adjunctive therapy after ASM monotherapy failure, and 

• Monotherapy in newly diagnosed or untreated patients 

 

Review seizure frequency reduction and convulsive seizure freedom data for FYCOMPA in patients with primary generalized tonic-clonic (or PGTC) seizures. 

 

Review Important Safety Information, including the Boxed WARNING for FYCOMPA for Serious Psychiatric and Behavioral Reactions, and examine the dosing and pharmacokinetics of FYCOMPA. 

 

In the United States, FYCOMPA was first approved in October 2012 as adjunctive therapy for the treatment of partial-onset seizures. 

 

Since then, FYCOMPA has been approved as adjunctive treatment for patients with PGTC seizures, as monotherapy for patients with partial-onset seizures (based on an extrapolation of data from 3 partial-onset seizures pivotal trials), and for partial-onset seizures in pediatric patients as young as 4 years old. 

 

In 2016, an oral suspension of FYCOMPA was approved. 

 

Numerous notable studies of FYCOMPA have been published since, including a study of its long-term effects on cognition in adolescents, a study of FYCOMPA as a first add-on for partial-onset seizures, an assessment of FYCOMPA monotherapy for partial-onset seizures, a pooled analysis of the effectiveness and tolerability of FYCOMPA, and a retrospective, noninterventional study of FYCOMPA in the real-world clinic. 

 

Worldwide, perampanel has been prescribed for more than 500,000 patients across different indications (through December 2021). In the United States, over 50,000 patients have been prescribed perampanel. 

 

It is a well-studied medication, with more than 100 global studies either published or ongoing and 11+ years of clinical experience. 

 

It is available in 2 formulations: tablet and oral suspension. 

 

Perampanel has been approved in 72 countries across different indications. 

 

FYCOMPA has a unique mechanism of action and is the first and only noncompetitive AMPA receptor antagonist. 

 

Glutamate is the primary neurotransmitter regulating excitatory synaptic transmission in the brain, and FYCOMPA is the only ASM with AMPA glutamate receptor activity as its therapeutic target. 

 

Note that the precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans is unknown. 

 

FYCOMPA is specifically engineered to block glutamate activity at postsynaptic AMPA receptors. It potentially targets hyperexcitatory neurotransmission by inhibiting AMPA glutamate receptor activity. 

Before we look at some data on FYCOMPA in the first adjunctive and newly diagnosed settings, I’d like to summarize the original randomized, controlled, pivotal trials that led to FYCOMPA’s initial approval for partial-onset seizures. 

 

There have been 3 randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of FYCOMPA for partial-onset seizures. The 3 trials were identical in design, apart from the doses studied and the study sites. 

 

Included in the intention-to-treat (or ITT) population were 1478 patients aged 12 years or older who experienced at least 5 seizures over the 6-week baseline period. Patients had inadequate seizure control and were receiving 1 to 3 concomitant antiseizure medications. 

 

Patients in these studies had a mean duration of epilepsy of approximately 21 years and a median baseline seizure frequency of 9 to 14 seizures per 28 days. 

 

There were 6 different ASMs used during the trial by at least 10% of the total safety population of the 3 trials, with carbamazepine, valproic acid, and lamotrigine received by approximately one-third of patients. 

 

More than 85% of patients were taking 2 to 3 ASMs, with approximately 50% on at least 1 inducer ASM. 

 

ASMs known to be significant inducers of FYCOMPA clearance are carbamazepine, oxcarbazepine, and phenytoin. 

 

Concomitant ASMs received by at least 10% of patients in the total safety population included: carbamazepine, 33%; valproic acid 32%; lamotrigine, 31%; levetiracetam, 29%; topiramate, 20%; and oxcarbazepine, 18%. 

 

Studies 1 and 2 compared 8-mg and 12-mg once-daily doses of FYCOMPA to placebo, while Study 3 compared 2-mg, 4-mg, and 8-mg doses to placebo. 

 

In these studies, only patients experiencing intolerable adverse reactions were permitted a dose reduction.1 

This graph shows reduction in seizure frequency from the ITT analysis set. 

 

FYCOMPA achieved significant reductions in partial-onset seizure frequency at doses of 4 mg/day and higher. 

 

The primary endpoint in all 3 phase 3 partial-onset seizure clinical trials was percent change in seizure frequency per 28 days during the treatment period as compared to the baseline period. 

 

The total treatment period was 19 weeks (6 titration; 13 maintenance). 

 

Patients had more than 5 partial-onset seizures during the 6-week baseline period. 

 

Median baseline partial-onset seizure frequency ranged from 9 to 14 per 28 days. 

 

A statistically significant decrease in seizure rate was observed at doses of 4 to 12 mg per day. 

 

Dose response was apparent at 4 mg to 8 mg with little additional reduction in frequency at 12 mg/day. 

 

A dose of 12 mg once daily resulted in somewhat greater reductions in seizure frequency than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. 

 

FYCOMPA achieved reductions in partial-onset seizure frequency with enzyme-inducer and non–enzyme-inducer ASMs. 

 

Combined data for reductions in seizure frequency from the 3 phase 3 partial-onset seizure clinical trials were also assessed by presence or absence of enzyme-inducing ASMs. 

 

In partial-onset seizures, FYCOMPA achieved seizure frequency reduction with inducer and non-inducer ASMs. 

 

In patients not on enzyme-inducing ASMs, median seizure reductions of 23%, 22%, 45%, and 54% were observed at the 2-, 4-, 8-, and 12-mg/day doses of FYCOMPA, compared with 16%, 16%, 19%, and 19% reductions in patients on the corresponding doses of placebo.

 

In patients on enzyme-inducing ASMs, median seizure reductions of 16%, 33%, 24%, and 22% were observed at the 2-, 4-, 8-, and 12-mg/day doses of FYCOMPA, compared with 14%, 14%, 12%, and 9% reductions in patients on the corresponding doses of placebo.

 

Up to 54% of patients experienced a 50% or greater reduction in partial-onset seizure frequency. 

 

A key secondary endpoint in all 3 phase 3 partial-onset seizure clinical trials was 50% responder rate, or the proportion of patients with at least 50% reduction in partial-onset seizure frequency. 

 

The combined data for the secondary endpoint for all 3 clinical trials was assessed by presence or absence of enzyme-inducing ASMs. 

 

In patients not receiving enzyme-inducing ASMs, up to 54% of patients on FYCOMPA experienced a 50% or greater reduction in partial-onset seizure frequency. 

 

In patients receiving enzyme-inducing ASMs, one-third of patients on FYCOMPA experienced a 50% or greater reduction in partial-onset seizure frequency. 

 

Patients with a ≥50% reduction in seizure frequency included 19% for placebo, 29% for 4 mg, 35% for 8 mg, and 35% for 12 mg.

 

Patients with secondarily generalized (or SG) seizures experienced up to a 75% frequency reduction in SG seizures with FYCOMPA. 

 

A prespecified exploratory endpoint (subgroup analysis) was reduction in SG seizures among the patients in the 3 phase 3 partial-onset seizure clinical trials who experienced this seizure type during the baseline period (a total of 564 patients). 

 

The analysis was not powered to show statistical significance of this prespecified exploratory endpoint. 

 

The outcome of this analysis shows a median reduction in seizure frequency ranging from 49% to 75% among patients with SG seizures receiving FYCOMPA at 4-mg, 8-mg, or 12-mg doses during the 13-week maintenance phase. 

 

This finding may be compared to that in patients receiving placebo, who experienced reductions ranging from 7% to 36%. 

 

The median baseline seizure frequency for SG seizures for these trials ranged between 3 to 4 per 28 days. 

 

A post hoc exploratory analysis was conducted to determine SG seizure freedom during the maintenance phase among patients who experienced this seizure type during baseline and completed the maintenance phase (N=489). 

 

Up to 36% of patients receiving FYCOMPA experienced SG seizure freedom during the maintenance period. 

 

As a reminder, these were patients who had inadequate seizure control and were receiving 1 to 3 concomitant ASMs. 

 

This was a post hoc exploratory endpoint that was not adjusted for multiple comparisons and not adequately powered to show statistical significance or support efficacy conclusions of treatment effect. 

 

The analysis included patients who experienced this seizure type during the baseline period. Seizure freedom was assessed during the maintenance period in patients who completed the phase 3 clinical trials’ maintenance phase. 

 

There were 1,038 patients in the partial-onset seizures trials who received FYCOMPA at doses of 2, 4, 8, or 12 mg once daily (the safety population). 

 

The table shows adverse reactions occurring in at least 5% of partial-onset seizure patients on FYCOMPA 8 or 12 mg and at least 1% higher frequency than in the placebo group. 

 

Dysarthria, anxiety, blurred vision, gait disturbance, weight gain, cough, upper respiratory tract infection and vomiting were all reported in at least 4% of patients receiving FYCOMPA 4, 8, or 12 mg and at least 1% higher frequency than in the placebo group. 

 

Most of these adverse reactions were dose related. Note that common side effects that occur with FYCOMPA are less frequent at the 4-mg dose compared with the 8-mg and 12-mg doses. 

 

The following adverse reactions were dose-related and occurred mostly during the titration phase: dizziness and disturbance in gait or coordination (including ataxia, gait disturbance, balance disorder, and abnormal coordination), somnolence, and fatigue-related events (including fatigue, asthenia, and lethargy). 

 

For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation. 

 

During the partial-onset seizure trials, discontinuations as a result of adverse reactions occurred in a dose-dependent fashion for the 4-, 8-, and 12-mg/day doses. 

 

The rate of discontinuation was highest among patients on the 12-mg/day dose, at 19%, and the rates for patients on 4- and 8-mg/day were 3% and 8%, respectively, compared to 5% for patients on placebo.1 

 

Dizziness and disturbance in gait or coordination led to discontinuation in 3% of FYCOMPA-treated patients vs 1% of placebo-treated patients. Somnolence or fatigue-related events led to discontinuation in 2% of FYCOMPA-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and pediatric patients. 

 

This section of the presentation will review the efficacy and safety data for FYCOMPA from 2 postapproval studies in patients 12 years of age and older with partial-onset seizures. 

 

The FAME study (Study 412) examined the use of FYCOMPA as first adjunctive therapy after monotherapy failure in patients aged 12 years and older with partial-onset seizures (with or without SG tonic-clonic seizures). 

 

A majority of patients received FYCOMPA 4 mg or 6 mg (82%), with more than half receiving 4 mg (51%). Note that final doses depended on clinical response and tolerability.

 

Remember that the FYCOMPA pivotal studies evaluated 8 mg and 12 mg (Studies 1 and 22,3) or 2 mg, 4 mg, and 8 mg (Study 34). 

 

The FREEDOM study (Study 342) evaluated the use of FYCOMPA as monotherapy in newly diagnosed or untreated patients with partial-onset seizures in patients aged 12 years and older. 

 

Eighty-nine patients were treated (in the ITT population). 

 

Seventy-three patients entered the 4-mg maintenance period (the modified or mITT population.) 

 

A majority of patients received FYCOMPA 4 mg (76%).5 Patients who were not controlled on the 4-mg dose were titrated to 8 mg daily (29%). 

 

The FAME study was a 24-week, multicenter, open-label, phase 4 prospective study of FYCOMPA as first adjunctive therapy after ASM monotherapy failure in patients aged 12 years and older with partial-onset seizures, with or without SG tonic-clonic seizures. 

 

There were 2 treatment periods in the FAME study (Titration and Maintenance) after subjects’ screening. 

 

For monotherapy to be considered to have “failed” during the 8-week Screening Period, patients had to have experienced a minimum of 2 partial-onset seizures at least 24 hours apart while taking ASM monotherapy administered at a stable dose. 

 

Patients whose seizures were not controlled with monotherapy were then started on FYCOMPA 2 mg/day once daily at bedtime. 

 

Throughout the 12-week Titration Period, the daily FYCOMPA dose was increased incrementally by 2 mg/day at intervals of at least 2 weeks and titrated up or down depending on clinical response and tolerability. 

 

Patients then took a maintenance dose ranging from 4 mg/day to 12 mg/day throughout the entire 24-week Maintenance Period, with the final dose again dependent on clinical response and tolerability.1 

 

The primary endpoint for the FAME study was the 50% responder rate for partial-onset seizures. 

 

Secondary endpoints included 75% and 100% responder rates for partial-onset seizures, as well as 50%, 75%, and 100% responder rates for SG tonic-clonic seizures (convulsive seizures). 

 

Treatment-emergent adverse events, withdrawal from treatment, and clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis) were also assessed. 

 

Before we review the results, please note that this study was open-label and did not include a control arm. Appropriate multiplicity adjustments were not applied, and this information is only descriptive in nature. In addition, please note that the study included a relatively small number of patients. 

 

Now let’s look at efficacy in the FAME study. Among the 85 patients in the full analysis set, 80% achieved a reduction in partial-onset seizures of at least 50%—the primary endpoint for the study.2 

 

More than 70% achieved a reduction of 75% or more, and nearly half of patients, 47%, experienced seizure freedom. 

 

For SG tonic-clonic seizures (or convulsive seizures), out of the 16 patients with such seizures, 87.5% achieved a reduction of at least 50% in convulsive seizure frequency. 

 

This same proportion of patients achieved a reduction of at least 75%, and three-quarters of patients experienced convulsive seizure freedom at 6 months. These convulsive seizure patients experienced seizure freedom at a final dose of 4 mg or 6 mg. 

 

The majority of patients in the study received a final maintenance dose of 4 mg or 6 mg, with 15 of 85 patients receiving a dose of 8 mg or higher. 

 

Of the 102 patients in the FAME study’s safety set, 77 (or 75.5%) reported treatment-emergent adverse events. 

 

The most common treatment-emergent adverse events were dizziness (50%; n=51), somnolence (9.8%; n=10), and headache (8.8%; n=9). 

 

Twenty-six patients discontinued treatment: 14 as a result of an adverse event, 4 due to withdrawal of consent, 3 because of a major protocol violation, 2 lost to follow-up, and 3 for some other reason. 

 

Now we’re going to look at the FREEDOM study. 

 

Note again that the initial approval of FYCOMPA for partial-onset seizures, with or without secondary generalization, was based on 3 trials in patients not controlled with 1 to 3 concomitant antiseizure medications. 

 

Based on an extrapolation of data from these 3 trials, the FYCOMPA indication was expanded to include monotherapy use in patients with partial-onset seizures. 

 

The FREEDOM study was a multicenter, uncontrolled, open-label study of FYCOMPA monotherapy in newly diagnosed or untreated patients with partial-onset seizures with or without secondary generalization. 

 

 

 

The primary study objective was to evaluate the seizure-freedom rate during a 26-week maintenance period of the study. 

 

The study was conducted at 31 sites in Japan and 7 sites in Korea. All patients were aged between 12 and 74 years and had a clinical diagnosis of epilepsy with partial-onset seizures with or without SG seizures. 

 

In all, 91 patients entered the study, and 89 received at least 1 dose of FYCOMPA in the ITT/safety analysis set. 

 

All patients presented with at least 1 of the following seizure types1: 

• Simple partial seizures (16%)
• Complex partial seizures (61%), and
• Complex partial-onset seizures with secondary generalization (64%)

 

Diagnosis was established by clinical history and an electroencephalogram that was consistent with localization-related epilepsy; normal interictal EEGs were allowed provided that the subject met other diagnosis criteria. 

 

The mITT set (n=73) was the subset of patients in the ITT population (N=89) who entered the 4-mg maintenance period and had at least 1 post-dose primary efficacy measurement in the 26-week maintenance period. 

 

Of the 73 patients in the mITT set, 96% (n=70) were newly diagnosed with epilepsy. 

 

These patients had a median baseline seizure frequency of 2 seizures per 12 weeks. 

 

During the 28-day pretreatment phase, all patients were screened and assessed for study eligibility. 

 

The treatment phase consisted of a 6-week titration period and a 26-week maintenance period. During the 6-week titration period, patients initiated FYCOMPA 2 mg once daily for 2 weeks, and then were uptitrated to FYCOMPA 4 mg once daily for 4 weeks. 

 

If no safety issues were noted at the end of the 6-week titration period, patients entered the 26-week 4-mg maintenance phase. 

 

If a patient experienced a seizure during the 26-week, 4-mg maintenance phase, the patient was titrated to FYCOMPA 6 mg once daily for 2 weeks, followed by 8 mg once daily at the discretion of the investigator. 

This graph illustrates the rates of seizure freedom at the end of the 26-week maintenance period for patients maintained on the FYCOMPA 4-mg dose. 

 

Seventy-three patients entered the 26-week 4-mg maintenance period of the treatment phase. Of the 73 patients with partial-onset seizures who entered the 26-week maintenance period, 63% (n=46) were seizure free on 4 mg at week 26. 

 

Twenty-one patients were not controlled on 4 mg and were titrated up to 8 mg/day. 

 

At baseline, 48 patients who entered the 26-week 4-mg maintenance period had partial-onset seizures with secondary generalization. Of these 48 patients, nearly two-thirds (65%; n=31) were free from convulsive seizures at week 26 of the maintenance period at a dose of FYCOMPA 4 mg. 

 

This study has some limitations. The study design was open-label and did not include a control arm; appropriate multiplicity adjustments were not applied, and the information is descriptive. 

 

The table shows adverse reactions reported during the treatment phase of the FREEDOM study occurring in ≥5% of patients receiving FYCOMPA 4 mg/day (the safety analysis set). 

 

Dizziness was the most frequent adverse reaction,1 reported in 26.5% of patients receiving FYCOMPA 4 mg/day. 

 

Additional adverse reactions reported in ≥5% of patients receiving FYCOMPA 4 mg included somnolence (13.2%), nasopharyngitis (13.2%), and headache (10.3%). 

 

Psychiatric disorders at 4 mg/day included: 

• Irritability (2.9%)
• Affect lability (1.5%)
• Depression (1.5%), and
• Insomnia (1.5%)

 

In all, 16 patients (~18%) discontinued during the 4-mg titration phase, and 6 (~7%) discontinued during the maintenance phase, for a total of 22 patients or 24.7%. 

 

Reasons for discontinuation included adverse events; subject choice (in the maintenance phase only); inadequate therapeutic effect; lost to follow-up; withdrawal of consent; compliance; history of polytherapy; and incorrect titration (in the titration phase only). 

 

In this section I’ll review the efficacy and safety data for FYCOMPA from the phase 3 pivotal clinical trial in patients 12 years of age and older with PGTC seizures. 

 

FYCOMPA is approved for use as adjunctive therapy in this patient population. This approval was based on results from a multicenter, randomized, double-blind, placebo-controlled clinical trial. 

 

There has been 1 randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial of FYCOMPA for PGTC seizures1 (noted as Study 4 in the FYCOMPA Prescribing Information2). 

 

The phase 3 PGTC seizure trial consisted of pre-randomization with a screening phase of up to 4 weeks and a baseline period of 4 or 8 weeks, followed by a double-blind phase that totaled 17 weeks.1 

 

Of the 307 total patients screened, there were 164 adolescent and adult patients (82 FYCOMPA patients and 82 placebo patients) aged 12 years and older who were eligible to continue in the trial, with 143 failing screening. 

 

In all, 162 patients were included in the ITT analysis. 

 

Patients had at least 3 baseline PGTC seizures and were on a stable dose of 1 to 3 concomitant ASMs1; 17% of patients were receiving enzyme-inducing ASMs, specifically carbamazepine, oxcarbazepine, or phenytoin. 

 

Concomitant ASMs received by at least 10% of patients in the safety population included valproic acid, 43%); lamotrigine, 39%; levetiracetam, 31%; topiramate, 15%; and zonisamide, 12%. 

 

Patients were titrated over 4 weeks up to a dose of 8 mg/day or the highest tolerated dose and treated for an additional 13 weeks on the last dose level achieved at the end of the titration period; study drug was given once per day. 

 

The primary endpoint of the phase 3 PGTC seizure clinical trial was median reduction in seizure frequency per 28 days. 

 

The outcome for the primary endpoint showed a 76% PGTC seizure frequency reduction for patients treated with FYCOMPA compared to 38% for placebo-treated patients, a difference that was highly statistically significant. 

 

The secondary endpoint was percentage of patients experiencing at least a 50% reduction in PGTC seizure frequency during the maintenance phase of the trial compared to the baseline phase. 

 

Outcomes for the secondary endpoint showed that 64% of patients achieved a 50% or greater reduction in seizure frequency in the FYCOMPA group compared to 40% of patients in the placebo group. 

 

When we look at the data for changes in PGTC seizure frequency during the maintenance phase of the trial, we can see that the large majority of patients experienced improvements. Nearly half of all FYCOMPA-treated patients (48%) experienced a reduction in PGTC seizure frequency ranging from 75% to 100%, compared to 24% of those receiving placebo. 

 

Seizure frequency increased in 10% of patients receiving FYCOMPA (n=8) and in 28% of patients receiving placebo (n=23). 

 

The design of Study 332 also prespecified an exploratory endpoint of percent of patients who achieved PGTC seizure freedom during the maintenance period. 

 

Thirty-one percent of patients receiving FYCOMPA experienced PGTC seizure freedom during the 13-week maintenance period compared to 12% in the placebo group. 

 

Note that no adjustments were made for multiple comparisons. 

 

In the PGTC seizure trial safety analysis set, 81 patients received at least 1 dose of FYCOMPA. 

 

The most incidences of adverse reactions were highest among patients randomized to FYCOMPA 8 mg. As shown here, specific adverse reactions were considered most common if they occurred in at least 5% of patients receiving FYCOMPA and more frequently than in those receiving placebo. 

 

Additional common adverse events occurring in ≥4% of patients and more frequently than placebo included: urinary tract infection, ligament sprain, balance disorder, and rash. 

 

Discontinuations during the PGTC seizure trial occurred in 11% of patients on FYCOMPA vs 6% of patients on placebo.2 The most common AEs responsible for these discontinuations were vomiting and dizziness. 

 

To summarize the data shared so far, once-daily FYCOMPA is a broad-spectrum agent that offers potential seizure control across both convulsive and nonconvulsive seizures, including partial-onset seizures with secondary generalization, PGTC seizures, and simple and complex partial seizures. 

 

For partial-onset seizures that are secondarily generalized, once-daily FYCOMPA is approved as adjunctive therapy or monotherapy for patients 4 years of age or older. 

 

For PGTC seizures, once-daily FYCOMPA is approved as adjunctive therapy for patients 12 years of age or older. 

 

For nonconvulsive seizures, FYCOMPA is approved for simple and complex partial seizures as adjunctive therapy or monotherapy for patients 4 years of age or older. 

 

Now I’d like to turn to a study I mentioned earlier, examining the long-term effects of FYCOMPA on cognition. 

 

This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase II study with an open-label extension phase, primarily designed to assess the effects of adjunctive FYCOMPA on cognition. 

So, the aim of the study was to evaluate long-term effects of adjunctive FYCOMPA on cognition, efficacy, safety, and growth and development in adolescents with inadequately controlled partial seizures. 

 

Study 235 was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase II study with an open-label extension phase. 

 

The study was conducted in adolescent patients (aged ≥12 to 18 years) who experienced partial seizures despite receiving a stable dose of 1 to 3 ASMs. 

 

Study 235 randomized patients (2:1) to receive either FYCOMPA (n=85) or placebo (n=48) for a 19-week study period that included a titration and maintenance phase. 

 

Patients who completed Study 235 were allowed to continue into the open-label extension. 

 

Phase A of the open-label extension included a 6-week conversion period where patients randomized to FYCOMPA continued at the dose achieved at the end of the double-blind phase. 

 

Those assigned to placebo switched to FYCOMPA 2 mg/day, which was uptitrated weekly in 2-mg increments. 

 

All titrations were based on tolerance. 

 

Phase B of the extension was available for 15 to 52 weeks for countries without commercially available perampanel or an activated extended-access program. 

This table reviews the broad patient population across various age groups included in this cognition study. Patients of diverse age, seizure type, and concomitant ASM history were assessed in the study. 

Changes in cognition from baseline were determined using the Cognitive Drug Research (or CDR) system, which comprises 5 domains. Changes in CDR system global cognition score and core domain scores were converted to normalized T-scores. 

 

Compared with baseline, there were no significant changes in mean global cognition T-score. FYCOMPA also had no effect on the CDR system domains of continuity of attention, quality of episodic memory, quality of working memory, or speed of memory. 

 

Interestingly, FYCOMPA was associated with a significant decline in mean power of attention score by 8.0 at the end of treatment when compared with baseline. 

 

An important caveat of this finding is that patients had marked impairments in the power of attention domain in baseline versus healthy age-matched controls. In addition, for the speed of memory domain, patients had large impairments in their ability to rapidly retrieve information from working or episodic memory. 

 

Patients or their caregivers recorded seizure counts and types daily in a seizure diary during part A of the extension phase; these data were used to calculate efficacy metrics on this slide and the following slide. 

 

The full analysis set for efficacy consisted of all patients who: received FYCOMPA during the extension phase; had baseline seizure frequency data; and had at least 1 observation of seizure diary data during the extension phase. 

 

There was a continuous increase in median percentage reduction in seizure frequency per 28 days throughout the extension phase. 

 

For the 53 patients exposed to FYCOMPA for at least 52 weeks who had data available, there was an observed 74.1% median reduction in seizure frequency at Weeks 40 to 52. 

 

These data are consistent with those observed in the prior double-blind phase of Study 235 and suggest that long-term control of seizures can be maintained. 

 

Patients or their caregivers recorded seizure counts and types daily in a seizure diary during part A of the extension phase; these data were also used to calculate the 50% responder rate. 

 

The overall responder rate increased throughout the extension phase. 

 

For the 53 patients exposed to FYCOMPA for at least 52 weeks who had data available, there was an observed 50% responder rate of 66.0% at Weeks 40 to 52. 

 

The most common TEAEs were dizziness (29.8%) and somnolence (19.3%), and the most common TEAEs related to hostility/aggression were aggression (11.4%) and irritability (6.1%).

 

Among patients who received FYCOMPA for at least 52 weeks, the incidence of the most common AEs was 74.6% at Weeks 1 to 13 and 26.9% at Weeks 40 to 52. 

 

A total of 23 SAEs occurred in 19 patients. Of these, only 2 SAEs occurred in more than 1 patient (convulsion [n=4] and aggression [n=4]). 

 

Next, let’s take a look at FYCOMPA’s dosing and pharmacokinetics. 

 

First, please note that FYCOMPA has a notably long half-life of up to 105 hours based on a model of 4-mg daily treatment over a period of 4 weeks. 

 

The half-life of FYCOMPA was established in phase 1 clinical trials with healthy adults. In pediatric patients ages 4-11, the half-life of FYCOMPA is long but is reduced by approximately half. 

 

In the presence of concomitant moderate or strong CYP3A4 inducers, FYCOMPA continues to have a long half-life but it is reduced by approximately half in both adults and pediatrics. 

 

FYCOMPA is administered as a tablet or an oral suspension (0.5 mg/mL) and as a single dose, once daily, to be taken at bedtime. 

 

FYCOMPA is dosed in children the same as it is in adolescents and adults. No weight-based dosing is required. 

 

Patients are initiated on FYCOMPA at a dose of 2-mg tablets once daily. Titration of FYCOMPA should be undertaken in 2-mg increments no more frequently than at weekly intervals, such as every 2 or 3 weeks, or even every 4 weeks. The dose is increased until the maximum tolerable dose or maximum dose of 12 mg once daily. Patients on FYCOMPA will continue to be monitored for clinical response and tolerability. 

 

The recommended maintenance dose range for patients with partial-onset seizures is 8 mg to 12 mg once daily; however, efficacy was seen as early as 4 mg in the partial-onset seizures pivotal trials. The recommended maintenance dose for patients with PGTC seizures is 8 mg once daily at bedtime. 

 

Dosage adjustment and close monitoring is recommended for patients when starting or withdrawing moderate or strong CYP3A4 inducers (including enzyme-inducing ASMs, such as carbamazepine, phenytoin, and oxcarbazepine). 

 

For patients with partial-onset seizures who are not taking a moderate or strong CYP3A4 inducer, the starting dose is 2 mg and the maintenance dose ranges from 8 mg to 12 mg, although some patients respond to a 4-mg dose. A dose of 12 mg/day resulted in somewhat greater reduction in seizure rate than 8 mg once daily, but with a substantial increase in adverse reactions. 

 

Among patients with PGTC seizures, the recommended starting dose for those not taking concomitant moderate or strong CYP3A4 inducers is 2 mg daily, with a recommended maintenance dose of 8 mg, although it can be titrated up to 12 mg. 

 

Moderate and strong CYP3A4 inducers, including enzyme-inducing ASMs such as phenytoin, carbamazepine, and oxcarbazepine, cause a reduction in FYCOMPA plasma levels. 

 

Patients with partial-onset seizures or PGTC seizures who are taking moderate or strong CYP3A4 inducers should start at 4 mg daily; there is no established maintenance dose; titration should be based on clinical response and tolerability; the highest dose studied in patients on concomitant enzyme-inducing ASMs was 12 mg once daily. 

 

Patients who miss a dose should be advised to continue with their daily dosing as normal, without trying to make up for the missed dose. Instruct patients to contact their health care provider if more than 1 day of dosing is missed. 

 

The FYCOMPA starting dose is 2 mg per day at bedtime. 

 

Dosage adjustment in specific populations should be based on clinical response and tolerability. 

 

For patients with mild or moderate hepatic impairment, dosage adjustment is recommended, while caution is recommended when using FYCOMPA in patients with moderate renal impairment. 

 

Use of FYCOMPA in patients with severe hepatic or severe renal impairment, or who are undergoing hemodialysis is not recommended. 

 

In the elderly population, dosage increases should occur no more frequently than every 2 weeks during titration. 

Due to FYCOMPA’s long half-life, it has a relatively low peak-to-trough fluctuation, which indicates that drug concentrations will remain relatively stable throughout the dosing interval. 

 

FYCOMPA, which is dosed once daily at bedtime, has a notably long half-life of up to 105 hours based on a model of 4-mg daily treatment over a period of 4 weeks. 

 

As noted earlier, the long half-life of FYCOMPA was established in Phase I clinical trials with healthy adults. In pediatric patients ages 4-11, the half-life of FYCOMPA is long but is reduced by approximately half. In the presence of concomitant moderate or strong CYP3A4 inducers, FYCOMPA continues to have a long half-life but it is reduced by approximately half in both adults and pediatrics. 

 

The time to maximum serum concentration of FYCOMPA ranges between 0.5 to 2.5 hours under fasted conditions. Steady state is achieved in about 2 to 3 weeks. 

 

Clinicians should allow sufficient time to evaluate the effect of any dose changes. 

 

The simulated concentration time profile shown here was based on 8 mg QD dosing in adults. 

 

This graph demonstrates modeled FYCOMPA plasma exposure in a patient who is not on concomitant enzyme-inducing ASMs, who has missed a dose at day 15 and resumed their regular dosing the following day. 

 

On day 15, the trough concentration declined by 18% and the peak concentration declined by 12%.

 

Within 6 to 7 days of the missed dose, modeled FYCOMPA exposure was very close to that of a patient who did not miss a dose. 

 

These simulated concentration time profiles were based on 8 mg QD dosing in adults. 

 

This graph demonstrates modeled FYCOMPA plasma exposure in a patient on concomitant carbamazepine who has missed a dose of FYCOMPA at day 15 and resumed their regular dosing the following day. 

 

On day 15, the trough concentration declined by 44% and the peak concentration declined by 15%. 

 

Within 3 to 4 days of the missed dose, modeled FYCOMPA exposure was very close to that of a patient who did not miss a dose. 

 

Remember that, per the prescribing information, FYCOMPA should be administered once daily at bedtime. 

 

Patients who miss a dose should resume dosing the following day at their prescribed dose. Instruct patients to contact their health care provider if more than 1 day of dosing is missed. 

 

Now please keep watching for additional Important Safety Information for FYCOMPA. 

 

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 led to dose reduction, interruption, and discontinuation. 

 

The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Patients 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 with FYCOMPA, especially when taking higher doses. 

Antiepileptic drugs, including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients. 

 

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. 

 

FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination, especially during the titration phase. 

 

FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events, especially during the titration phase. 

 

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 were more common in patients taking FYCOMPA at doses of 8 mg and 12 mg versus placebo. 

Drug reaction with eosinophilia and systemic symptoms, also known as multiorgan hypersensitivity, has been reported in patients taking AEDs, including FYCOMPA. DRESS may be fatal or life-threatening. 

 

Evaluate your patients if these signs or symptoms are present. 

 

A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency. 

 

The most common adverse reactions include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety. 

 

FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel. 

 

Plasma levels of perampanel were decreased when administered with moderate and strong CYP3A4 inducers. 

 

FYCOMPA may enhance the effects of alcohol on vigilance, alertness, anger, confusion, and depression. 

 

These effects may also be seen when FYCOMPA is used in combination with other CNS depressants. 

Caution should be exercised when FYCOMPA is administered to pregnant or nursing women. 

 

Thanks for watching. To learn more about FYCOMPA, please explore the other videos on this website. 

 

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