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Perampanel. Scientific Platform Version 1.0-2011-approval c. Table of Contents . Preface and Instructions for Use. Current Overarching Communication Concepts for Perampanel. Section 1: Burden of Illness. Section 2: Unmet Need. Section 3: Mechanism of Action. Section 4: Clinical Efficacy .

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Perampanel


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    1. Perampanel Scientific Platform Version 1.0-2011-approval c

    2. Table of Contents Preface and Instructions for Use Current Overarching Communication Concepts for Perampanel Section 1: Burden of Illness Section 2: Unmet Need Section 3: Mechanism of Action Section 4: Clinical Efficacy Section 5: Clinical Safety and Tolerability Section 6: Ease of Use Section 7: Economic and Patient Outcomes Appendix 1: References Cited

    3. Preface and Instructions for Use

    4. Preface Dear Colleague – Welcome! Thank you for accessing the Perampanel Scientific Platform (PSP). This resource is here to assist the development of data-driven communications on the potential role of perampanel in the treatment of patients with epilepsy The PSP provides validated and/or peer-reviewed data wherever possible on key issues facing patients and clinicians: the overall burden epilepsy imposes on patients, caregivers, and society; the stigma that is associated with untreated or poorly treated disease; the limitations of current anti-epileptic drug (AED) treatments, including poor tolerability and/or treatment refractoriness; the rationale for AEDs with new and complementary mechanisms of action that target important neuropathological pathways in epilepsy; and clinical data to date for perampanel that support its potential to offer an effective option for the treatment of epileptic seizures across a variety of patient populations and disease types The PSP tells a scientific story in chapters that are defined by Overarching Concepts (slide 8). These concepts are discussed in individual sections and form the essential foundation for perampanel communications Preface and Instructions for Use

    5. Preface – continued In turn, within each section, the rationale for each overarching concept is explained by Key Story Points (KSPs) – fundamental issues for perampanel that are rigorously supported by statements of data and relevant scientific citations that all feed back to the overarching concept. To help understand and expand on PSP data, cross-referring to the Knowledge Resource – Perampanel in Epilepsy is highly recommended. Please realize that the PSP is a “living document”; it will be updated periodically as new data accrue. In this way, it is anticipated that currently “aspirational” statements may be fully supported over time. The goal of the PSP is twofold: 1. help with the development of scientifically sound communications and 2. support the development of consistent communications throughout diverse educational settings around the world. With proper use, the PSP can achieve these goals by providing not only essential education about epilepsy and the potential role of perampanel, but also the highest quality clinical data on its efficacy, safety, and tolerability in diverse clinical settings. Please use, and enjoy, the evolving story of perampanel in epilepsy and data on its potential role in this globally important neurological disorder. Preface and Instructions for Use

    6. Instructions Follow these simple guidelines to ensure the optimal use of the PSP • “References Cited” are provided for your information and convenience (Appendix 1) • Each section of the PSP is available separately for convenience and specificity • Each section of the PSP is associated with a respective, individualized set of full-text references which have been annotated (“ref pak”) • Annotated ref paks are required for approval-to-use procedures; consult with your regulatory personnel for specific instructions • All initiatives that incorporate content from this deck must be separately reviewed by each affiliate’s applicable review committee(s) or disciplines as required by that country Preface and Instructions for Use

    7. Instructions – continued Please do: • Take the time to review the entire PSP and familiarize yourself with the flow of the Overarching Concepts and Key Story Points  • Use KSPs and data to form a framework for planned communications  • Accurately cite data and references provided in the PSP and bibliography  • Consult the Knowledge Resource for complementary data / information  • Corresponding parts are noted at the beginning of each section of the PSP Please do not: • Alter the content of the PSP and / or cited reference  • Cite aspirational statements as factual or fully substantiated at this time  • Share this document externally – this is an internal resource only • Hesitate to either point out significant errors or make suggestions for additional data / information to consider  Preface and Instructions for Use

    8. Current Overarching Communication Concepts for Perampanel

    9. Communication Concepts for Perampanel by Section 1 Burden of Illness 2 Unmet Need 3 Mechanism of Action Current Overarching Communication Concepts for Perampanel 4 Clinical Efficacy 5 Clinical Safety and Tolerability 6 Ease of Use 7 Economic and Patient Outcomes

    10. Section 1 Burden of Illness Corresponds to Knowledge Resource Part 1. Epilepsy Background

    11. Section 1 This slide deck is intended as an internal resource only. All initiatives that incorporate content from this deck must be separately reviewed by each affiliate’s applicable review committee(s) or disciplines as required by that country.

    12. Section 1 Burden of Illness Epilepsy is a common, chronic and complex neurological disorder, with serious effects across all age groups that include treatment-refractoriness, cognitive impairment, stigma, and a significant economic burden

    13. Key Story Point (KSP)-1: Epilepsy is a commonly occurring neurological disorder • More than 50 million people worldwide suffer from epilepsy (International League Against Epilepsy [ILAE] 2007-p4) • In the EU, the prevalence of epilepsy is 8.2 per 1000 people with ~6,000,000 currently affected (ILAE 2007-p11) • Epilepsy is the third most common neurological disorder in the US after Alzheimer’s disease and stroke (Epilepsy Foundation – Against Epilepsy 2011-p1) • Close to 90% of epilepsy cases worldwide are found in developing regions (World Health Organization [WHO] 2009-p1) • Worldwide age-adjusted incidence generally ranges from 16 to 51 new cases per 100,000 people per year (Banerjee et al. 2009-p7) • Stigma has been shown to be strongly associated with epilepsy (Kumari et al. 2009-p360) • 25 population studies of all ages have reported a prevalence of partial onset seizures of 8-92%; Estimations were highly variable and were dependent on accuracy of history, diagnostic methods, and age at which seizure type was classified (Banerjee et al. 2009-p6) • Partial epilepsy accounted for 20–66% of incident epilepsies in 8 population studies of all ages (Banerjee et al. 2009-p9) • Complex partial seizures occur in ~35% of epilepsy patients (Carroll and Benbadis 2011-p2) • Partial seizures with secondary generalization occur in about 60% of patients (Shorvon 2005-p4) BURDEN OF ILLNESS

    14. KSP-2: Response to epilepsy treatment varies among affected individuals with a significant proportion of patients remaining refractory to treatment • Estimates of the proportion of patients diagnosed with epilepsy who are or will become refractory to treatment range from 20% to as high as 40% (French 2007-p3; Perucca et al. 2007-p793) • Uncontrolled chronic epilepsy is associated with an increased risk of mortality, morbidity, seizure-related spinal and head injury, psychiatric disorders and poor quality of life as a result of restricted life-style, stigma and prejudice (Schmidt 2002 – p8) • Factors that predict refractoriness include type of epilepsy, underlying syndrome, etiology, and patient history (French 2007-pp3-4) • Status epilepticus and symptomatic etiology were significant risk factors for the development of refractory epilepsy (univariate, P<0.05) (Altunbasak et al. 2007-p197); status epilepticus and mixed type of seizures were significant and independent risk factors for refractory epilepsy (multivariate, P<0.05) (Altunbasak et al. 2007-p198) • A 30-year cohort study of children followed into adulthood found four independent predictors of AED refractoriness: poor short-term outcome of AED therapy;occurrence of status epilepticus; high initial seizure frequency; and remote symptomatic seizure etiology (Sillanpää 1993-p933) • Status epilepticus is frequently refractory to treatment and provokes increased functional disability, hospitalization, serious medical complications, and even death (Mayer 2002-p208) BURDEN OF ILLNESS

    15. KSP-3: Recurring seizures can cause neuronal loss and contribute to cognitive decline • In a battery of neuropsychological tests, epilepsy was shown to affect cognitive functioning in patients (Treitz et al. 2009-p66, 68, 69) • Deficits in cognition may be more pronounced in patients with shorter seizure-free periods (Treitz et al. 2009-p69) • Young age of seizure onset is consistently reported as a risk factor for impaired cognitive function (Braakman et al. 2011-p853) • Cognitive impairment is a major complicating factor of epilepsy and extends beyond memory deficits in patients with temporal lobe epilepsy (Bell et al. 2011-pp159-161) • Age of onset, longer duration, and higher lifetime seizure frequency affect cognitive functioning in patients with temporal lobe epilepsy (Black et al. 2010-p412, 417) BURDEN OF ILLNESS

    16. KSP-4: Gaps in the understanding and awareness of epilepsy remain, and therefore stigma is a significant issue for patients, to the detriment of their quality of life • In the EU, stigma was among the main commonest problems identified in epilepsy (ILAE 2007-p36) • Stigma has been shown to be strongly associated with epilepsy (Kumari et al. 2009-p360) • There is no difference in the perception of stigma between treated and untreated patients with epilepsy (Kumari et al. 2009-p360) • Levels of stigma are associated with interactions between seizure worry and employment status, self-efficacy and social support, and quality of care and age at seizure onset (Smith et al. 2009-p484, 489) • Patients diagnosed with epilepsy perceive their life satisfaction to be lower as a consequence of their diagnosis (Naess et al. 2009-p627,629) • Depressive symptoms and stigma are negatively correlated with quality of life (Whatley et al. 2010-p575, 579, 581) • Patients want to know more about epilepsy partly due to fear of the stigma associated with it (Prinjha et al. 2005-p435) • Reducing stigma is a major focus for support groups globally and there is evidence that reducing epilepsy stigma is an achievable goal (Fernandes et al. 2011-p55) BURDEN OF ILLNESS

    17. KSP-5: Epilepsy is associated with significant direct and indirect economic costs • In the EU, the estimated total cost of epilepsy in 2004 was €15.5 billion (Pugliatti et al. 2007-p2224) • Indirect costs (€8.6 billion) were higher than direct health care costs €2.8 billion (AED costs were €400 million) • However, direct non-medical costs were €4.2 billion • In the US, annual direct, indirect, and total costs are all significantly higher per patient with epilepsy than per control patient (demographically matched patients without epilepsy) (Ivanova et al. 2010a-p681) • The indirect costs of epilepsy, associated with losses in the labor market and reductions in household productivity, are estimated to account for ~ 85% of the total cost of epilepsy (Begley et al. 2000-p348) • In China, the overall mean annual per-patient cost for epilepsy is approximately $773, equating to more than half of the mean annual income (Hong et al. 2009-p2192,pp2196-2197) • Absenteeism-related costs are higher in patients with epilepsy compared with employed controls (Ivanova et al. 2010a-p681). Caregivers also bear the indirect costs of seizures, e.g. time away from work and loss of employment (O’Dell et al. 2007-p678) • Employees with partial onset seizures have significantly higher absenteeism costs compared with controls (Ivanova et al. 2010b-pp841-842) • AED non-adherence in adults with epilepsy was associated with cost increases related to increased utilization of inpatient and emergency department services (Davis et al. 2008-p449; Faught et al. 2009-p504,507) • There was a large net positive effect on costs of non-adherence despite reduced prescription drug use (Davis et al. 2008-p449) • Non-adherence to AED medication in elderly patients results in significantly higher seizure frequency in patients and significantly higher inpatient, outpatient, emergency, and total healthcare costs (Ettinger et al. 2009-p324,327) BURDEN OF ILLNESS

    18. KSP-6: Epilepsy impacts the ability to gain and maintain employment for both patients and caregivers • In the EU, unemployment is 2–3 times higher among people with epilepsy than in the general population (Heaney 1999-p44) • Patients with epilepsy have significantly lower employment rates and incomes compared with controls (Jennum et al. 2011-p951) • 65% of patients with childhood-onset epilepsy thought their epilepsy made it harder to get and retain a paid job at age 33 (Chin et al. 2011-p1516) • Caregivers and family members also bear the indirect costs of seizures, including time away from work and loss of employment (O’Dell et al. 2007-p678) • Children have access to medical services only with the help of a caregiver, for whom there may be lost work days or under-employment (Beghi et al. 2005-p29) BURDEN OF ILLNESS

    19. KSP-7: Special populations, such as children, adolescents, the elderly, and women, each face particular challenges • Children aged 8–15 with new-onset epilepsy have significantly poorer quality of life across multiple domains compared with healthy children and children with asthma (Taylor et al. 2011-p1494) • In the EU, seizures can influence the behavior and life-style of adolescents, expressed as poor performance at school, fewer outings, weight gain or loss, drinking, smoking, or substance abuse (ILAE 2007-p24) • Adolescents often do not report minor seizures for fear of having to increase their medication • Depression, suicide, and sexual abuse can sometimes be the consequences of perceived [treatment] failure • The incidence and prevalence of epilepsy are higher in the elderly than in younger populations, mortality rates are higher in older epilepsy patients, and they present with status epilepticus more often (Wattebot O’Brien et al. 2011-pM88, M90; Leppik 2006-p65; Cloyd et al. 2006-pS40; Towne 2007-p111) • In the EU, hormonal dysfunction leading to premature menopause has been reported in women with epilepsy, which is likely to be related to higher seizure frequency and may be relevant for women who plan to become pregnant at an older age (ILAE 2007-p23) • In women with epilepsy, use of multiple AEDs is an important predictor of infertility (Sukumaran et al. 2010-p1353-54) • Some AEDs, including carbamazepine, phenobarbital, phenytoin, topiramate, and lamotrigine, have drug–drug interactions (DDIs) with hormonal contraceptives (Gaffield et al. 2011-p28) • Prenatal exposure to certain AEDs is associated with a greater risk of major congenital malformations (Tomson et al. 2011-p609, 614) BURDEN OF ILLNESS

    20. Section 2 Unmet Need Corresponds to Knowledge Resource Parts 1 & 2. Epilepsy Background; Biological Basis of Epilepsy and Seizures

    21. Section 2 This slide deck is intended as an internal resource only. All initiatives that incorporate content from this deck must be separately reviewed by each affiliate’s applicable review committee(s) or disciplines as required by that country.

    22. Section 2 Unmet Need There remains a critical need for well-tolerated, effective AEDs that target the underlying disease with a low potential for toxicities. New AEDs should enhance quality of life and therapeutic outcomes in epilepsy

    23. Key Story Point (KSP)-1: There are many AEDs across various drug classes, yet for a substantial number of patients, seizures remain uncontrolled and/or become refractory to further treatment • There are >20 AEDs currently available to treat epilepsy and >30 different drug/drug formulations; choice of AED encompasses many variables from drug-specific factors to patient-specific factors (Perucca and Tomson 2011-p446; Epilepsy Foundation – Medications database 2011-pp1-2) • In the past two decades, 12 new AEDs have been approved by the FDA, however these newer AEDs have shown no better efficacy than the classic drugs (Asconapé 2010-pp843-845, 851) • Estimates of the proportion of patients diagnosed with epilepsy who are or will become refractory to treatment range from 20% to as high as 40% (French 2007-pp3-4; Perucca et al. 2007-p793) • Uncontrolled chronic epilepsy is associated with an increased risk of mortality, morbidity, seizure-related spinal and head injury, psychiatric disorders and poor quality of life as a result of restricted life-style, stigma and prejudice (Schmidt 2002 –p8) • Factors that predict refractoriness include type of epilepsy, underlying syndrome, etiology, and patient history (French 2007-p4) UNMET NEED

    24. KSP-2: Idiosyncratic, potentially life-threatening toxicities occur with many AEDs • Idiosyncratic AEs account for 10% or more of all adverse drug reactions and are a major source of concern as they encompass most life-threatening effects of AEDs (Zaccara et al. 2007-p1223,1232) • There is a need for regular monitoring with 1st-generation AEDs, many of which are still used (Anderson et al. 2008-p173, 176) • AED toxicity is frequent and contributes to a high proportion of treatment failures and low retention rates (Bootsma et al. 2009-p330; Toledano and Gil-Nagel 2008-p317) • The most common AED adverse events are CNS-related issues, e.g. dizziness, somnolence, and nausea (Stephen and Brodie 2011-p93, 95, 96, 98, 100-102) • Some AEDs cause weight changes: gabapentin, pregabalin, valproic acid, vigabatrin, and possibly carbamazepine are associated with weight gain; felbamate, topiramate, and zonisamide are associated with weight loss (Ben-Menachem 2007-p43, 44) • AEDs may also be associated with more serious AEs such as hyponatremia (carbamazepine and oxcarbazepine), aplastic anemia (felbamate), liver failure (felbamate), glaucoma (topiramate), nephrolithiasis (zonisamide and topiramate), rash (lamotrigine), and cognitive effects (topiramate) (Asconapé 2002-p30,32,36,37; Willmore 2000-p446, 448) • With aging, hepatic mass and blood flow decline along with renal function, resulting in a higher incidence of adverse events (AEs) and drug interactions, which can make treating the elderly difficult (Willmore 2000-p445) UNMET NEED

    25. KSP-3:The use of multiple AEDs increases the likelihood of AEs and DDIs, which can lead to poor compliance and treatment discontinuation, especially problematic in patients with epilepsy • Therapy-related causes of poor adherence including regimen complexity and pattern of AEs are well established (WHO 2003-p102, 104; Golay 2011-p599) • Adverse effects of AEDs are considered by patients to be at least as important as repetitive seizures in terms of quality of life (Toledano and Gil-Nagel 2008-p317 (1)) • AED toxicity is frequent and contributes to a high proportion of treatment failures and low retention rates (Bootsma et al. 2009-p330; Toledano and Gil-Nagel 2008-p317 (2)) • Patients with refractory epilepsy are often co-prescribed multiple AEDs; they are therefore more likely to experience DDIs and AEs, resulting in high rates of discontinuation • Treatment retention generally improves with slower dose titration (Schmitz et al. 2010-p2231, 2237-2238) • Screening for adverse reactions to AEDs is not included in everyday clinical practice; it is likely that they remain underestimated (Toledano and Gil-Nagel 2008-p317 (3)) • Because there is little difference between AEDs in terms of efficacy, drug selection is often based on the AE profile (Toledano and Gil-Nagel 2008-p317 (4)) UNMET NEED

    26. KSP-4: There is a need for an AED that can reduce patient and caregiver burden through improved disease management • Uncontrolled partial seizures can lead to cognitive deterioration, a restricted lifestyle, and poor quality of life (Thompson and Duncan 2005-p1785, 1786; Wheless 2006-p756]) • Epilepsy has been shown to affect cognitive functioning (Treitz et al. 2009-p66, 68) • Patients with epilepsy have significantly lower employment rates and incomes compared with control subjects (Jennum et al. 2011-p951) • Patients diagnosed with epilepsy perceive their life satisfaction to be lower as a consequence of their diagnosis (Naess et al. 2009-p627,629) • Non-adherence to AED medication in elderly patients results in significantly higher seizure frequency (Ettinger et al. 2009-p324,327) • Caregivers and family members bear the indirect costs of seizures, including time away from work and loss of employment (O’Dell et al. 2007-p678) UNMET NEED

    27. KSP-5: Better seizure control and improved AED tolerability may also reduce the impact of associated comorbidities that can reduce quality of life in epilepsy • Numerous studies have demonstrated depression and anxiety to be major negative predictors of quality of life in patients with epilepsy (Huang et al 2011-p231,233; Whatley et al. 2010-p575, 579, 581) • Depressive symptoms have been shown to have 3 times the impact of seizure frequency in predicting quality of life in both adolescents and older adults with epilepsy (Canuet et al. 2009-p62) • Loss of seizure control (breakthrough seizures) has a negative impact on quality of life (Berg et al. 2008-p527) • AED AE profiles can be a predictor of quality of life (Kwon and Park 2011-p530) • Data suggest that administering two drugs that act on the same pharmacologic pathway, such as sodium channel blockade, is less effective than administering two drugs with different mechanisms of action • A “pharmacomechanistic approach” based on drugs’ differing modes of action has been advocated but data are scarce (Kwan et al. 2011-p922) UNMET NEED

    28. KSP-6: Oral, once-daily AEDs that are effective and convenient to take may be expected to improve patient compliance • In one longitudinal study, almost 30% of patients with epilepsy had adherence rates of less than 60% (Briesacher et al. 2008-p7) • Therapy-related causes of poor adherence including regimen complexity and pattern of AEs are well established (WHO 2003-p102, 104; Golay. 2011-p599) • Daily drug dosing frequency is related to compliance in patients with epilepsy (Chen et al. 2010-p46) and once-daily AED dosing may lead to better compliance (Cramer et al. 1989-p3273,3275) • Each increase in dose frequency (one, two, three, or four times daily) increases the likelihood of seizure after a missed dose by 36% (Cramer et al. 2002-p341) • Non-adherence is associated with reduced seizure control and reduced quality of life (Hovinga et al. 2008-p318; Jones et al. 2006-pp507-508) • Higher adherence rates are reported in patients with chronic diseases who receive once-daily vs three times a day and twice-daily regimens (Golay. 2011-p603) • RANSOM showed that non-adherence was associated with an 86% higher incidence of hospital admission, a greater than 3-fold increased risk of mortality and a significantly higher incidence of emergency department visits, motor vehicle injuries, and fractures (Faught et al. 2008-p1574-1575) UNMET NEED

    29. KSP-7: An AED that offers a conceptually novel mechanistic approach would expand the options available for rational polytherapy and the potential for improved seizure control • All current AEDs fall into two main categories (Bialer and White 2010-p70,73; Brodie 2010-pp651-652) • Enhancement of the γ-aminobutyric acid (GABA) system (increasing inhibition) • Reduction of neuronal excitability or neurotransmitter release • An AED with a novel mechanistic approach could be rationally combined with other AEDs, eg, glutamate antagonists targeting AMPA* receptors (French and Faught 2009-p65) • This approach may offer particular benefits in managing refractory epilepsy • The final common pathway for seizure activity is glutamate, but all available AEDs target glutamate transmission indirectly or non-selectively (Brodie 2010-pp651-652; Rogawski 2011-p56, 57, 58, 61) • A large proportion (20-40%) of patients do not achieve adequate seizure control either with monotherapy or when treated with multiple AEDs (French 2007-pp3-4; Perucca et al. 2007-p793) *AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid UNMET NEED

    30. Section 3 Mechanism of Action Corresponds to Knowledge Resource Parts 2, 4, & 5. Biological Basis of Epilepsy and Seizures; Management of Epilepsy; Perampanel in Epilepsy

    31. Section 3 This slide deck is intended as an internal resource only. All initiatives that incorporate content from this deck must be separately reviewed by each affiliate’s applicable review committee(s) or disciplines as required by that country.

    32. Section 3 Mechanism of Action Perampanel is a first in class, oral, AMPA-type glutamate receptor antagonist that selectively targets the neuroexcitatory pathways thought to be important in many types of epilepsy

    33. Key Story Point (KSP)-1: Glutamate facilitates excitatory neurotransmission in the CNS, predominantly through its activity at the AMPA receptor • Glutamate is the major excitatory neurotransmitter in the mammalian nervous system (Meldrum 2000-p1007S) • Glutamate activity is mediated via action at metabotropic and ionotropic receptors (Meldrum 2000-p1007S) • Ionotropic glutamate receptors mediate fast excitatory synaptic transmission in the CNS and are localized on neuronal and non-neuronal cells (Traynelis et al. 2010-p406) • Ionotropic glutamate receptors consist of 18 gene products across three families: AMPA, NMDA, and kainate (Meldrum 2000-p1007S; Traynelis et al. 2010-p406) • AMPA receptor opening is controlled by glutamate • Excessive glutamate transmission can lead to overwhelming influx of Ca2+ and excitotoxic events, including neurodegeneration (Arundine and Tymianski 2003-p326, Rogawski 2011-p56, 57) MECHANISM OF ACTION

    34. KSP-2: AMPA receptors are located postsynaptically at central synapses and mediate glutamate fast excitatory signaling • AMPA receptors are the most abundant ionotropic glutamate receptors in the mammalian brain (Traynelis et al. 2010-p406; Rogawski 2011- (1) p57) • AMPA receptors are localized to excitatory synapses in the CNS (Traynelis et al. 2010-p406; Rogawski 2011- (2) p56) • AMPA receptors are located postsynaptically and under normal conditions transduce responses to glutamate released from presynaptic terminals to mediate the fast component of the excitatory postsynaptic potential (EPSP) (Meldrum 2000-p1008S; Rogawski 2011- (3) p56, 60) • Summation of EPSPs results in action potential firing and is the final step in glutamate-mediated excitatory signaling (Rogawski 2011- (4) p56) MECHANISM OF ACTION

    35. KSP-3: Excitatory neurotransmission subsequent to AMPA receptor activation plays an important role in epilepsy • Excessive glutamate release is observed during seizure activity, and glutamate binding to the AMPA receptor plays an important role in epilepsy (During and Spencer 1993-p1607,1609; Rogawski 2011- (1) p57, 58) • AMPA receptor agonists stimulate seizure activity (Meldrum and Rogawski 2007-p19) • AMPA receptors play a role in the initiation and spread of epileptic activity (Rogawski and Donevan 1999-p948; Rogawski 2011- (2) p60) • AMPA receptor antagonists may be able to inhibit seizure activity by reducing the (over)stimulation of the AMPA receptor, and mitigating the ionic imbalance and excitotoxicity initially induced by excessive glutamate neurotransmission (Meldrum 2002-pp487-488) • The intracellular (neuronal) correlate of electroencephalogram spike is the paroxysmal depolarization shift (PDS) and the PDS is an important marker for seizure activity (Ayala et al. 1973-p5; Chapman 2000-p1043S) • AMPA receptors are responsible for initial depolarization in the PDS, which is subsequently maintained by N-methyl-D-aspartic acid (NMDA) receptors (Chapman 2000-p1043S) MECHANISM OF ACTION

    36. KSP-4: Perampanel is a first in class, orally active, non-competitive AMPA receptor antagonist • Perampanel was identified using a high-throughput screening strategy to discover inhibitors of AMPA-induced Ca2+ flux in rat cortical neurons (Rogawski 2011-p59) • Perampanel is a potent inhibitor of AMPA-mediated responses (Hanada et al. 2011-p1332) • Perampanel binds non-competitively, as demonstrated in radio-ligand binding assays where [3H]perampanel binding is not displaced by glutamate, but is inhibited by a non-competitive AMPA receptor antagonist (CP465022) (Hanada et al. 2011-p1335) • Perampanel is orally bioavailable and in clinical studies demonstrates pharmacokinetics consistent with once-daily oral dosing (Hanada et al. 2011-p1339; Templeton 2009-p99) • Perampanel has a long half-life: in a population pharmacokinetic analysis of pooled data from 19 Phase 1 studies, the average t1/2 of perampanel was 105 hours (DRAFT SmPC) MECHANISM OF ACTION

    37. KSP-5: Perampanel reduces neuronal excitability induced by glutamate activation of AMPA receptors • At resting membrane potential, Na+ is the main carrier of the AMPA receptor depolarizing current (Rogawski 2011- (1) p56) • AMPA receptors containing an edited GluA2 subunit (post-transcriptional editing of glutamine to arginine in GluA2 pre-RNA) are predominant in the CNS and are not permeable to Ca2+ (Rogawski 2011- (2) p57) • Ca2+-permeable AMPA receptors, lacking an edited GluA2, are common in certain neuronal populations in some physiological and pathological states (Isaac et al. 2007-p865, 866) • Perampanel inhibits AMPA-mediated Ca2+ flux in vitro in rat cortical neurons and therefore would be expected to reduce neuronal excitability in response to glutamate release (Hanada et al. 2011-p1334; Rogawski 2011- (3) p59) MECHANISM OF ACTION

    38. KSP-6: Perampanel selectively binds AMPA receptors, exerting little activity at other glutamate receptors • In vitro, perampanel is a potent antagonist at native AMPA receptors in rat cortical neurons (Hanada et al. 2011-p1334) • Perampanel only weakly inhibits activity induced by NMDA or the selective kainate agonist SYM2081 (Hanada et al. 2011-p1337; Rogawski 2011- (1) p59) • Perampanel has not been found to interact with other molecular targets (Rogawski 2011-(2) p59) • Perampanel’s selectivity for AMPA receptors directly targets the underlying pathways involved in initiation and spread of seizure activity, with minimal off-target effects (Hanada et al. 2011-p1338; Rogawski 2011-(3) p60, 61) MECHANISM OF ACTION

    39. KSP-7: Perampanel reduces calcium influx. Reduced excitotoxic calcium has neuroprotective effects in animal models • Glutamate is implicated in acute and chronic neurodegeneration (Meldrum 2000-p1010S; Lau and Tymianski 2010-pp527-528) • AMPA and NMDA receptor activation can cause excitotoxic cell death (Meldrum 2000-p1010S) • Increased numbers of Ca2+-permeable AMPA receptors are observed in neurodegenerative conditions such as amyotrophic lateral sclerosis and stroke (Lau and Tymianski 2010-pp527-528) • AMPA receptor antagonists may have neuroprotective effects by preventing the excitotoxic influx of Ca2+ associated with neuronal death (Meldrum 2002-pp487-488; Stone and Addae 2002-p289) • AMPA antagonists are neuroprotective in animal models of neurodegenerative disorders (Szénási et al. 2008-p179) MECHANISM OF ACTION

    40. Section 4 Clinical Efficacy Corresponds to Knowledge Resource Part 5. Perampanel in Epilepsy

    41. Section 4 This slide deck is intended as an internal resource only. All initiatives that incorporate content from this deck must be separately reviewed by each affiliate’s applicable review committee(s) or disciplines as required by that country.

    42. Section 4 Clinical Efficacy Perampanel is a novel AED with proven clinical efficacy in adults and adolescents with epilepsy who experience partial-onset seizures, regardless of previous treatment

    43. Key Story Point (KSP)-1: Perampanel is the first AED to exhibit clinical efficacy against partial-onset seizures by selectively blocking AMPA receptor-mediated excitatory neurotransmission • Most AEDs act via inhibition of sodium or calcium channel function (decreasing excitation and neurotransmitter release) or enhancement of GABA actions (increasing inhibition) (Brodie 2010-pp651-652). • Perampanel specifically targets AMPA receptors and leads to reduced glutamate excitatory neurotransmission (Hanada et al. 2011-p1337) • Perampanel (4–12 mg/day) significantly reduced seizure frequency and increased responder rate vs placebo in three Phase III studies (Krauss et al. 2011a-p1; French et al. 2011b [Slide 8 in IEC]; French et al. 2011c [Slide 7 & 8 in AAN]) • Perampanel’s novel mechanistic target (post-synaptic AMPA receptor) may avoid AEs associated with increased inhibitory GABAergic neurotransmission (e.g. negative effects on cognition and mood) (Sankar and Holmes 2004-pS12; Cavanna et al. 2010-p1, 2, 5) • Perampanel’s novel mechanistic target may minimize DDIs with existing AEDs: perampanel does not affect in a clinically meaningful way the plasma concentrations of other concomitant AEDs (Krauss et al. 2008-p47) CLINICAL EFFICACY

    44. KSP-2: Perampanel is clinically effective when given as adjunctive therapy for patients with refractory partial-onset seizures (with or without secondary generalization) • In three Phase III clinical trials, once-daily perampanel (4–12 mg) significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures compared with placebo (Krauss et al. 2011a-p1; French et al. 2011b [Slide 8 in IEC],c [Slide 7 in AAN]) • The proportion of patients achieving a 50% reduction in seizure frequency was significantly increased with once-daily perampanel (4–12 mg) compared with placebo (Krauss et al. 2011a–p1; French et al. 2011b [Slide 8 in IEC]) • More patients treated with perampanel 4 mg/day and 8 mg/day than placebo experienced large (≥75%) decreases in seizure frequency (Steinhoff et al. 2011-p254) • Perampanel (4 and 8 mg/day) increased the proportion of patients who achieved seizure freedom compared with placebo, and increased the number of seizure-free days compared with placebo (Steinhoff et al. 2011-p254) • 77% of patients completing the Phase II studies continued on to the Phase II open-label extension (OLE) (Krauss et al. 2011d-p4; Study 207, DATA ON FILE-CSR-p5) • 96% of patients completing the Phase III studies continued on to the Phase III OLE (Study 307, DATA ON FILE-CSR-p5) CLINICAL EFFICACY

    45. KSP-3: Perampanel demonstrates efficacy across the range of doses evaluated in clinical trials • Perampanel at doses as low as 4 mg/day significantly reduced seizure frequency and improved responder rate compared with placebo (Krauss et al. 2011a-p1) • In Study 306, a significant perampanel dose response was demonstrated for percent change in seizure frequency during the Maintenance Period over the dose range 4–8 mg/day (Krauss et al. 2011a-p1) • Patients who escalated from 8 mg/day to 12 mg/day in the blinded (first 3 months) portion of the Phase III extension study (Study 307) experienced greater efficacy with minimal increases in AEs (median change in seizure frequency increased from -32% to -43%) (DATA ON FILE-ISE-p107) • Pharmacokinetic/pharmacodynamic analyses demonstrated a concentration-dependent (4–12 mg/day) decrease in 28-day seizure frequency and increased probability of response relative to placebo (Fuseau et al. 2010-p1) CLINICAL EFFICACY

    46. KSP-4: Perampanel is clinically efficacious with once-daily, oral dosing • Maximal plasma concentrations (Cmax) ofperampanel are reached within approximately 1 hour (Templeton 2009-p99) • Perampanel has pharmacokinetics consistent with once-daily dosing; mean half-life ranged from 59 to 129 hours (Templeton 2009-p99) • Steady-state plasma concentrations are reached by day 14 (Templeton 2009-p99) • In Phase III clinical studies, once-daily perampanel was well tolerated and efficacious (French et al. 2011b [Slide 12 in IEC],c [Slide 11 in AAN]; Krauss et al. 2011a-p1,b-p1) • Studies support a recommendation of bedtime dosing (Hussein et al. 2011-p248; SmPC-pp2, 3) • Dose escalation of perampanel is achieved by 2 mg weekly increments to a maximal dose of 12 mg/day (French et al. 2011b [Slide 4 in IEC],c [Slide 3 in AAN]) CLINICAL EFFICACY

    47. KSP-5: Perampanel is clinically effective across different patient subpopulations, including those who are typically difficult to treat • Adjunctive perampanel is effective in refractory patients experiencing uncontrolled seizures, despite concomitantly taking 1–3 approved AEDs (Krauss et al. 2011a-p1; French et al. 2011b [Slide 5 &12 in IEC],c [Slide 3 & 11 in AAN]) • Perampanel significantly reduced seizure frequency in patients experiencing complex partial and/or secondarily generalized seizures at baseline and increased responder rates in patients experiencing these more severe, clinically important seizure types (French et al. 2011b [Slide 8 in IEC], c [Slide 8 in AAN]; Krauss et al. 2011c-p253) • Perampanel reduced seizure frequency and increased responder rates in adolescent patients (12–17 years) by a similar magnitude compared with the overall population (Villanueva et al. 2011-p242) CLINICAL EFFICACY

    48. Section 5 Clinical Safety and Tolerability Corresponds to Knowledge Resource Part 5. Perampanel in Epilepsy

    49. Section 5 This slide deck is intended as an internal resource only. All initiatives that incorporate content from this deck must be separately reviewed by each affiliate’s applicable review committee(s) or disciplines as required by that country.

    50. Section 5 Clinical Safety and Tolerability Perampanel is a novel AED with proven safety and tolerability in a wide range of patients with epilepsy who experience partial-onset seizures