First Adjunctive Therapy After ASM Monotherapy Failure in Partial-Onset Seizures

Hello, I am Dr Atiya Khan, a pediatric neurologist practicing in Fort Wayne, IN. I have been treating patients with epilepsy for many years.

Today I am here to talk about data from a partial-onset seizure clinical trial of FYCOMPA (perampanel) as first adjunctive therapy after antiseizure (ASM) monotherapy failure. In addition, we will take some time to review a case study of a real patient with focal onset, impaired awareness epilepsy.

To begin, let’s review some important safety information for FYCOMPA.

[Narrator] 

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

WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS

Please see full Important Safety Information at the end of this video.

Now let me briefly summarize the pivotal clinical trials of FYCOMPA.

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.

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.

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. Specifically, 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.

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).

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

And now we’ll take a moment to turn to our case study. Please note that this case study of an actual patient is presented, illustrative purposes only; individual results will vary for efficacy and/or safety.

Drugs referenced are specific to this case study and are not intended to imply a comparison of efficacy or safety.

Please see the full Prescribing information as well as Important Safety information, including Boxed WARNING.

And now, let’s meet Daniel.

Daniel is a college student who will be graduating next year with a bachelor’s degree in computer science.

He has a history of 2 febrile seizures at 3 and 4 years old.

Daniel reports no history of drug use and does not drink alcohol.

Daniel initially presented to an epilepsy clinic 2 years ago with focal onset, impaired awareness seizure, or FIAS.

He did not present with aura, but did present with staring, unresponsiveness, lip smacking, left-hand dystonia, and motor automatism of the right hand.

FIAS occurred 3 to 4 times per week and evolved to bilateral tonic-clonic activity 2 times per month.

Daniel was seen in the emergency department after his first bilateral tonic-clonic seizure. His MRI showed right hippocampal sclerosis, and his EEG showed right anterior temporal sharps.

At this stage, he was prescribed lamotrigine 25 mg daily, with upward titration every 2 weeks to 100 mg twice a day, as his initial ASM treatment.

Daniel’s initial responses included FIAS decreasing from 3 to 4 times per week to once per week, and his bilateral tonic-clonic seizures decreasing from twice per month to once per month.

The lamotrigine dose was increased to 300 mg twice a day.

Daniel continued to experience seizures 6 months after his initial treatment, so his driver’s license was suspended. He will have to commute by bus to get to school.

He stated that he had not been very adherent, and, at times, seizures have occurred due to missed doses.

With final exams approaching, Daniel has admitted to forgetting his antiseizure medication more than usual.

We’ll get back to Daniel a little bit later.

Now I’ll talk about the FAME study, a 24-week, multicenter, open-label, phase 4, prospective, maintenance study of FYCOMPA as the first adjunctive therapy after ASM monotherapy failure in patients aged 12 and older with partial-onset seizures, with or without secondarily generalized tonic-clonic seizures.

There were 2 treatment periods, Titration and Maintenance, after subject 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.

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 secondarily generalized tonic-clonic seizures (or 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 results from 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.

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

For secondarily generalized 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 the 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 only 15 of 85 needing a dose of 8 mg or higher.

With this information in mind, would you consider FYCOMPA to treat Daniel, whom we met earlier? 

Let’s take a look at his treatment plan.

Daniel returned to the epilepsy clinic, where his health care provider started him on FYCOMPA 2 mg daily.

The physician was able to take advantage of a starter sample to get Daniel initiated on FYCOMPA.

There were no adjustments to his other ASM dose.

Daniel returned to the clinic 3 weeks later for reevaluation. He complained that he initially struggled with sleepiness, but it resolved after a week or so.

After 1 month, Daniel’s FYCOMPA dose was increased to 4 mg daily, and he continued to take lamotrigine.

Daniel’s dose increase is covered under the FYCOMPA voucher program.

Daniel is currently seizure-free, and no dose adjustments to FYCOMPA or lamotrigine have been needed.

His doctor is continuing to monitor for efficacy, safety, and tolerability.

Recall that the FAME study evaluated FYCOMPA as first adjunctive therapy after ASM monotherapy failure.

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

The most common treatment-emergent adverse events were dizziness (50%), somnolence (9.8%), and headaches (8.8%).

Twenty-six patients discontinued treatment. This included 14 due to an adverse events, 4 due to withdrawal of consent, 3 due to a major protocol violation, 2 lost to follow-up, and 3 for some other reason.

Another vital 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.

Study 235 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 the long-term effects of adjunctive FYCOMPA on cognition, efficacy, safety, and growth and development in adolescents with inadequately controlled partial seizures.

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 to 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.

However, 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 treatment emergent adverse events were dizziness (29.8%) somnolence (19.3%), and the most common treatment emergent adverse events related to hostility/aggression were aggression in 11.4% and irritability in 6.1%.

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

A total of 23 serious adverse events occurred in 19 patients. Of these, only 2 serious adverse events occurred in more than 1 patient. So convulsion with [n=4] and aggression with [n=4].

Before I wrap up, I’d like to provide 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. 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 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.

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. 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.

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, defined as when head hits the pillow.

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.

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

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS

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)