Transcript Dr. Cabrera Kang`s PowerPoint slides

Recent Research Expands Our
Understanding of Perampanel
Christian M. Cabrera Kang, MD
Emory University School of Medicine, Atlanta, Georgia
A REPORT FROM THE 69th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY
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Mechanism of Action and Indications

Perampanel is a novel selective, noncompetitive
antagonist of the -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) glutamate
receptor.

It was originally approved by the FDA in October
2012 for adjunctive treatment of partial-onset
epilepsy, with or without secondarily generalized
seizures, in patients  12 years of age.

In June 2015, perampanel was also approved for
adjunctive treatment of primary generalized tonicclonic seizures (PGTCS) in the same age group.
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Effect of Baseline Seizure Frequency
Patients with partial
epilepsy who had
 7.5 seizures over
6 weeks prior to
treatment with
perampanel (4–12
mg/d) experienced a
greater reduction in
seizure frequency than
did those with more
frequent seizures
before being treated
with perampanel.
Williams B et al. AES 2015, Poster 1.188
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Effect of Baseline Seizure Frequency continued
Likewise, patients
with partial epilepsy
who had  7.5
seizures prior to
treatment with
perampanel had
higher responder
rates (50% or greater
reduction in seizure
frequency) to
perampanel than
those who had more
frequent seizures.
Williams B et al. AES 2015, Poster 1.188
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Combination Antiepileptic Therapy

Treatment with perampanel plus only one other
antiepileptic drug (AED) produced a greater
reduction in frequency of PGTCS (87.6%) than did
using perampanel with two (64.1%) or three (66.6%)
other AEDs, as would be expected if it is assumed
that patients using one AED are less refractory to
pharmacotherapy.

None of the five most common AEDs used to treat
PGTCS—valproic acid, lamotrigine, levetiracetam,
topiramate, and zonisamide—was more effective
than another when given together with perampanel.
Kirmani B et al. AES 2015, Poster 1.191
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Duration of Partial Epilepsy
Patients with
uncontrolled partial
seizures who were
diagnosed  20 years
ago were more likely
to respond to
therapeutic doses of
perampanel (8–12
mg/d) than those
who had a longer
history of epilepsy.
Halford J et al. AES 2015, Poster 1.193
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Long-term Efficacy and Safety

In all, 1,217 patients patients with drug-resistant
partial seizures were included in the open-label
extension trial; 681 of these were treated with
perampanel for  2 years.

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.

More than half of the 47 patients achieving seizurefreedom did so within 26 weeks of beginning therapy.

The rate and type of treatment-emergent adverse
events (10% overall) in these groups were similar to
those in the entire study population.
Yang H et al. AES 2015, Poster 1.196
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Perampanel in Generalized Seizures

Patients with secondarily generalized seizures (SGS)
or PGTCS given 8 mg/d of perampanel experienced a
significant reduction in monthly seizure frequency
when compared with those taking placebo (–65.5%
vs –24.6% , respectively; P < 0.0001) and higher
50% and 75% responder rates, irrespective of the
number of concomitant AEDs being used.

Generalized seizure freedom rates were 26.9% with
perampanel therapy versus 12.6% with placebo.

Treatment-emergent adverse effects were
experienced by 79% of patients taking perampanel
and 67.5% of the placebo group.
O’Brien T et al. AES 2015, Poster 2.250
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Adolescents With Partial Seizures

Fifty-three adolescents with inadequately controlled
partial seizures exposed to perampanel for  52
weeks experienced a 50% responder rate (66%) and
a median reduction in seizure frequency of –74.1%
within 40–52 weeks.

Treatment-related adverse events were observed in
70.2% of patients and led to discontinuation in 6.1%.

Dizziness, somnolence, and aggression were the
most common adverse events.

No clinically important changes in mean laboratory
values were seen during the study.
Villanueva V et al. AES 2015, Poster 2.263
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Asians and Pacific Islanders

Treatment with 8 or 12 mg/d of perampanel of Asian
and Pacific Islander patients with uncontrolled
partial seizures led to a significant reduction in
seizure frequency and higher 50% responder rate
compared with placebo.

Patients with SGS seemed to have a greater response
with a higher seizure-freedom rate than did the
partial-seizure group, with or without SGS.

Dizziness, somnolence, and headache were the most
frequently reported adverse events, and their
frequency seemed to increase with escalation in the
dose of perampanel.
Nishida T et al. AES 2015, Poster 3.256
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Psychiatric and Behavioral Events
Psychiatric and behavioral adverse events were seen in
24.7% of 163 patients with PGTCS taking perampanel
and 19.5% of those on placebo. Most of these events
were mild to moderate in severity.
Dobrinsky C et al. AES 2015, Poster 1.190
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Falls

In all, 163 patients with inadequately controlled
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 placebotreated 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.
Leppik IE et al. AES 2015, Poster 1.194
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Laboratory Abnormalities
In the same study, no
clinically relevant
changes in mean
laboratory values from
baseline to the end of
the treatment period
were found in patients
with PGTCS taking
perampanel or
placebo. The data did
not suggest a need for
routine clinical
laboratory monitoring.
McElveen WA et al. AES 2015, Poster 1.195
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Long-Term Cognitive Effects
Perampanel therapy had no significant long-term (up
to 52 weeks) cognitive effects in 114 adolescents with
partial seizures. Only power of attention, one of the five
domains of the Cognitive Drug Research System, was
impaired—and then only very mildly.
Fain R et al. AES 2015, Poster 3.260
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Growth and Development

No remarkable change in height or weight from
baseline was noted in 114 adolescents with
uncontrolled partial seizures who were treated with
up to 12 mg/d of perampanel for up to 104 weeks.

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.
Kumar D et al. AES 2015, Poster 3.262
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Conclusions

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.

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.

Among adolescents with partial seizures, efficacy was
directly related to length of perampanel exposure.
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Conclusions continued

The drug appears to be more effective in patients
who have:
» A lower frequency of partial seizures at baseline;
» PGTCS and were taking fewer concomitant AEDs;
» Been diagnosed with partial epilepsy shortly before
treatment began; and
» Treatment-responsive partial seizures.

Dizziness, somnolence, and aggression observed in
adolescents had no apparent relationship to dose.

Asian/Pacific Islanders with SGS seemed to have a
greater response rate and higher freedom from
seizures than other patients with partial seizures.
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Conclusions continued

In Asian/Pacific Islanders with partial seizures,
dizziness, somnolence, and headache were directly
related to dose escalation.

Psychiatric and behavioral events occurred in one
fourth of patients with PGTCS taking perampanel;
most were mild to moderate in severity.

Laboratory abnormalities, including elevated ALT
and cholesterol/triglyceride levels, were clinically
insignificant in patients with PGTCS.

Perampanel had no clinically meaningful effect on
growth or development in adolescents with partial
seizures.
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