Investor Update. AES 2018 Annual Meeting. December 3, 2018

Transcription

1 Investor Update AES 2018 Annual Meeting December 3, 2018

2 Forward Looking Statement Zogenix cautions you that statements included in this presentation that are not a description of historical facts are forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "indicates," "will," "intends," "potential," "suggests," "assuming," "designed" and similar expressions are intended to identify forward-looking statements. These statements are based on the company's current beliefs and expectations. These forward-looking statements include statements regarding Fintepla /ZX008 s potential as a treatment for seizures associated with Dravet syndrome or Lennox Gastaut syndrome, that the results observed to date supports Zogenix's believe of the potential long-term safety and efficacy of FINTEPLA, and the projected timing of Zogenix s applications for regulatory approvals of Fintepla /ZX008 in the U.S. and Europe. The inclusion of forward-looking statements should not be regarded as a representation by Zogenix that any of its plans will be achieved. Actual results may differ from those set forth in this presentation due to the risks and uncertainties inherent in Zogenix's business, including, without limitation: the uncertainties associated with the clinical development and regulatory approval of product candidates such as FINTEPLA; the data presented is based on Zogenix s analysis of the efficacy and safety data received to date, and such data may be supplemented as Zogenix receives additional data related to the studies and such data may not accurately reflect the complete results of the studies, and the FDA may not agree with Zogenix's interpretation of such results; unexpected adverse side effects or inadequate therapeutic efficacy of FINTEPLA that could limit approval and/or commercialization, or that could result in recalls or product liability claims; the potential that the FDA will disagree Zogenix's analysis of Study 1503, Study 1504 or Study 1, including the safety profile of FINTEPLA; the potential that the results from the ongoing open-label extension study and earlier studies may not be predictive of future results; the potential for the FDA's earlier marketing approval of drugs other than FINTEPLA to cause the FDA to revoke Breakthrough Therapy designation; ; and other risks described in Zogenix's prior press releases as well as in public periodic filings with the Securities and Exchange Commission (the SEC ). You are cautioned not to place undue reliance on these forwardlooking statements, which speak only as of the date hereof, and Zogenix undertakes no obligation to revise or update this presentation to reflect events or circumstances after the date hereof. All forwardlooking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of

3 Welcome and Panel Introduction Dr. Stephen Farr Zogenix Phase 3 Trial Results on the Efficacy and Safety of FINTEPLA (ZX008) in Dravet Syndrome Dr. Joseph Sullivan UCSF Benioff Children s Hospital Historical and Clinical Context of Fenfluramine and Valve Regurgitation Dr. Susan Cheng Brigham and Women s Hospital, Harvard Medical School Smidt Heart Institute, Cedars-Sinai Medical Center FINTEPLA: Clinically Meaningful Impact on Seizure And Non-Seizure Outcomes Dr. Arnold Gammaitoni Zogenix FINTEPLA Development Highlights in Dravet syndrome and Lennox-Gastaut Dr. Farr Q&A - Full panel

4 Phase 3 Trial Results on the Efficacy and Safety of FINTEPLA (ZX008) in Dravet Syndrome Dr. Joseph Sullivan Director, Pediatric Epilepsy Center UCSF Benioff Children s Hospital

5 AMERICAN EPILEPSY SOCIETY MEETING DECEMBER 3, 2018 FINTEPLA (Fenfluramine HCl Oral Solution) Reduces Convulsive Seizure Frequency in Dravet Syndrome Patients Receiving an Antiepileptic Drug Treatment Regimen Containing Stiripentol: A Phase 3, Randomized, Placebo-Controlled Clinical Study (Study 1504) Rima Nabbout, Hôpital Universitaire Necker - Enfants Malades, Paris, France Stéphane Auvin, Robert Debré University Hospital & Paris-Diderot University, Paris, France Sameer Zuberi, Royal Hospital for Children Glasgow, Glasgow, UK Nathalie Villeneuve, APHM, Hôpital de la Timone, Marseille, France Antonio Gil-Nagel, Hospital Ruber Internacional, Madrid, Spain Rocio Sanchez-Carpintero, Clínica Universidad de Navarra, Pamplona, Spain Ulrich Stephani, Christian-Albrechts-University, Kiel, Germany Linda Laux, Northwestern Univ. Feinberg School of Medicine, Chicago, IL, USA Elaine Wirrell, Mayo Clinic, Rochester, MN, USA Kelly Knupp, Children s Hospital Colorado, Aurora, CO, USA Catherine Chiron, Necker-Enfants Malades Hospital, Paris, France Gail Farfel, Bradley S. Galer, Glenn Morrison, Michael Lock, Arun Mistry, Zogenix, Inc., Emeryville, CA, USA

6 Introduction Dravet syndrome (DS) 1-4 Severe developmental and epileptic encephalopathy with an incidence of approximately 1:15,700 Presents in the first 1-18 months of life with frequent, treatment-refractory convulsive seizures Results from a recent phase 3 clinical study (Study 1) of add-on fenfluramine (FFA) for DS showed that: 5 FFA significantly reduced mean monthly convulsive seizure frequency (MCSF) Mean percent difference from placebo in reduction in mean MCSF: 63.9% for the FFA 0.8 mg/kg/day treatment group Odds of achieving a profound ( 75%) reduction in MCSF: 50 and 10 times higher than placebo in the FFA 0.8 mg/kg/day and 0.2 mg/kg/day treatment groups Patients receiving stiripentol (STP) were not included in Study 1 1. Dravet C. Epilepsia. 2011;52(suppl 2): Wirrell EC, et al. Pediatr Neurol. 2017;68: Wu YW, et al. Pediatrics. 2015;136:e1310-e Ziobro J, et al. Curr Treat Options Neurol. 2018;20: Lagae L, et al. AES [poster 2.434], Dec 1-5, 2017, Washington, DC. 6

7 Objective & Methods OBJECTIVE: To determine the efficacy and safety of add-on FFA in patients with treatment-refractory DS receiving an AED regimen that included STP KEY INCLUSION CRITERIA: Children and young adults (ages 2 to 18 years, inclusive) with a diagnosis of DS Stable AED regimen that included STP, as well as clobazam (CLB) and/or valproic acid (VPA) 4 weeks; could also include ketogenic diet and/or vagus nerve stimulation 6 convulsive seizures (tonic-clonic, tonic, clonic) during the 6-week baseline period KEY EXCLUSION CRITERIA: Pulmonary hypertension or current/past history of cardiovascular or cerebrovascular disease (eg, cardiac valve regurgitation, myocardial infarction, or stroke) Concomitant treatment with cannabinoid products or modulators of serotonergic activity DESIGN: Screening 6 Weeks Baseline Observation N=87 Ages convulsive seizures/ 6 weeks baseline 1:1 Randomization 3 Weeks Titration 12 Weeks Maintenance FFA 0.5 mg/kg/day + AED regimen including STP + VPA and/or CLB n=43 Placebo + AED regimen including STP + VPA and/or CLB n=44 Transition to openlabel safety study Taper, Exit the study Maximum daily dose: 20 mg/day 7

8 Patient Baseline Characteristics Placebo FFA 0.5 mg/kg/day n Age, years, mean±sd (min, max) 9.4±5.1 (2, 19) 8.8±4.6 (2, 18) Age group <6 years, n (%) 12 (27.3) 12 (27.9) Male, n (%) 27 (61.4) 23 (53.5) Race, n (%) Caucasian 29 (65.9) Not reported a 11 (25.0) 23 (53.5) 13 (30.2) BMI, kg/m 2, mean±sd 19.1± ±2.7 Convulsive seizure frequency per 28 days Median Mean±SD (min, max) 11 22±28 (3, 163) 14 28±37 (3, 213) a Not reported or missing: privacy laws in some regions/countries preclude disclosure of certain personal information. BMI, body mass index; FFA, fenfluramine; SD, standard deviation. 8

9 % Difference From Placebo in Reduction in Mean Monthly Convulsive Seizures (T+M) Results Primary Endpoint: Reduction in Mean MCSF in FFA Treatment Group vs Placebo Cumulative Response Curves for Percent Reduction in Mean MCSF from Baseline P< % 20 0 FFA 0.5 mg/kg/day FFA, fenfluramine; MCSF, monthly convulsive seizure frequency; T+M, combined titration and maintenance period. *Key secondary endpoint. P values are vs placebo. Results are plotted for combined T+M periods. MCSF, monthly convulsive seizure frequency; OR, odds ratio vs placebo. 9

10 % Reduction From Baseline (T+M) Median Percent Change in Convulsive Seizures Median Percent Reduction From Baseline in Convulsive Seizures Per 28 Days During Combined Titration and Maintenance Periods 100 Median Percent Change in MCSF Over Time 80 P< FFA 0.5 mg/kg/day 1.1 Placebo FFA, fenfluramine; T+M, combined titration and maintenance period. FFA, fenfluramine; MCSF, monthly convulsive seizure frequency. 10

11 Seizure Freedom & Near Seizure Freedom Longest Convulsive Seizure-Free Interval* Median Duration of Longest Interval Between CS (Days) P=0.004 FFA 0.5 mg/kg/day Placebo Proportion of Patients Achieving Seizure Freedom or Near-Seizure Freedom ( 1 Seizure) Days Placebo 0 P=NS P= Seizures 1 Seizure FFA 0.5 mg/kg/day Patients (%) *Key secondary endpoint. P values are vs placebo. CS, convulsive seizures; FFA, fenfluramine; NS, not significant. 11

12 Clinical Global Impression (CGI) Investigator Parent/Caregiver Combined titration and maintenance (T+M) periods; P values by Cochran-Haenszel test (placebo control vs FFA). CGI, clinical global impression; FFA, fenfluramine. NS, not statistically significant. 12

13 Safety Cardiovascular Safety: Prospective cardiac monitoring throughout the study demonstrated that all patients had normal mitral and aortic valve function at every visit No cases of US FDA-defined cardiac valvulopathy or pulmonary hypertension were observed in any patient at any time during the study Most Common ( 10%) Non-Cardiovascular TEAEs in Any Treatment Group FFA, fenfluramine; TEAE, treatment-emergent adverse event. 13

14 Conclusions FFA (0.5 mg/kg/day) demonstrated robust efficacy in this phase 3 study in patients with DS optimized on an AED regimen that included STP with CLB and/or VPA The odds of experiencing a clinically meaningful ( 50%) and profound ( 75%) reduction in MCSF were 26 and 24 times higher, respectively, in patients with FFA vs placebo added to their STP regimen FFA was generally well tolerated, with the most common AEs being decreased appetite, pyrexia, and fatigue No echocardiographic signs of cardiac valvular heart disease or pulmonary hypertension were observed in any patient at any time FFA may represent an important and effective new treatment option for patients with DS who are receiving STP as part of their AED regimen 14

15 AMERICAN EPILEPSY SOCIETY DECEMBER 3, 2018 FINTEPLA (Fenfluramine HCl Oral Solution) Provides Long-Term Clinically Meaningful Reduction in Seizure Frequency: Results of an Open-Label Extension Study Lieven Lagae, 1 Department of Paediatric Neurology, University of Leuven, Leuven, Belgium Joseph Sullivan, University of California, San Francisco Benioff Children s Hospital, San Francisco, CA, USA Rima Nabbout, Hôpital Universitaire Necker - Enfants Malades, Service de Neurologie Pédiatrique Centre de Référence Épilepsies Rares (CReER), Paris, France Milka Pringsheim, Department of Pediatric Cardiology, German Heart Centre Munich, Munich, Germany; Pediatric Neurology, Schön Klinik Vogtareuth, Vogtareuth, Germany Gail Farfel, Bradley Galer, Glenn Morrison, Michael Lock, Arnold Gammaitoni, and Arun Mistry, Zogenix, Inc., Emeryville, CA, USA

16 Objective & Methods OBJECTIVE: To assess the long-term safety and efficacy of fenfluramine in patients with DS KEY INCLUSION CRITERIA: Patients who completed any of the program s phase 3 studies were eligible to enroll in the OLE study Core study treatments included Placebo FFA 0.2 mg/kg/day FFA 0.5 mg/kg/day FFA 0.8 mg/kg/day METHODS: All patients began at a dose of 0.2 mg/kg/day added to their current antiepileptic drug regimen After 4 weeks, the FFA dose could be flexibly titrated Maximum 0.8 mg/kg/day (maximum dose 30 mg/day) or 0.5 mg/kg/day (maximum dose 20 mg/day) if on STP Effectiveness and tolerability were assessed at Months 1, 2, and 3, and thereafter at 3-month intervals 16

17 Results: Patient Demographics Demographic N = 232 (as of March 13, 2018, the interim analysis cutoff date) Age, years; mean±sd (median) Min, max Age group, n (%) < 6 years 6-18 years >18 years Sex, n (%) Race, n (%) White Unknown* 9.1±4.7 (9.0) 2, (28.0) 166 (71.6) 1 (0.4) Male 128 (55.2) Region, n (%) Canada or US Rest of world 172 (74.1) 35 (15.1) 111 (47.8) 121 (52.2) Baseline convulsive seizure frequency per 28 days median (min, max) # 19.7 (0, 1464) Demographic N = 232 (as of March 13, 2018, the interim analysis cutoff date) Days of treatment with FFA in OLE Median (min, max) 256 (58, 634) Patients discontinuing treatment n (%) Reasons Lack of efficacy Patient/caregiver withdrawal Adverse event Death (SUDEP) Physician decision 22 (9.5) * Privacy laws in some regions/countries preclude disclosure of certain personal information # Determined during the core study; does not include patients from Study 1504 Cohort 1. 17

18 Median Percent Change in Convulsive Seizure Frequency Change in Convulsive Seizure Frequency 0 Over the First 18 Months of OLE Study * * * * * * * * (215) (215) (214) (209) (175) (121) (80) (42) Open-label Treatment Month Decrease in N due to staggered entry into the study. *P < compared with no change (Wilcoxon signed rank test) 18

19 Change in Convulsive Seizure Frequency By Dose Group in RCT* Placebo n=64 Fenfluramine 0.2 mg/kg/day = 38 Fenfluramine 0.5 mg/kg/day = 21 Fenfluramine 0.8 mg/kg/day = 35 * Does not include 58 Pts who s RCT dose is still blinded 19

20 % of Patients Responder Rates for Patients with DS Treated With FFA in the OLE Study Interim Analysis (Median 256 Days) % % % % 25% 50% 75% 100% % Reduction in Convulsive Seizure Frequency Individual patient percent reduction in convulsive seizure frequency was calculated for each patient s entire time in the OLE 20

21 Percent of Caregivers Percent of Investigators Clinical Global Impression of Improvement (CGI-I) Parents/Caregivers Investigators % % Very Much Minimally much improved improved improved No change Minimally worse Much worse Very much worse 0 Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse CGI-I Category CGI-I Category 21

22 Tolerability No patient demonstrated valvular heart disease or pulmonary arterial hypertension at any time during the OLE study period (median 256 days) Adverse Events Occurring in More Than 10% of Patients Adverse Event n (%) Pyrexia 50 (21.6) Nasopharyngitis 45 (19.4) Decreased appetite 37 (15.9) Influenza 27 (11.6) Diarrhea 25 (10.8) Upper respiratory tract infection 24 (10.3) 22

23 Conclusions FFA provided a sustained clinically meaningful reduction (-66.8%) in convulsive seizure frequency during the entire OLE study period (median 256 days) A clinically meaningful ( 50%) reduction in convulsive seizure frequency was observed in 64.4% of patients A profound ( 75%) reduction in convulsive seizure frequency was observed in 41.2% of patients FFA was generally well tolerated as shown by the low withdrawal rate and adverse event profile Consistent with observations in the randomized controlled studies No patient at any time developed valvular heart disease or pulmonary arterial hypertension 23

24 Fenfluramine & Valve Regurgitation ZX008 (FINTEPLA ) Long-Term Data Historical and Clinical Context Dr. Susan Cheng Co-Director, Echocardiography Laboratory, Framingham Heart Study Associate Director, Cardiac Imaging Core Laboratory, Brigham and Women s Hospital, Harvard Medical School Director, Public Health Research, Smidt Heart Institute, Cedars-Sinai Medical Center 24

25 Fenfluramine and Valve Regurgitation in Context Brief review & sources of variation in the fenfluramine literature Long term ECHO findings of ZX008 in Dravet syndrome Insignificance of trace/physiologic regurgitation 25

26 A Brief Review and Sources of Variation in the Fenfluramine Literature 26

27 Published Prevalence Rates of Diet Pill Related Valvulopathy Over Time Prevalence of valvular regurgitation (using the FDA criteria) in patients on diet pills using large, published controlled studies with standardized Echo [Weissman, NJ. Am J Med Sci 2001;321(4): ] With improvement of scientific methods, reported prevalence decreased 27

28 Sources of Variation in Literature Scientific Issues with Interpretation of Fenfluramine CV Literature Lack of baseline Echo assessment Limited accounting for pre-existing valve disease risk factors Widely variable study design Reporting and bias Recall bias Unblinded Echo readings Variation in Echo Machine settings Reading technique Definitions of pathology Many reports evaluated combination fenfluramine + phentermine ( Fen-Phen ) 28

29 Variation in ECHO Assessment Technique- Evolution of Technology 1990s 2000s 1970s 1980s 2010s 1990s 29

30 Variation in ECHO Assessment Technique- Sources of Variation Patient related Body habitus, volume status, blood pressure, position and breathing (e.g. Valsalva) Sonographer related Insonation angle, view, Nyquist limit, color gain, overall gain, frequency, frame rate (sector width, depth, etc.) Was likely issue with many of the legal settlement cases (Fen-Phen) Reader related Selection of views, reference criteria used, internal and external adjunctive information considered (e.g. bias) 30

31 HEALTHY PERSON WITH CHANGE OF ECHO PARAMETERS 31

32 Given the Imperfect Scope of Available Data Reliably estimating the valve regurgitation risk associated with fenfluramine requires more unbiased data, including studies that Measurement of pre-treatment baseline echocardiogram Longitudinal standardized echocardiographic evaluation Unbiased blinded standardized readings using current Guidelines Accounting for variation in patient s cardiovascular risk profile Initial prevalence rates of VHD associated with fenfluramine likely over-estimated risk 32

33 ZX008 Cardiovascular ECHO Monitoring Program Most extensive ECHO monitoring program ever performed on children Checks all of the necessary scientific boxes not present in prior fenfluramine studies Measurement of pre-treatment baseline echocardiogram Longitudinal standardized echocardiographic evaluation Unbiased blinded standardized readings using current Guidelines Accounting for variation in patient s cardiovascular risk profile 33

34 Long Term ECHO Findings of ZX008 in Dravet syndrome 34

35 ZX008 Long Term CV Safety (Study 1503) - Methods Upon completion of a phase 3 study, patients enrolled in the open label extension study Color Doppler ECHO was performed at study entry, week 4 or 6, and then every 3 months All Echos performed with standardized views and machine settings All Echos blindly read with a standardized procedure with oversight from an independent expert review board All grades of regurgitation reported, including trace Although 2017 ECHO Guidelines recommend not reporting trace/physiologic regurgitation Valvular Heart Disease (VHD), ie valvulopathy, defined using FDA-approved definitions Mitral valve VHD > moderate regurgitation Aortic valve VHD > mild regurgitation 35

36 ZX008 Long Term CV Safety 232 patients enrolled Interim cutoff date March Mean age 9.1 years (range, 2-19 years) Duration of fenfluramine treatment Median duration of fenfluramine treatment 256 days (range, days) ~ 161 patient-years of treatment Total of 703 ECHOs performed and read 36

37 Cumulative Incidence of FDA-defined Valvular Heart Disease or Pulmonary Arterial Hypertension in Study

38 Severity Severity Mitral and Aortic Valve ECHO Observations During Study 1503 Mitral Valve Aortic Valve Severe Severe Moderate Moderate Mild Trace Mild Trace Absent Absent Months in Open-label Extension Months in Open-label Extension No VHD Fluctuations observed (absent trace regurgitation) as expected 38

39 Prevalence (%) Prevalence (%) ZX008 Long Term CV Safety Results A. Mitral valve B. Aortic valve Months in Open-label Extension Months in Open-label Extension Prevalence point estimate (± 95% CI) for trace regurgitation in 396 normal healthy children aged years as reported by Webb, R.H. et al. J. Am. Soc. Echocardiogr. 2015; 28:

40 Insignificance of Trace/Physiologic Regurgitation 40

41 Trace Valve Regurgitation is Physiologic (Normal) Cardiac valves are complex anatomical structures Some degree of regurgitation can often be observed under normal conditions Can be due to normal physiologic factors, such as cardiac hemodynamics During normal childhood/adolescent growth and puberty Changing body size and habitus Structure and function of the entire cardiovascular system undergoes a series of dramatic alterations and adaptations Multiple studies, including subjects with a wide range of ages, indicate that Trace or mild regurgitation are frequently seen in healthy normal youth Degree of regurgitation fluctuates with ongoing cardiac growth and anatomic maturation A majority of trace or even mild valve regurgitation seen in youth is within normal limits 41

42 Expert Guidelines Consensus on the Insignificance of Trivial Valve Regurgitation Routine surveillance of trace valvular regurgitation is labeled as inappropriate 42

43 Expert Guidelines Consensus on the Insignificance of Trivial Valve Regurgitation Doppler techniques are very sensitive, and thus trivial or physiologic valve regurgitation, even in a structurally normal valve, can be detected... 43

44 Expert Guidelines Consensus on the Insignificance of Trivial Valve Regurgitation The consensus...is to classify grading of severity of regurgitation into mild, moderate, and severe (Omitting trace ) 44

45 Expert Guidelines Consensus on the Insignificance of Trivial Valve Regurgitation Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful 45

46 Conclusions ZX008 data to date demonstrates no cardiotoxicity Median duration of fenfluramine treatment 256 days (range, days) ~ 161 patient-years of treatment History of fenfluramine s association with cardiotoxicity Must be evaluated and interpreted in a scientific context Initial prevalence rates of VHD associated with fenfluramine likely over-estimated risk 46

47 FINTEPLA : Clinically Meaningful Impact on Seizure & Non- Seizure Endpoints Arnold Gammaitoni, Pharm.D. VP, Global Medical & Scientific Affairs

48 Epileptic Encephalopathy Conditions in which epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone 48

49 What Defines Clinically Meaningful Changes in Seizure Frequency? Analysis of Data From a Phase 3 Clinical Study of Low-Dose Fintepla (Fenfluramine HCl Oral Solution) in Dravet Syndrome Rima Nabbout, Joseph Sullivan, Dennis Dlugos, Douglas Haney, Gail Farfel, Bradley S. Galer, Glenn Morrison, Michael Lock, Arnold Gammaitoni INTRODUCTION: It s good to be better but its better to be good OBJECTIVE: To use data from Study 1 to answer the question: What degree of change in seizure frequency is clinically meaningful? METHODS: Post-hoc analysis to assess the degree of change in seizure frequency that was associated with CGI-I of Much Improved or Very Much Improved on Clinical Global Impression of Improvement scale Results Based on CGI-I rating assessments from investigators (114 patients) and caregivers (112 patients) at Visit 12 49

50 Results Cutpoint for Clinically Meaningful Change Cumulative Response Data From Study 1 CGI-I Category Change in MCSF Cutpoint (%) Caregiver Assessment of CGI-I Very Much Improved -60% Much Improved or Better (Clinically Meaningful) -44% Investigator Assessment of CGI-I Very Much Improved -67.5% Much Improved or Better (Clinically Meaningful) -44% MCID by ROC Analysis ( 44%) 75% 46% 13% 50

51 Improved Everyday Executive Function With Fintepla (Fenfluramine HCl Oral Solution): Results From a Phase 3 Study in Children and Young Adults With Dravet Syndrome Kim I. Bishop, Gerard A. Gioia, Peter K. Isquith, Arnold R. Gammaitoni, Gail Farfel, Bradley S. Galer, Arun Mistry, Michael Lock, and Glenn Morrison INTRODUCTION: Antiepileptic drugs have often been associated with negative impacts on cognition Cognitive/Developmental delay one of the biggest challenges for caregivers OBJECTIVE: Post-hoc Analysis to assess everyday executive function before and during treatment in Study 1 METHODS: Analyze data from BRIEF to determine the proportion of patients that had Clinically Meaningful Improvement or Clinically Meaningful Worsening on executive function 1. Dravet C. Epilepsia. 2011;52(suppl 2): Lagae L, et al. AES [poster 2.434], Dec 1-5, 2017, Washington, DC. 3. Zogenix Press Release, July 12,

52 BRIEF 2 Clinical Scales and Indexes 52

53 Percentage of Patients with Clinically Meaningful Change in BRIEF-2 Index Scores Clinically Meaningful Improvement (RCI > 90%) Clinically Meaningful Worsening (RCI > 80%) Placebo FFA 0.2 mg/kg/day FFA 0.8 mg/kg/day Placebo FFA 0.2 mg/kg/day FFA 0.8 mg/kg/day Behavior Regulation Index (BRI) P=0.02 Behavior Regulation Index (BRI) P=0.6 Emotion Regulation Index (ERI) P=0.02 Emotion Regulation Index (ERI) P=0.2 Cognitive Regulation Index (CRI) P=0.5 Cognitive Regulation Index (CRI) P= Percentage of Patients Percentage of Patients 53

54 Conclusions 14 weeks of treatment with FINTEPLA resulted in significant improvement in Behavior Regulation and Emotion Regulation Building blocks that enable higher-level cognitive regulation function The impact of treatment with FINTEPLA on behavior and emotion regulation might be expected to enable improvements in higher-level cognitive regulation with longer-term treatment Will continue to be assessed in the long-term, open-label extension study (NCT ) 54

55 FINTEPLA - Mechanism of Action Antiepileptic effect of the enantiomers of fenfluramine and nor-fenfluramine in a Dravet zebrafish model Jing Li, Daniëlle Copmans, Lieven Lagae, and Peter A. M. de Witte Fenfluramine is a sigma-1 receptor positive modulator in mice Tangui Maurice, Arnold Gammaitoni, Bradley S. Galer, Parthena Martin A Specific Serotonin Receptor Is Critical in the Ability of Fenfluramine to Prevent Seizure-Induced Respiratory Arrest (S-IRA) in the DBA/1 Mouse Model of SUDEP Carl L. Faingold, Srinivasan Tupal Both Fenfluramine & Norfenfluramine Contribute to anti-seizure effects Sigma-1 Receptor activity likely contributes to anti- Seizure effects Serotonin Receptor contributing to prevention of SUDEP distinct from those modulating anti-seizure effects 55

56 Development Updates Dravet syndrome Lennox-Gastaut syndrome

57 2018 FINTEPLA Highlights Highly significant efficacy results in second Phase 3 placebo controlled trial in Dravet syndrome Positive Pre-NDA Meeting in Dravet syndrome Pre-submission meetings with EMA; Rapporteur and Co-rapporteur selected for MAA review PMDA Scientific Advice Meeting in Dravet syndrome and LGS Initiated Rolling NDA submission for Dravet syndrome Continued enrollment in global Phase 3 placebo-controlled trial in LGS 57

58 LGS: 1601 Study Design Study 1601 is a randomized, double-blind, placebo-controlled study of two doses of ZX008 (0.2 mg/kg/day and 0.8 mg/kg/day) compared to placebo in children and adults with Lennox-Gastaut syndrome Single global study for regulatory submissions seeking approvals in USA, Europe and Japan 4 WEEK BASELINE OBSERVATION 2 WEEK TITRATION 12 WEEK MAINTENANCE 54 WEEK OPEN LABEL SAFETY EXTENSION FINTEPLA/ZX mg/kg/day Max: 30 mg/day 2wk Transition Screening N = 225 Ages :1:1 Randomization Fintepla /ZX mg/kg/day Max: 30 mg/day FINTEPLA/ZX008 Up to 0.8 mg/kg/day 0.2 mg/kg/d increments Max: 30 mg/day Placebo Study primary endpoint: Change from baseline in frequency of seizures that result in drops in subjects receiving ZX008 (0.8 mg/kg/day) compared to placebo 58

59 Continuing Momentum in 2019 Milestone Anticipated Date Complete NDA and MAA submissions in Dravet syndrome Q Dravet syndrome PDUFA target date, if NDA accepted Q Fintepla commercial launch in US, if approved Q Complete enrollment of global Phase 3 trial of ZX008 in LGS H Initiate Phase 3 placebo-controlled trial in Doose syndrome H Top-line results of Phase 3 trial in LGS Q

60 Investor Update AES 2018 Annual Meeting December 3, 2018