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Study 307- Long term open label extension data

Study 307- Long term open label extension data. Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, Yang H, Gee M, Zhu J, Laurenza A

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Study 307- Long term open label extension data

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  1. Study 307- Long term open label extension data Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, Yang H, Gee M, Zhu J, Laurenza A Perampanel, a selective, non-competitive AMPA receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from Phase III, extension study 307Epilepsia 2013 Jan;54(1):126-34 Fycompa-EU0042 Date of preparation: August 2013

  2. Study 307: part of comprehensive Phase III clinical development plan for perampanel 3 Phase III studies of adjunctive perampanel in patients with refractory POS rolled into extension study 307 Phase III • 3061 • Efficacy, safety • 706 patients • Low-dose study (2, 4, and 8 mg) • 3042 • 3074 • Efficacy, safety • 388 patients (304) • 386 patients (305) • High-dose studies(8 and 12 mg) • Extension study, N=1218 • Patients rolled in from:5 • 304: N=311 • 305: N=312 • 306: N=595 • 3053 1Krauss GL et al. Neurology 2012;78(18):1408–1415; 2French JA et al. Neurology 2012;79:589–596; 3French JA et al. Epilepsia. Epub 20 Aug 2012; 4Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 5Perampanel data on file PER008, August 2012

  3. Study design • IVRS=Interactive voice-response system; Krauss et al. Epilepsia. 2013 Jan;54(1):126-34. Double-blind study final dose Follow-up phase(4-weeks) Maintenance period(256-week duration) Blinded conversion period (16-week duration) Titration every 2 weeks 12 mg or MTD 10 N (enrolled)=1218 96.4% of double-blind completers entered the OLE 8 6 4 2 4 mg 2 mg 10 mg 6 mg 8 mg 12 mg Placebo arm 4 5 6 7 12 End of trial Follow-up 1 Visit: Enrollment (visit 8 of the double-blind study) Study 307

  4. Study design Design • An extension study for patients completing the double-blind phase of 3 core Phase III trials (studies 304, 305, and 306) • Blinded conversion period: patients were titrated in 2 mg increments every 2 weeks during a 16-week period to their individual maximum tolerated dose (MTD, maximum 12 mg) • Open-label maintenance period: up to 256 weeks Participants • Patients aged ≥12 years who had completed 1 of the double-blind Phase III studies • Uncontrolled partial-onset seizures despite treatment with 1–3 approved AEDs • 249 study sites in 39 countries Analysis period • First patient in (FPI), October 2008 • Cut-off date for the interim analyses was • December 2010 • 120 day safety update - November 2011 Treatments • Open-label perampanel 12 mg or maximum tolerated dose (MTD) • Once daily, at bedtime, with food • Patients who could not tolerate at least 2 mg were discontinued Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 Study 307

  5. Study objectives and endpoints Krauss et al. Epilepsia. 2013 Jan;54(1):126-34. Study objectives Primary: To evaluate long-term safety and tolerability of perampanel as an adjunctive treatment for refractory POS Secondary: To evaluate the maintenance effect of perampanel for treatment of refractory POS Safety assessments Adverse events (AEs), vital signs, clinical laboratory values, body weight, and ECGs Seizure-related endpoints Median % change from pre-perampanel baseline in SZ frequency per 28 days Responder rate: % of patients with ≥50% reduction from pre-perampanel baseline in SZ frequency Study 307

  6. Patient characteristics and disposition (Dec 2010) Patient characteristics and disposition1 1Krauss et al. Epilepsia. 2013 Jan;54(1):126-34; 2Data on File, Eisai Inc. Study 307

  7. Patient demographics Patient demographics and pre-perampanel baselinea characteristics Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 Study 307

  8. Epilepsy historyMost patients were taking 2 or more AEDs Epilepsy history at baselinea 86% were taking 2 or more AEDs Mean number of AEDs: 2.2 Krauss et al. Epilepsia. 2013 Jan;54(1):126-34. Study 307

  9. Extent of exposure to perampanelNearly 50% of patients received perampanel for >1 year Cumulative extent of patient exposure to perampanel (%) • Duration • 49% exposed to perampanel for >1 year • Median exposure: 51.4 weeks (1.1–128.1) • Dose • 91.4% received 10 or 12 mg/day • Mean dose: 10.1 mg Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 Study 307

  10. Incidence of AEs % of patients experiencing AEs Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 Study 307

  11. Most common AEsoccurring in ≥10% subjects • Incidence of AEs occurring in ≥10% of patients As duration of exposure to each dose of perampanel varied in this study, it was not possible to determine if the incidence of AEs was dose-related Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 . Study 307

  12. Serious adverse events • Serious adverse events (SAEs) occurred in 13.2% of patients • The only SAEs that occurred in >1% patients were those related to seizures • Reported by n=24 patients (2%) • Status epilepticus was reported as an SAE in 9 (<1%) patients • Non-seizure-related SAEs that occurred in >5 patients were • Aggression (n=10, <1%), • Psychotic disorder (n=6, <1%) • Suicidal ideation (n=6, <1%) • Hospitalization was required in 4 of these patients; perampanel was discontinued in 4 • 3 deaths occurred • 1 due to a road traffic accident, 1 due to sudden unexpected death in epilepsy, and 1 due to cerebral hemorrhage • None of the deaths were considered to be related to study treatment AEs are reported for the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34. Study 307

  13. Incidence of worsening seizures Patients (%)with worsening seizuresa Incidence of worsening seizures did not increase between end of conversion phase and 1 year of maintenance phase aDefined as a >50% increase in seizure frequency compared with pre-perampanel baseline. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 Study 307

  14. Laboratory values and vital signs • There was a low incidence (0–4.5%) of markedly abnormal laboratory values • <1% of patients had AST or ALT levels >3-times the ULN • 1.7% of patients had CPK levels >5-times the ULN • The majority of markedly abnormal laboratory values at double-blind baseline were in patients taking concomitant carbamazepine, oxcarbazepine, or valproic acid: • 34 of all 34 patients with abnormally low sodium • 41 of the 50 patients with low neutrophil values • 14 of the 24 patients with markedly low white blood cell count • No clinically important changes in ECG parameters • No patients had a QTcF orQTcB value >500 ms • <1% patients had a >60 ms change from baseline in QTcF or QTcB • Few patients (2%) had clinically notable changes in systolic or diastolic blood pressure (≥20 mmHg or ≥15 mmHg change, respectively) AST=aspartate aminotransferase; ALT=alanine aminotransferase; ULN=upper limit of normal; CPK=creatinine phosphokinase. Analysis period represents the entire duration of perampanel exposure (including the double-blind phase for patients who took perampanel in the core Phase III studies). Safety analysis set. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

  15. Patient weight Changes in weight after 50 weeks of perampanel exposure Krauss et al. Epilepsia. 2013 Jan;54(1):126-34 Study 307

  16. Efficacy endpoints: change in SZ frequencyFrom double-blind study through extension Median % change from pre-perampanel baseline in seizure frequency/28 days Open-label extension Core Phase III Maintenance period (weeks) N=7 N=64 N=29 N=71 N=21 N=119 N=369 N=838 N=164 N=422 N=369 N=817 N=237 N=589 N=291 N=175 ITT population. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34. Study 307

  17. Efficacy endpoints: responder rate From double-blind study through extension Responder ratea N=369 N=838 N=369 N=817 N=237 N=589 N=164 N=422 N=291 N=175 N=119 N=64 N=29 N=71 N=21 N=7 Maintenance period (weeks) Core Phase III Open-label extension a% patients achieving ≥50% reduction in seizure frequency/28 days compared with pre-perampanel baseline. ITT population. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

  18. Efficacy endpoint: seizure freedom Seizure-free rate by duration of perampanel exposure Duration of perampanel treatment includes the double-blind phase for patients who took perampanel in the core Phase III studies, and includes just the extension phase for patients who took placebo in the core studies. Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

  19. Conclusions • Long-term adjunctive perampanel (mean dose 10 mg/day) has a favorable tolerability profile in patients with refractory partial-onset seizures • Retention rate was >70% after average treatment duration of nearly 1 year • Long-term safety and tolerability were consistent with Phase II and III clinical trial data • Most frequent adverse events were dizziness, somnolence, headache, and fatigue • No new safety events were reported • Long-term perampanel treatment maintains the efficacy improvements seen in the double-blind studies, with data up to 2 years • Patients converting from placebo quickly matched efficacy improvements seen in double-blind studies • Improvements in seizure frequency and responder rate were seen at end of conversion period compared with double-blind maintenance period • These are likely to reflect the up-titration of perampanel dose Krauss et al. Epilepsia. 2013 Jan;54(1):126-34

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