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Najm: Hello. I am Imad Najm. I’m the director of the Epilepsy Center at the Cleveland Clinic in Cleveland, Ohio.
I am joined by Dr. Amir Arain, Professor of Neurology and head of the epilepsy division at the University of Utah, and Dr. Trevor Resnick, a pediatric epileptologist in the Comprehensive Epilepsy Program at Nicklaus Children’s Hospital in Miami, Florida.
Najm: In this first chapter of a 3-part video series, we are going to talk about the pivotal studies supporting the use of perampanel for the treatment of patients with partial-onset seizures, and to discuss the FAME study of perampanel as first-adjunctive therapy after the failure of initial antiepileptic monotherapy. Please note that perampanel is a schedule III controlled substance.
Before we begin, Dr. Arain, would you please remind our viewers of the indication and Boxed WARNING for perampanel?
Arain: Certainly. FYCOMPA, or perampanel, is indicated for partial-onset seizures with or without secondarily generalized seizures in patients aged 4 and older with epilepsy.
FYCOMPA is also indicated as adjunctive therapy for patients aged 12 and older for primary generalized tonic-clonic seizures.
Arain: FYCOMPA has a Boxed WARNING for serious psychiatric and behavioral reactions. Serious or life-threatening psychiatric and behavioral adverse reactions, including aggression, hostility, or irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA.
These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression.
We need to advise our patients and their caregivers to contact a health care provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical of the patients are observed while taking FYCOMPA or after discontinuing FYCOMPA.
We should also closely monitor patients, particularly during the titration period and at higher doses of FYCOMPA. FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening.
I would ask that you please note important safety information about FYCOMPA within this video and please refer to the full prescribing information for FYCOMPA, as well.
Najm: Thank you, Dr. Arain.
Worldwide, perampanel has been prescribed for the more than 300,000 patients across different indications. In the United States, perampanel was first approved in October 2012 as adjunctive therapy for the treatment of patients with partial-onset seizures. In 2015, it was approved as adjunctive treatment for the primary generalized tonic-clonic seizures. And in 2016, an oral suspension of the drug was approved.
The FDA approved perampanel as monotherapy for partial-onset seizures in 2017. Of note, the monotherapy indication was based on an extrapolation of data from 3 partial-onset seizure pivotal trials, and in 2018, the FDA approved perampanel for the treatment of partial-onset seizures in pediatric patients as young as age 4.
Najm: Let’s first review perampanel pivotal data in partial-onset seizures. I would like to ask Dr. Arain if he can please help us to refresh the audience’s memory on this pivotal data.
Arain: Thanks, Dr. Najm. I would be happy to do so. I’ll be summarizing the original randomized control pivotal trials that led to the approval of FYCOMPA for partial-onset seizures.
There have been 3 randomized double-blind placebo-controlled trials. These phase 3 trials were identical in design, apart from the doses studied and the study sites. You can see the intent-to-treat population, 1478 patients, all of whom were aged 12 or older and had a diagnosis of focal epilepsy with partial-onset seizures.
All patients had to have at least 5 partial-onset seizures during the 6-week baseline phase. Patients had a mean duration of epilepsy of about 21 years, and a median baseline frequency of 9 to 14 seizures per 28 days. All patients were receiving 1 to 3 concomitant AEDs.
Studies 1 and 2 compared FYCOMPA 8 milligrams and 12 milligrams with placebo, and Study 3 compared FYCOMPA 2, 4, and 8 milligrams with placebo.
Arain: The takeaway is that in all 3 trials, FYCOMPA achieved proven reductions in partial-onset seizures at a dose of 4 milligrams per day or higher.
The primary endpoint in these studies was median percent reduction in partial-onset seizure frequency per 28 days. And as you can see, a dose response was seen at 4 milligrams and 8 milligrams, with little additional reduction in frequency at 12 milligrams. And in Study 2, 8 milligrams did better than 12 milligrams.
Arain: They stratified based on the concomitant AEDs, whether the patients were on enzyme-inducing AEDs or without enzyme-inducing AEDs. FYCOMPA achieved seizure frequency reduction with enzyme-inducing AEDs as well as without enzyme-inducing AEDs.
Arain: Up to 54% of patients experienced a 50% or greater reduction in partial-onset seizures. This was a secondary endpoint, 50% responder rate. The combined data for the key secondary endpoint for all 3 trials was assessed by presence or absence of enzyme-inducing AEDs. And you can see there was a dose response, and with a higher dose there was more reduction in seizure frequency.
Now, with enzyme-inducing AEDs, there was around a 33% reduction in seizure frequency at 12 milligrams, and without enzyme-inducing AEDs there was about a 54% reduction in seizure frequency at 12 milligrams.
Patients with a 50% or greater reduction in seizure frequency included 19% of those receiving placebo and, for FYCOMPA, 29% of those on 4 milligrams, 35% of those on 8 milligrams, and 35% of those on 12 milligrams.
Arain: Looking at the side-effect profile, there are 1038 patients in partial-onset seizure trials who received FYCOMPA at doses of 2 milligrams, 4 milligrams, 8 milligrams, or 12 milligrams once a day. And this was the safety population.
Adverse reactions occurring in at least 5% of partial-onset seizure patients on FYCOMPA 4, 8, or 12 milligrams, and at least 1% higher frequency than the placebo are shown in the table at left. These were primarily dizziness, somnolence, headache, and irritability.
You can see that the side effects were lower in the FYCOMPA 4-milligram arm compared to the 12-milligram arm. Most of these adverse reactions were dose related.
During the partial-onset seizure trials, discontinuation as a result of adverse reactions occurred in a dose-dependent fashion for 4-, 8-, and 12-milligram doses.
Discontinuation due to side effects in the placebo arm was 5%. And about 3% of patients in the 4-milligram arm, 8% of patients in the 8 milligram arm, and 19% of patients in the 12-milligram arm discontinued due to adverse reactions.
Najm: Thank you, Dr. Arain, for that very clear summary of the pivotal trials of perampanel. Of course, perampanel’s indication has grown since its initial approval, and our understanding of its utility earlier in adjunctive care has grown, as well.
Two manuscripts were published in 2020 that are consistent with perampanel’s current label. The first was the FREEDOM study. That was a 26-week open-label monotherapy study of newly diagnosed or untreated patients with partial-onset seizures.
The second was the FAME study, which was a 24-week, multicenter, open-label, phase 4, prospective study that assessed perampanel as first adjunctive therapy after AED monotherapy failure in patients with partial-onset seizures, with or without secondarily generalized tonic-clonic seizure.
We are going to focus on the FAME study and perampanel as first adjunctive therapy after initial AED monotherapy failure in patients with partial-onset seizures. Dr. Resnick, will you please describe this study?
Resnick: Thank you. Dr. Najm. So again, the FAME study is a 24-week, multicenter, open-label, phase 4 prospective study of FYCOMPA as first adjunctive therapy after antiepileptic monotherapy failure in patients aged 12 years of age and older with partial-onset seizures with or without secondarily generalized seizures.
If we review the design of the study, patients were originally screened for a 2-month period. They had to have had more than 2 partial-onset seizures at intervals of more than 24 hours during that 8-week screening period.
Patients had to be taking their AED monotherapy at the stable dose during the screening period, and adverse events, withdrawal from treatment, and clinical laboratory evaluations were assessed during the rest of the study.
Now, if you look at the right-hand side of the graphic, FYCOMPA was dosed once daily at bedtime. The initial dose was 2 milligrams per day, and then patients were titrated up or down depending upon clinical response and tolerability. The daily dose was increased incrementally by 2 milligrams per day at intervals of at least 2 weeks. Thus, the maintenance dose was dependent upon clinical response and tolerability, and the dosage range was between 4 and 12 milligrams.
Now a review of the endpoints: The primary endpoint was the 50% responder rate, which is the percentage of patients with at least a 50% reduction in total seizure frequency during the maintenance phase as compared to baseline.
The secondary endpoints included both the responder rate at 75% and at 100% for all seizure types and, importantly, the 50%, 75%, and 100% responder rates for those patients who had secondarily generalized tonic-clonic seizures.
Resnick: Now a couple of important points regarding the study. The first is that the majority of patients had a final maintenance dose of either 4 or 6 milligrams. Just under 85% of patients were on either 4 or 6 milligrams, indicating that when physicians were allowed to dose based upon response and tolerability, the dosage their patients ended up being on the majority of the time was 4 or 6 milligrams.
Please note that this was an open-label study that did not include a control arm. The appropriate multiplicity adjustments were not applied, and the study had a relatively small number of patients. Thus, the data has to be viewed as descriptive.
Nevertheless, if you look at the outcome and the efficacy of FYCOMPA in this group of patients, if you look at all partial-onset seizures, 80% of patients had a more than 50% reduction in seizure frequency, 72% had a 75% reduction in seizure frequency, and nearly half of the patients in this group experienced seizure freedom during the maintenance period.
Importantly, if you look at the right-hand side of the graph as it relates to efficacy in those patients who had secondarily generalized seizures, 87.5% of patients had either a 50% or 75% responder rate, and 75% of patients experienced seizure freedom during the maintenance period.
With regard to adverse events, there were 102 patients in the FAME study safety set. These were patients whom at some point had taken FYCOMPA during the study.
The most common treatment-emergent adverse events were dizziness, at 50%, and then somnolence and headache at 9.8% and 8.8%, respectively.
During the study, 13.2% of patients discontinued due to adverse events, and the remainder discontinued because of withdrawal of consent, protocol violations, patients lost to follow-up, or other reasons.
Najm: I think the FAME study is a very positive study for perampanel in this setting. Finally, Dr. Resnick, will you review the Selected Safety Information for perampanel?
Resnick: Of course. 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 and 12 milligrams per day, respectively. This is 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.
Now, the combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Therefore, patients should avoid the use of alcohol while taking FYCOMPA.
Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events, and patients should be monitored during treatment with FYCOMPA, especially when taking higher doses of the medication.
Antiepileptic drugs, including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients with epilepsy.
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 and 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, which is the most important phase of starting a medication.
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 depression when FYCOMPA is used with other drugs with sedative properties because of the potential additive effects.
Falls were more common in patients taking FYCOMPA at doses of 8 and 12 milligrams versus placebo, which as we know are the higher doses of FYCOMPA.
Drug reaction with eosinophilia and systemic symptoms, also known as DRESS or multiorgan hypersensitivity, has been reported in patients taking AEDs including FYCOMPA. DRESS may be fatal or life-threatening. We should always evaluate our patients if these signs or symptoms are present.
A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency.
Now, the most common adverse reactions include dizziness, somnolence, fatigue, irritability, falls, weight gain, nausea, vertigo, headache, ataxia, vomiting, contusion, abdominal pain, and anxiety.
Resnick: FYCOMPA may also decrease the efficacy of contraceptives containing levonorgestrel.
Plasma levels of FYCOMPA were decreased when administered with moderate or 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 central nervous system depressants.
Therefore, 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.
Finally, FYCOMPA is a schedule III controlled substance and has the potential to be abused and lead to drug dependence and withdrawal symptoms.
And again, we encourage you to review the FYCOMPA full prescribing information, including Boxed WARNING.
Najm: Thank you, Dr. Resnick and Dr. Arain, for sharing all of this valuable information.
I would like to close by encouraging viewers to watch the next 2 chapters in this video series. In Chapter 2, Dr. Arain and Dr. Resnick share real patient cases drawn from their clinics and that feature perampanel as first-adjunctive therapy after AED monotherapy failure, and in Chapter 3 they discuss dosing and pharmacokinetics data for perampanel.
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