Recent Research Expands Our Understanding of Perampanel

Recent Research Expands Our Understanding of Perampanel

Christian M. Cabrera Kang, MD

Emory University School of Medicine, Atlanta, Georgia

Perampanel is a selective, noncompetitive, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate-receptor antagonist. It has proven valuable in managing both partial seizures, with or without secondary generalization, and primary generalized tonic-clonic seizures. Studies presented at the 2015 Annual Meeting of the American Epilepsy Society expanded our knowledge of the drug by looking at various factors that might affect its efficacy, including baseline seizure frequency, the concomitant use of adjunctive antiepileptic drugs (AEDs), the duration of epilepsy, and its use in patients who are drug resistant. Perampanel efficacy in specific patient populations, such as adolescents and patients of Asian/Pacific Islander descent, also was analyzed. Finally, experts examined the risk of such specific adverse effects as falls, cognitive impairment, growth, development, and psychiatric and behavioral events related to perampanel therapy. These subgroup analyses and clinical trials provide insight and future directions of research to further expand our knowledge of an AED that offers a unique mechanism of action.

Christian M. Cabrera Kang, MDPerampanel is a novel antiepileptic drug (AED) that is a selective, noncompetitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate-receptor. Its exact mechanism of action for reducing seizure activity is unclear; apparently, it blocks AMPA receptor-mediated induction of intracellular calcium and reduces neuronal transmission in vitro.1 Perampanel was approved by the US Food and Drug Administration (FDA) in October 2012 and by the European Medicines Agency (EMA) of the European Union in July 2012. It is indicated for adjunctive treatment of partial-onset epilepsy, with or without secondary generalization, in patients ≥ 12 years of age and for primary generalized tonic-clonic seizures (PGTCS) in patients ≥ 12 years of age.2

The results of pivotal clinical trials summarized in the following paragraphs set the framework for the perampanel efficacy and tolerability studies presented at the 69th Annual Meeting of the American Epilepsy Society. The main themes of the new research presented at the meeting included the effects on perampanel efficacy of baseline seizure frequency, adjunctive use of other AEDs, duration of epilepsy, and drug-resistant epilepsy; the use of perampanel in specific patient populations (adolescents, Asians, and Pacific Islanders); and the frequency of specific adverse events (eg, psychological, behavioral, cognitive, growth, and developmental) associated with the use of perampanel.

SUMMARY OF PIVOTAL CLINICAL TRIALS
The safety and tolerability of perampanel were assessed in two consecutive, randomized, multicenter, double-blind, placebo-controlled phase 2 trials (studies 206 [n= 153] and 208 [n = 48]). These studies included patients with refractory partial epilepsy who were randomized to receive adjunctive perampanel (1–12 mg/d) or placebo for 12–16 weeks.3 Efficacy was determined by investigators involved in three concurrent, randomized, multicenter, multinational, double-blind, placebo-controlled, phase 3 trials (studies 304 [n = 388], 305 [n = 386], and 306 [n = 706]).4–6 The study population included patients with refractory partial epilepsy who already were being treated with one to three AEDs, of which only one could be a cytochrome P 3A4 enzyme inducer.

The design was similar across all studies, with a 6-week baseline period before randomization, titration of various daily doses (2, 4, 8, or 12 mg) or placebo over a 6-week interval, and a 13-week maintenance period. Primary endpoints were median reduction of seizure frequency over 28 days and percentage of patients achieving at least a 50% reduction in seizure frequency. Pooled analysis of the trials showed efficacy at doses of 4, 8, and 12 mg/d.7

An open-label extension (OLE) trial, study 307, was available to participants who completed the phase 3 trials. Patients in the perampanel groups continued to use the study drug, and those in the placebo group underwent a 16-week blinded conversion from placebo to perampanel with a subsequent maintenance period and 2-year follow-up.8 Primary endpoints were safety and tolerability, and the secondary endpoint was maintenance of efficacy. Patients who transitioned from placebo experienced seizure control at the end of the conversion period that was similar to that of patients randomized to perampanel in the original studies, whereas patients who continued on long-term perampanel over the whole of the OLE study period maintained their improvements.

In 2015, the FDA approved the use of perampanel for adjunctive treatment of PGTCS in the same age group, based on the results of a multicenter, double-blind, randomized, placebo-control trial (study 332 [n= 162]).9 The study design included a 4- or 8-week baseline period before randomization to perampanel or placebo with 4-week titration and 13-week maintenance intervals (maximum perampanel dose, 8 mg/d). The primary endpoints were the same as for studies 304, 305, and 306. Perampanel produced a greater median percent reduction in tonic-clonic seizure frequency per 28 days than placebo (–76.5% vs –38.4%; P < 0.0001) and a higher 50% responder rate (64.2% vs 39.5%; P = 0.0019).

EFFICACY IN EPILEPSY

Baseline Seizure Frequency
Williams et al10 evaluated the efficacy of perampanel in individuals with drug-resistant partial seizures based on how frequently they experienced seizures during the phase 3 core and OLE studies. The 1,217 patients were stratified into three groups based on the number of seizures (≤ 7.5, > 7.5 to ≤ 19.1, and > 19.1) that occurred during the 6-week prerandomization period.

Patients on therapeutic doses of perampanel (4–12 mg/d) who had ≤ 7.5 seizures during the prerandomization phase showed a greater median percent reduction of seizures and greater responder rates (≥ 50% reduction of seizure frequency during the maintenance period) than did those in the other two groups (Figure 1).10 When the investigators examined patients with secondarily generalized seizures (SGS), they observed a greater median percent reduction in seizure frequency and responder rates in the group that had ≤ 3.7 seizures during the prerandomization period than in patients who experienced > 3.7 seizures. Overall, perampanel therapy seemed to produce better results among patients who had less-frequent seizures.

Figure 1

FIGURE 1 Perampanel efficacy, as measured by changes in baseline seizure frequency, in patients with partial seizures. DB = double-blind; OLE = open-label extension; PER = perampanel; PBO = placebo. During the OLE maintenance period, all patients were treated with perampanel. Adapted, with permission, from Williams et al.10

Combination Therapy
Kirmani and colleagues11 analyzed the efficacy and safety of perampanel therapy based on the type and number of concomitant baseline AEDs used by patients with uncontrolled PGTCS (study 332). Participants were taking fixed doses of one to three AEDs for at least 30 days before baseline; only one of these drugs could be an enzyme inducer (specifically, carbamazepine, oxcarbazepine, or phenytoin). In separate pharmacokinetic studies, use of these enzyme inducers significantly increased the apparent oral clearance of perampanel, thereby reducing plasma concentrations; however, the actual plasma concentration-response relationship for efficacy and safety was not altered.12

The 162 patients were randomized to receive up to 8 mg/d of perampanel or placebo. The five most frequently used AEDs were valproic acid, lamotrigine, levetiracetam, topiramate, and zonisamide, the major AEDs used to treat PGTCS.

A higher median percent reduction in PGTCS frequency per 28 days during the titration and maintenance periods was noted among patients using perampanel plus just one AED (87.6%) than among those given perampanel plus two or three AEDs (64.1% and 66.6%, respectively). This result would be expected if it is assumed that patients using one AED are less refractory to pharmacotherapy. The responder rate was higher among those using perampanel than among the placebo groups and was not significantly affected by the number of AEDs used in combination. These results were similar when comparing perampanel plus an individual AED—none of the five most common AEDs used was more effective when given together with perampanel. Dizziness, fatigue, headache, irritability, and somnolence were the most frequently reported adverse effects (≥ 10%). The small sample size for perampanel plus inducer AEDs (n = 9) and a large variability in the median percent change in PGTCS frequency did not allow for any significant meaningful conclusions.

Duration of Epilepsy
Halford et al13 reported on the influence of epilepsy duration on the effectiveness of adjunctive perampanel therapy in patients with uncontrolled partial seizures (studies 304, 305, and 306). In all, 766 patients were diagnosed with partial seizures for ≤ 20 years, and 709 patients were diagnosed for > 20 years. Patients were randomized to receive 19 weeks of 8 or 12 mg/d of perampanel or placebo (6-week titration period and 13-week maintenance therapy).

Median percent reduction in seizure frequency was not significantly different between the two subgroups for overall partial seizures, complex partial seizures with or without SGS, or only complex partial seizures with SGS. Pooled analysis showed a statistically significant median percent reduction in seizure frequency and greater responder rates among the group receiving therapeutic perampanel doses (4–12 mg/d) than among the placebo group (Figure 2).13 Also, a greater proportion of patients with the shorter duration of epilepsy achieved freedom from seizures than did the group that had experienced seizures for a longer time. Notably, this post hoc analysis was not statistically powered to measure differences between the two groups.

Figure 2

FIGURE 2 Effect of epilepsy duration on adjunctive perampanel therapy in patients with drug-resistant partial seizures. Adapted, with permission, from Halford et al.13

Long-Term Efficacy and Safety of Perampanel in Treatment-Responsive Partial Seizures
Yang and others14 reported on the long-term efficacy and safety of patients with uncontrolled partial seizures who experienced a ≥ 75% reduction in seizure frequency per 28 days from baseline or seizure freedom after perampanel treatment for at least 2 years.

In all, 1,217 patients were included in the OLE study, and 681 of them were treated with perampanel for ≥ 2 years. Baseline characteristics generally were consistent between the two efficacy subgroups and the overall population enrolled in the OLE study. The majority of patients who were ≥ 75% responders (71.2%) or who were free of seizures (78.7%) were taking 12 mg/d of perampanel. Further, > 50% of the 47 patients achieving seizure-freedom did so within 26 weeks of beginning perampanel therapy. The rate and type of treatment-emergent adverse events in these groups were similar to those in the entire participant population (10% overall).

Efficacy and Tolerability of Perampanel in Generalized Seizures
O'Brien et al15 conducted a post hoc analysis of pooled efficacy and tolerability data (studies 304, 305, 306, and 332) in patients with SGS or PGTCS who were randomized to receive placebo (n = 254) or 8 mg/d of perampanel (n = 238).

Patients given perampanel experienced a significant median percent reduction in generalized seizure frequency per 28 days when compared with those in the placebo group (–65.5% vs –24.6%, respectively; P < 0.0001), as well as greater 50% and 75% responder rates, irrespective of the number of concomitant AEDs used. Generalized seizure freedom rates were 26.9% with perampanel therapy and 12.6% with placebo. Treatment-emergent adverse effects were experienced by 79% of patients taking perampanel and 67.5% of the placebo group.

DIFFERENT PATIENT POPULATIONS

Efficacy and Tolerability in Adolescents With Partial Seizures
Villanueva and colleagues16 analyzed data from a multicenter, randomized, double-blind, placebo-controlled, phase 2 study (study 235) primarily focused on the short- and long-term effects of adjunctive perampanel therapy in 114 adolescents (ages ≥12 to < 18 years) with inadequately controlled partial seizures, with or without SGS. Over a 6-week titration, patients received placebo or 2 mg/d of perampanel that was uptitrated weekly in 2-mg increments to a target dose of 8–12 mg/d, followed by a 13-week maintenance period (maximum dose, 12 mg/d). Those completing the blinded phase could receive perampanel in an OLE, which involved a 6-week conversion period plus a 27-week maintenance interval. In countries without commercially available perampanel or an activated extended-access program, a further OLE (15–52 weeks) was available. The study period was up to 104 weeks.

A total of 53 patients exposed to perampanel for ≥ 52 weeks experienced a 50% responder rate (66%), and a median percent reduction in seizure frequency of –74.1% was achieved at 40–52 weeks. Efficacy apparently was directly related to the length of perampanel exposure, specifically ≥ 39 weeks, that was maintained for up to 52 weeks. Treatment-related adverse events were seen in 70.2% of patients without an apparent dose relationship and led to discontinuation of perampanel therapy in 6.1% of patients. Dizziness, somnolence, and aggression were the most common adverse events that led to an increase or reduction in the dose of perampanel or interruption of perampanel therapy. No clinically important changes in mean laboratory values were assessed during the study (eg, hematology, blood chemistry, urinary values).

Efficacy and Safety in Asians and Pacific Islanders
Nishida and others17 reported on a large, randomized, placebo-controlled, phase 3 trial (study 335) of the efficacy and tolerability of perampanel in 710 patients with uncontrolled partial seizures in the Asia-Pacific region. The design of the study included a 6-week baseline period followed by randomization to treatment with 4, 8, or 12 mg/d of perampanel or placebo with a 6-week titration and 13-week maintenance period.

More patients in this study were using three concomitant AEDs and enzyme-inducing AEDs than were included in the previous phase 3 studies. A significant difference was identified for reduced seizure frequency and 50% responder rate in the group given 8–12 mg/d of perampanel than was seen in the placebo groups. Patients with SGS seemed to have a greater response with a higher seizure-freedom rate (17.5%, 28.1%, 20.9% for 4, 8, and 12 mg/d of perampanel, respectively) than did the partial-seizure group, with or without SGS (2.9%, 4%, 4.4%, respectively). Dizziness, somnolence, and headache were the most frequently reported adverse effects, and their frequency seemed to increase with escalation in the dose of perampanel.

TREATMENT-EMERGENT ADVERSE EVENTS

Psychiatric and Behavioral Events
The perampanel package insert includes a boxed warning regarding serious psychiatric and behavioral reactions. Prior clinical trials in patients with partial seizures reported increased irritability in those receiving 8–12 mg/d of perampanel when compared with placebo, discovered by a search of narrow and broad Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) terms for hostility/aggression.2,9

Dobrinsky et al18 analyzed psychiatric and behavioral events in 163 patients with PGTCS (study 332). Psychiatric adverse effects were seen in 24.7% of the perampanel group and 19.5% of the placebo group (Table 1), the majority of which were considered to be mild to moderate in severity by the study team. These effects included anxiety, depression, hallucination, mood swings, nervousness, and stress. The time to first occurrence of treatment-emergent adverse events related to hostility/aggression occurred by the first week in three patients treated with perampanel (median dose, 8 mg/d) and by week 5 in one patient given placebo.

Table 1

Falls
Prior clinical trials in patients with partial seizures looked at falls as a treatment-emergent adverse event without differentiating whether or not they resulted from seizures. Leppik and colleagues19 analyzed data collected from study 332 that distinguished between seizure-related versus nonseizure-related falls occurring in patients receiving perampanel or placebo.

In all, 163 patients diagnosed with PGTCS who were taking one to three concomitant AEDs were randomized to receive perampanel (maximum dose, 8 mg/d) or placebo; the titration period lasted for 4 weeks, and maintenance therapy lasted for 13 weeks. Nonseizure-related falls occurred in one placebo-treated and two perampanel-treated subjects. Most of the falls occurred during the maintenance period; none of them led to removal of the patient from the study.

Laboratory Abnormalities
McElveen et al20 reported on abnormal clinical laboratory results (eg, hematology, chemistry, and urinalysis) noted during the PGTCS phase 3 study. Findings were considered clinically relevant if they led to any intervention, withdrawal of study drug, or worsening of severity relative to baseline by two or more Common Toxicity Criteria grades.

No clinically relevant changes in mean laboratory values from baseline to the end of the treatment period were found in the perampanel-treated or placebo group. Alanine aminotransferase (ALT), cholesterol, and triglyceride levels in the perampanel group shifted from normal baseline to above normal and were at least twice as high as those seen in the placebo group during two consecutive treatment period visits. Of patients with an adverse event associated with an abnormal laboratory value, 14.8% were in the perampanel group and 9.8% were in the placebo group. However, the data (Table 2)20 did not suggest a need for routine clinical laboratory monitoring.

Table 2

Long-Term Cognitive Effects
Perampanel therapy had no significant overall short-term cognitive effects relative to placebo administration in earlier clinical trials involving patients with partial seizures. Fain and others21 presented data on long-term (up to 52 weeks) cognitive effects in 114 adolescents ≥ 12 and < 18 years old with partial seizures who were treated with perampanel (study 235).

Evaluation of cognition was based on the Cognitive Drug Research (CDR) System, Controlled Oral Word Association Test (COWAT), and Lafayette Grooved Pegboard Test (LGPT). The CDR System evaluated five core domains: power of attention, continuity of attention, quality of episodic memory, quality of working memory, and speed of memory (Figure 3).21 Power of attention was impaired over two standard deviations on measures of focused attention and information processing. No significant change in mean letter fluency, as measured on the COWAT, or the mean change in time taken to complete the LGPT was noted. The cognitive effects of perampanel therapy were considered very mild in this adolescent partial-seizure population.

Figure 3

FIGURE 3 Mean T-scores for Global Cognition Score and the five core Cognitive Drug Research (CDR) System domains. Results are shown for the full analysis set for cognition, defined as all randomized subjects who received perampanel in the open-label extension trial, had baseline cognition data, and had at least one post-dose CDR System cognitive test battery assessment after week 27. An increase in T-scores indicates improvement, whereas a decrease indicates worsening. Adapted, with permission, from Fain et al.21

Growth and Development of Adolescents
Kumar and colleagues22 reported on long-term (up to 104 weeks) growth and development in 114 adolescents with uncontrolled partial seizures (study 235). Data were collected on height, weight, bone age, Tanner staging, and blood levels of thyroid-stimulating hormone (TSH) and insulin-like growth factor-1 (IGF-1).

No remarkable change in height and weight from baseline was noted. A slight reduction in bone age (–2 months) was not considered to be clinically important. The majority of patients advanced by more than one Tanner stage or remained stable. Changes in TSH and IGF-1 levels were not clinically important. Overall, treatment with perampanel did not seem to have a clinically meaningful effect on growth or development in adolescents. Long-term therapy with the drug at doses up to 12 mg/d were safe and well tolerated.

DISCUSSION
In these follow-up studies, treatment with perampanel outperformed the use of placebo in terms of decreasing seizure frequency, increasing the responder rate, and showing greater efficacy in patients with less-refractory epilepsy. These effects were seen in patients who had a lower frequency of partial seizures at baseline, patients with PGTCS who used one concomitant AED as opposed to two or three AEDs, patients who had been diagnosed with partial epilepsy shortly before treatment began, and patients who had treatment-responsive partial seizures (≥ 75% responders or seizure freedom).

Among adolescents experiencing partial seizures, efficacy was directly related to the length of perampanel exposure (namely, ≥ 39 weeks and < 52 weeks). Dizziness, somnolence, and aggression observed in adolescents had no apparent relationship to the dose of perampanel they took every day. The opposite was seen among Asian/Pacific Islanders with partial seizures, in whom the most common adverse effects of dizziness, somnolence, and headache were related directly to dose escalation. Additionally, SGS patients within this population seemed to have a greater response and a higher seizure-freedom rate than did the overall partial seizure group with or without that seizure type.

Lastly, aside from dizziness, somnolence, and headache, the major adverse effects stemming from perampanel therapy were irritability and aggression in patients with PGTCS. Laboratory abnormalities included increased ALT and cholesterol/triglyceride levels, which were not clinically significant in those with PGTCS, suggesting that there does not seem to be a need for routine clinical laboratory monitoring during perampanel therapy. Three nonseizure-related falls were seen in patients with PGTCS given perampanel or placebo. Mild cognitive effects, specifically impaired attention and information processing, were reported in the adolescent partial-seizure population, and there was no clinically meaningful effect on growth or development.

Questions still remain about the best use of perampanel, and some experts suggest that the drug may be most effective when used early in patients with less pharmacoresistant seizures. It will be interesting to see if physician practice will change as more providers become comfortable with prescribing this relatively new AED. Many different patient populations, including adolescents and adults, seem to respond to and tolerate the medicine, and more research into its efficacy and tolerability in the pediatric population is needed. The side-effect profile of perampanel is encouraging, with only irritability and aggression standing out from the usual adverse effects associated with its use.

Overall, perampanel therapy seems to be similarly effective in patients with partial or generalized seizures when compared with other AEDs, and it offers a relatively favorable side-effect profile. Its novel mechanism of action provides another option for physicians treating patients with epilepsy.

REFERENCES

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  11. Kirmani B, Laurenza A, Yang H, et al. Subanalysis by baseline antiepileptic drugs (AEDs): results from perampanel study 332 in subjects with primary generalized tonic-clonic seizures (PGTCS). Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 1.191.
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  14. Yang H, Krauss G, Williams B, et al. Long-term perampanel treatment in patients with drug-resistant partial seizures: ≥ 75% responders and seizure-free status. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 1.196.
  15. O'Brien T, Patten A, Bibbiani F, et al. Efficacy and tolerability of perampanel in patients with secondarily generalized or primary generalized tonic-clonic seizures: a pooled analysis of four randomized, phase III studies. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 2.250.
  16. Villanueva V, Renfroe JB, Yang H, et al. Efficacy and safety of adjunctive perampanel in adolescents with inadequately controlled partial seizures: randomized, double-blind, and open-label extension study. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 2.263.
  17. Nishida T, Kaneko S, Inoue Y, et al. A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of perampanel as adjunctive therapy in patients with refractory partial-onset seizures from the Asia-Pacific region. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 3.256.
  18. Dobrinsky C, Ettinger AB, Rosenfeld W, et al. Psychiatric and behavioral events with perampanel in patients with primary generalized tonic-clonic seizures: study 332. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 1.190.
  19. Leppik IE, Williams B, Ma T, et al. Analysis of falls in the phase III perampanel study of primary generalized tonic-clonic seizures. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 1.194.
  20. McElveen WA, Vossler DG, Williams B, et al. Clinical laboratory evaluation and treatment-emergent adverse events related to cardiac, hepatic, and renal disorders: perampanel PGTCS phase III study 332. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 1.195.
  21. Fain R, Meador KJ, Lagae L, et al. Long-term cognitive effects of adjunctive perampanel in adolescents for treatment of partial seizures: randomized, double-blind, and open-label extension study. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 3.260.
  22. Kumar D, Lagae L, Pina-Garza, JE, et al. Effect of adjunctive perampanel on growth and development in adolescents with inadequately controlled partial seizures: randomized, double-blind, and open-label extension study. Presented at the 69th Annual Meeting of the American Epilepsy Society; December 4–8, 2015; Philadelphia, PA. Poster 3.262.

Dr. Cabrera Kang is a Clinical Neurophysiology Fellow at Emory University School of Medicine, Atlanta, Georgia.

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