Pooled Analysis of 45 Real-World, Investigator-Led Trials Explores Efficacy and Safety of an Antiseizure Medication in Focal and Generalized Epilepsy

 

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Hi, I’m Dr Michael Chez, a pediatric epileptologist and professor at California North State University. I have been treating patients with epilepsy for 34 years. 

 

Today, I am here to talk about the PERMIT Extension study, a pooled analysis of data from 2 large, clinical practice studies conducted to assess the effectiveness, safety, and tolerability of FYCOMPA in everyday clinical practice for patients with focal and generalized seizures. 

 

First, let me cover some important background information on 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 this presentation 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 perampanel, 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. 

 

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

 

FYCOMPA had 3 pivotal trials in partial-onset seizures with or without secondarily generalized seizures. 

 

Patients were titrated every week over a 6-week titration period at doses of 2 mg, 4 mg, 6 mg, 8 mg, and 12 mg. 

 

The primary endpoint, median percent reduction in partial-onset seizure frequency per 28 days, was met.1-4 FYCOMPA achieved proven reductions in partial-onset seizure frequency at doses of 4 mg/day, 8 mg/day, and 12 mg/day, with inducer and non-inducer ASMs. 

 

The secondary endpoint of 50% or greater reduction in partial-onset seizure frequency also was met.1 Up to 54% of patients experienced a 50% or greater reduction in partial-onset seizure frequency with FYCOMPA. 

 

The prespecified exploratory endpoint of median percent reduction in secondarily generalized seizure frequency per 28 days was met as well.5 Up to a 75% frequency reduction in secondarily generalized seizures was seen with FYCOMPA. 

 

The post hoc exploratory endpoint of seizure freedom in secondarily generalized seizures was also met.5 Up to 36% of patients with secondarily generalized seizures were convulsive seizure free during the 13-week maintenance phase. 

 

The most common adverse reactions were: 

• 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)

 

Discontinuation due to adverse reactions occurred in participants with placebo (5%), FYCOMPA 4 mg (3%), FYCOMPA 8 mg (8%), and FYCOMPA 12 mg (19%). 

 

Ok, now let’s discuss the PERMIT Extension study. This was a pooled analysis of data from people with epilepsy included in 2 large, previous clinical practice studies (PERMIT and PROVE) to assess the effectiveness, safety, and tolerability of FYCOMPA in everyday clinical practice for focal and generalized seizures. 

 

In this meta-analysis, deidentified individual participant data from the PERMIT and PROVE studies were pooled for analysis to assess efficacy and safety. 

 

The PERMIT study was a pooled analysis of prospective, retrospective, and cross-sectional studies and work groups in which patients with focal and generalized epilepsy were treated with FYCOMPA. 

 

Broad inclusion and exclusion criteria were included to represent the heterogeneous groups of patients treated in clinical practice. 

 

The PROVE study was a retrospective, noninterventional, and observational phase IV study in which data were obtained from medical and pharmacy records at sites across the United States. 

 

Patients were eligible for inclusion if they had a diagnosis of epilepsy, had been prescribed FYCOMPA after January 1, 2014 (based on their treating clinician’s recommendation), and had attended their usual epilepsy clinic. 

 

Effectiveness was assessed based on: change from baseline in seizure frequency; responder rate, defined as at least a 50% seizure frequency reduction from baseline since the previous visit; seizure freedom, meaning no seizures since the previous visit; and proportions of patients with unchanged or worsening seizure frequency. 

 

Safety and tolerability was assessed by looking at AEs, AE-related discontinuations, psychiatric AEs, and psychiatric AEs associated with discontinuation. 

 

Here you see the broad patient population across various age groups that was included in the PERMIT Extension. Patients of diverse age, seizure duration, psychiatric history, seizure etiology, seizure type, and concomitant ASM history were assessed in this study. 

 

Note that while patients younger than 18 report seizures with a genetic cause at a much higher rate, patients older than 18 much more commonly report seizures attributed to structural findings. 

 

This slide shows response rates in patients with partial-onset seizures. 

 

At 12 months and the last visit, 55.2% and 47.9% of patients between the ages of 12 and 17 reached the ≥50% responder rate, respectively. 

 

52.9% and 44.6% of patients between the ages of 18 and 64 reached the ≥50% responder rate, respectively. 

 

And 74.2% and 69.1% of patients 65 years and older reached the ≥50% responder rate, respectively. 

 

Here we are looking at response rates in patients with generalized seizures. 

 

At 12 months and the last visit, 73.3% and 68.4% of patients between the ages of 12 and 17 reached the ≥50% responder rate, respectively. 

 

79.8% and 73.5% of patients between the ages of 18 and 64 reached the ≥50% responder rate, respectively. 

 

And 76.9% and 70.6% of patients 65 years and older reached the ≥50% responder rate, respectively. 

Up to 44.7% of patients with partial-onset seizures had seizure freedom. 

 

At 12 months and the last visit, 19.1% and 17.9% of patients between the ages of 12 and 17 experienced seizure freedom, respectively. 

 

17.2% and 14.6% of patients between the ages of 18 and 64 experienced seizure freedom, respectively. 

 

And 39.5% and 39% of patients 65 years and older experienced seizure freedom, respectively. 

Up to 64% of patients with generalized seizures had seizure freedom. 

 

At 12 months and the last visit, 37.8% and 40.8% of patients between the ages of 12 and 17 experienced seizure freedom, respectively. 

 

54.1% and 52% of patients between the ages of 18 and 64 experienced seizure freedom, respectively. 

 

And 61.5% and 52.6% of patients 65 years and older experienced seizure freedom, respectively. 

 

This Kaplan-Meier curve represents retention on FYCOMPA treatment over 12 months. 

 

Overall retention rates were 88% at 3 months, 77.6% at 6 months, and 61.4% at 12 months. 

 

The mean time on FYCOMPA treatment over that time was 10.5 months. 

 

The reasons for treatment discontinuation over 12 months were AEs (15.9%), lack of efficacy (8.9%) both lack of efficacy and AEs (2.4%), seizure worsening (0.8%), and other reason not specified (1.8%). 

The most common adverse events were dizziness/vertigo (13.4%), somnolence (8.8%), and irritability (7.3%. 

 

21.5% of patients reported psychiatric AEs, and 10.8% of patients with psychiatric AEs discontinued due to AEs. 

 

23.5% of enrolled patients had a preexisting psychiatric comorbidity. 

 

The most frequently reported psychiatric AEs (occurring in ≥1% of patients) among those who discontinued due to AEs were irritability (3.1%), behavioral disorders (3.0%), aggression/aggressiveness (1.7%), and mood disturbance (1.6%). 

Another important safety consideration with ASMs is their potential impact on a patient’s cognition. So I’d like to share some data from another study, 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. 

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]). 

 

Before I wrap up, I’d like to present some additional background on FYCOMPA and its clinical profile. 

 

Here are 5 reasons why clinicians should consider FYCOMPA as first adjunctive therapy in patients with partial-onset seizures: broad-spectrum utility, a novel mechanism of action, a long half-life, the fact that it is a small pill with once daily administration, and its efficacy and safety profile. 

 

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. 

 

Due to its long half-life, FYCOMPA 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. 

 

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.3 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 on this slide was based on 8 mg QD dosing in adults. 

 

This graph demonstrates modeled FYCOMPA plasma exposure in a patient with and without concomitant enzyme-inducing ASMs, carbamazepine, who has missed a dose at day 15 and resumed their regular dosing the following day. 

 

Without carbamazepine, 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. 

 

With carbamazepine, 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.2 

 

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. 

 

FYCOMPA should be titrated slowly.1 The recommended maintenance dose range is 8 mg to 12 mg once daily, although some patients with partial-onset seizures may respond at 4 mg.1,2 In children, FYCOMPA is dosed the same as it is in adolescents and adults. No weight-based dosing is required. 

 

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,1 defined as when head hits the pillow.

 

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 daily1; however, efficacy was seen as early as 4 mg in the partial-onset seizures pivotal trials.2 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. 

 

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 perampanel 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 perampanel significantly worsened mood and increased anger. Patients should avoid the use of alcohol.

 

Patients, their caregivers, and families should be informed that perampanel may increase the risk of psychiatric events.

 

Patients should be monitored during treatment with perampanel, especially when taking higher doses. 

Antiepileptic drugs, including perampanel, 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. 

 

Perampanel 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 perampanel is known. 

 

Patients should be carefully observed for signs of central nervous system (CNS) depression when perampanel 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. 

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. 

FYCOMPA is a Schedule III controlled substance and has the potential to be abused and lead to drug dependence and withdrawal symptoms. 

 

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

 

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