Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations

 
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
NASDAQ: ZGNX

Therapeutic Solutions
for Rare Diseases

Corporate Overview

September 23, 2019
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
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 the expected timing, completion and
effects of the acquisition of Modis and the other related transactions; the size of the patient population of TK2 deficiency; Zogenix's
expectations that the RETRO study will serve as a pivotal study for FDA review of MT1621 for treatment of TK2d; the potential for MT1621
to significantly improve outcomes in patients with TK2 deficiency; the potential of MT1621 to receive for accelerated regulatory review in
the U.S. or Europe; and Zogenix's expectations that it discuss next steps with regulatory authorities for MT1621 program and that it will re-
submit the NDA for FINTEPLA in patients with Dravet syndrome and the potential acceptance by the FDA thereof. 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
closing conditions for the transaction may not be satisfied or waived; risks associated with the acquisition of Modis and integration of Modis'
operations into Zogenix's business; the inherent risks of clinical development of MT1621; the data Modis has reported is based on
preliminary analysis of key efficacy and safety data, and such data may change following a more comprehensive review of the data related
to the trial and such data may not accurately reflect the complete results of the trial; risks associated with relying on a retrospective
analysis for pivotal efficacy and safety data for MT1621; Breakthrough Therapy and PRIME designations do not guarantee that the FDA or
EMA will approve MT1621 or expedite its review of MT1621; 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 forward
looking 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 forward looking 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 1995.

2
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
About Zogenix
A global pharmaceutical company developing rare disease therapies

•   A strong and growing organization
    o   Headquarters in the San Francisco Bay Area
    o   Additional operations in Europe; partnership in Japan
    o   130 employees

• Experienced leadership
    o Leadership team with expertise in rare disease
      development and commercialization

• Advancing two very promising potential therapies
    o ZX008 (FINTEPLA®) for Dravet syndrome
      and for Lennox-Gastaut syndrome
    o MT1621 for TK2 deficiency

                                                                    Zogenix headquarters
                                                                    in Emeryville, CA

3
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
Our mission
Making a difference in the lives of patients and their families

•   Our goal is to provide therapeutic solutions with
    the potential to transform the lives of patients
    and their families living with serious rare diseases.

•   We seek best-in-class leadership – scientific,
    medical, and commercial – in the areas in which we
    participate.

•   We strive to make a difference in the lives
    of patients, their families, and our employees
    through collaboration, ethical decision making,
    and open communication.

4
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
Rare disease pipeline
         Product/Platform         Discovery        Preclinical   Phase 1   Phase 2       Phase 3          Regulatory

     Rare Pharmaco-resistant Epilepsies

                                  Dravet Syndrome

                                  Lennox-Gastaut Syndrome
          Fenfluramine

            ZX008
       Low-dose fenfluramine      Doose Syndrome & Other Rare Epilepsies

     Thymidine Kinase 2 (TK2) Deficiency

           MT1621                 TK2 Deficiency                                     Registration Trial
    Pyrimidine deoxynucleosides

5
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
FINTEPLA® (ZX008, fenfluramine)
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
Dravet & Lennox-Gastaut syndromes
Severe childhood-onset epilepsies with catastrophic impact

• Dravet Syndrome
    o Average age of onset is 5 months of age1
    o Accounts for ~ 6% of epilepsies that start before 3 years of age1
    o 20,000-30,000 people living with Dravet syndrome in the US & Europe
      combined (~10,000 of those are children ages 2-18) 2

• Lennox-Gastaut Syndrome
    o Onset usually between 2-7 years of age
    o Accounts for ~1-4 % of all cases of childhood epilepsy1
    o 60,000-100,000 living with LGS in the US and Europe combined2

      1.   NORD website https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/ Accessed May 20, 2019
      2.   Zogenix company estimates

7
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
Urgent need for new treatment options
Most patients’ seizures remain uncontrolled even on multiple anti-epileptic drugs

• Frequent and prolonged seizures; multiple seizure types

• Significant intellectual, behavioral, and motor disabilities

• Higher risk of status epilepticus
    (a medical emergency that can lead to brain damage or death)

• Higher risk of sudden death (SUDEP, sudden unexplained death in epilepsy)

• Patients require constant lifelong care, severely impacting family quality of life

            Significant need to reduce or eliminate high seizure burden and comorbidities

8
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
Phase 3 development programs
ZX008 for the treatment of uncontrolled seizures in rare epileptic encephalopathies

                  Two positive pivotal Phase 3 trials
     Dravet
    Syndrome      Primary endpoint and all key secondary endpoints
                   met with high statistical significance

     Lennox-     •   Global Phase 3 trial ongoing
     Gastaut     •   Top-line data anticipated Q1 2020
    Syndrome

9
Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
ZX008 for Dravet Syndrome
Efficacy – Study 1 Phase 3 trial
Study 1 met all primary and key secondary endpoints

     Primary Endpoint: Reduction in Mean Monthly Convulsive                                  Cumulative Response Curves for Convulsive Seizure Reduction
         Seizure Frequency in ZX008 Groups vs. Placebo                                                             from Baseline

Study 1 was an international, double blind, placebo-controlled Phase 3 study of 119 patients ages 2-18 years randomized to one of three treatment groups: ZX008 0.8 mg/kg/day
(30 mg maximum daily dose; n=40), ZX008 0.2 mg/kg/day (n=39) and placebo (n=40) in which ZX008 or placebo was added to current regimens of antiepileptic drug.

Data originally presented at AES 2017

10
ZX008 for Dravet Syndrome
Efficacy – Study 1504 Phase 3 trial
Consistent with Study 1, Study 1504 met primary endpoint and all key secondary endpoints

     Primary Endpoint: Reduction in Mean Monthly Convulsive                                            Cumulative Response Curves for Convulsive Seizure
      Seizure Frequency (MCSF) in ZX008 Group vs. Placebo                                                           Reduction from Baseline

                         in ZX008 Groups vs. Placebo

Study 1504 was an international, double-blind, placebo-controlled Phase 3 study of 87 patients age 2-19 taking a background anti-epileptic drug regimens that included stiripentol,
randomized to placebo (n=44) or FINTEPLA 0.5 mg/kg/day (n=43).

Data originally presented at AES 2018

11
ZX008 for Dravet Syndrome
Efficacy & Safety – Phase 3 pivotal studies
Rapid and clinically meaningful reductions in convulsive seizures at all test doses

•    Safe and well-tolerated across studies.            Median Change in Monthly Convulsive Seizure Frequency
                                                         During Double-Blind Treatment (Study 1 & Study 1504)
•    Decreased appetite, diarrhea, fatigue, lethargy,
     pyrexia, and nasopharyngitis were the most
     common adverse events (AEs).

•    Incidence of serious AEs comparable across
     placebo and ZX008 treatment groups.

•    No development of valvular heart disease or
     pulmonary hypertension in any patient.

12
ZX008 for Dravet Syndrome
Efficacy – Study 1503 open label extension study
Robust seizure reduction sustained in OLE with no waning of therapeutic effect

                  Median Change in Monthly Convulsive Seizure Frequency During Open Label Treatment
                       over the first 18 months of the ongoing Open Label Extension (Study 1503)

13
Regulatory status – Dravet syndrome
Application under review in Europe; US NDA resubmission planned Q3 2019

                           UNITED STATES
                           o   NDA resubmission planned Q3 2019

                           EUROPE
                           o   MAA accepted March 2019 and under review by the EMA

                           JAPAN
                           •   Studies ongoing to support submission in Japan

14
ZX008 for Lennox-Gastaut Syndrome
Top-line LGS data expected in Q1 2020 (Study 1601)
Enrollment and patient randomization complete for global Phase 3 trial

•    A multi-national, randomized, double-blind, placebo-controlled study of ZX008 at two fixed doses
     compared to placebo in LGS children and adults.
•    Single global study                                               Lennox-Gastaut Phase 3 Global Study
     to support regulatory
                                                                                           12-WEEK                        54-WEEK OPEN LABEL
     submissions in the US,                 4-WEEK
                                           BASELINE
                                                                         2-WEEK
                                                                        TITRATION        MAINTENANCE                       SAFETY EXTENSION
     Europe, and Japan.
•    Primary endpoint:                                                                  ZX008
                                                                                        0.8 mg/kg/day
     change from baseline                                                               Max: 30 mg/day
     in frequency                                                                                               2wk

                                                       Randomization
                                                                                                             Transition
     of seizures that                       Patients
                                                                                        ZX008                                    ZX008

                                                           1:1:1
                               Screening   Ages 2-35
     result in drops.                                                                   0.2 mg/kg/day                     Up to 0.8 mg/kg/day
                                                                                                                           Max: 30 mg/day

                                                                                        Placebo

15
ZX008
Strong intellectual property position
Patents and regulatory exclusivity provides proprietary protection up to 2036 and beyond

        Global              •   Exclusive worldwide license
        Commercialization   •   Full data and patent rights in rare epileptic encephalopathies
        Rights

        Orphan                     US                                     Europe                        Japan
        Drug                • Dravet: 7.5-year Orphan &           • Dravet: 12-year Orphan       • Dravet & LGS:
        Exclusivity           Pediatric Drug exclusivity            & Pediatric Drug               Seeking Orphan Drug
                            • LGS: 7-year Orphan Drug               exclusivity                    exclusivity
                              exclusivity                         • LGS: 10-year Orphan
                                                                    Drug exclusivity

        Strong              •   US & International patents with expiry to 2036 and potentially beyond
        Patent              •   Coverage for Dravet syndrome (pending for additional epilepsy indications)
        Portfolio           •   Coverage for proprietary methods of manufacture (API),
                                drug product formulation (pending), and REMs
                                Exploring other potential patent protections

16
Commercialization
HCP and caregiver awareness; integrated support from enrollment through continued use

              Clinical Education                         FINTEPLA® Hub                          Long-Term Support

     •   Clinician and caregiver education      •   Integrated support programs and    •    Dedicated case management to
         about unmet medical needs and               specialty pharmacy distribution        ensure proper monitoring and
         Fintepla® clinical data                                                            education for long-term therapy.

                                      US & Europe: Zogenix in-house commercial teams
                                       Japan: Commercial partner Nippon Shinyaku Co. Ltd.

17
Market preparations underway
Increasing levels of engagement with Dravet community, physicians, and advocacy groups

• Meetings, medical conferences, and medical education programs

• Strong interest and participation in both EAP and ongoing open-label extension studies
     o 380 Dravet patients being treated with FINTEPLA

     o More than 260 Dravet patients on therapy for a year or longer

• New U.S. awareness campaign and website to help clinicians
  understand the need for better seizure control and quality of life

• Hiring of key roles completed in the US and EU.
     o Additional hiring underway
                                                                       www.draveturgency.com

18
Product manufacturing
Validated commercial scale in place for drug substance and finished drug product

• Proprietary synthesis of fenfluramine
• Room-temperature, stable, aqueous oral solution
• Production via leading third party CMOs with GMP-licensed facilities
• Specialty pharmacy operation up and running, providing FINTEPLA to EAP participants.

       API Sourcing &     Labeling &   Specialty Pharmacy   Physician
     Bulk Manufacturing   Packaging       / Distribution     / Patient

19
MT1621 (Pyrimidine deoxynucleosides)
Thymidine kinase 2 (TK2) deficiency
Rare, genetic, progressive and often fatal mitochondrial DNA depletion syndrome
                                                                                                                                                                                                                             U.S. TK2d population
• Autosomal recessive mutations in TK2 gene
• First patient described in 2001
                                                                                                                                                                                                                                65,000-75,000
• Clinically characterized by severe muscle weakness,                                                                                                                                                                       mitochondrial disease1
                                                                                                                                                                                                                                   patients
  profoundly impairing movement, breathing, eating/nutrition
  and other normal functions                                                                                                                                                                                                   6,500-13,500 mtDNA
                                                                                                                                                                                                                                depletion2 patients
• Untreated patients show progressive decline, which is
  often fatal. No spontaneous recovery has been reported                                                                                                                                                                               650-2.5k TK2d3
                                                                                                                                                                                                                                          patients
• Age of onset is prognostic for outcome; younger patients
  have high mortality
                                                                                                                                                                                                                      43%                  41%          16%
• Currently no approved therapies; treatment limited to supportive care
                                                                                                                                                                                                                   Infantile             Childhood       Late
                                                                                                                                                                                                                    onset4                onset4        onset4

     1Gorman G Ann Neurology 2015 Lightowlers et al Science 2015 Banworth et al BMJ 2013 | 2A Rotig et al Genomic Medicine 2nd Edition 2015 A Rotig and J Poulton Biochemica et BioPhyica Acta 2009 | E Sarzi et al J Pediatr 2007 |

21   CJ Macmillan et al Pediatric Neurology 1996 | 3Spinazzola et al J Inherit Metab Dis 2009 | Carrozzo et al Human Mutation 2003 | Mancuso et al Neurology 2002 | 4Garone C, et al. J Med Genet 2018
MT1621 dC/dT substrate enhancement therapy
An investigational deoxynucleoside combination therapy for TK2 deficiency

• TK2 phosphorylates deoxycytidine (dC) and
  deoxythymidine (dT), fundamental building
  blocks in production of mitochondrial DNA
  (mtDNA)
• MT1621 uses nucleoside salvage pathway and
  residual TK2 activity to restore mitochondrial
  function
• Deoxynucleoside combination therapy
  improves nucleotide balance, increases mtDNA
  copy number, improves cell function, and
  prolongs life in preclinical models of TK2d.
• Given orally as a dissolved solution.

22
Strong pre-clinical data
dC/dT combination therapy demonstrated disease modifying mechanism of action in preclinical
mouse models

                              TK2D Prolongs Survival in TK2d
                                Knock-in Mouse Models (1)

                       (1) Lopez-Gomez et al. Ann Neurol 2017

23
MT1621 clinical efficacy RETRO study

                                                            Dominguez
                                                            -Gonzalez        Wang 2018
                                                              2019             n=82
                                                              n=16

                                                Additional          Garone          RETRO
                                               case reports          2018            Study
                                                   n=6               n=92            n=38

              Triaged for age-matching,
     duplicates, data discrepancies, etc.

                          Modified Untreated Dataset                                   RETRO Dataset (MT1621 Treated)
                                    n=68                                                          n=38

                Sourced from natural history publications                          Eight clinical sites in U.S., Spain, and Israel
                & additional updates                                               Patient set representative of broad TK2d
                Characterizes course of untreated disease                          population

                Serves as matched age comparator for                               Treatment period from 3 months to 7 years
                patient survival analysis

24
MT1621 RETRO study preliminary data
Statistically significant survival in treated vs. untreated (natural history) groups

                                       Survival                                                                   Functional Outcomes
                  Survival Analysis Curves Modeled from Treated                               •   MT1621 treated patients demonstrated
                          and Modified Untreated Groups                                           improvements in functional domains (motor,
                                                                                                  respiratory, feeding)
                                                                                              •   A number of MT1621 treated patients re-acquired
                                                           Treated(1)                             previously lost motor milestones (e.g., ambulation,
                                                           Natural History
                                                                                                  discontinuing respiratory support)

                                                                                                                          Safety
                                                                                          •       MT1621 was generally safe and well tolerated
                                                                                          •       Most common treatment-related adverse event: mild
                                                                                                  to moderate diarrhea (63%)
                                                                                          •       Four patients experienced Serious Adverse Events
                                                                                                  related to study drug
                                                                                          •       Two patients discontinued due to increased liver
                                        Survival (years)
                                                                                                  enzymes
 Survival analysis comparing treated patients in RETRO study with untreated patients
  (TK2d Natural History data set) showed statistically significant effect of pyrimidine
                          nucleosides on survival (p
MT1621 development plan
MT1621 has received FDA Breakthrough Therapy and EMA PRIME designations

                         Clinical Efficacy, Safety, PK                        Product (CMC)

 RETRO– Complete                                                        Process development,
 Retrospective treatment study using Natural History as control         scale up and validation of
 • 38 patients: ~80 patient years total exposure                        commercial manufacturing
                                                                        processes - Ongoing
 Prospective continuation study for RETRO patients and new patients –
 Initiated Q3 2019
 • Avg of 6 months                                                             Non-clinical
 • Measure ongoing efficacy, safety and tolerability
 • More thorough safety assessment                                      Chronic toxicology studies -
                                                                        Ongoing
 • Durability of efficacy
                                                                        Development and
                                                                        reproductive toxicology
 Single escalating dose PK in healthy volunteers – Ongoing
                                                                        studies - Planned

26
Diagnosis rate improvements in comparable rare diseases

Pompe Disease - France                                        Fabry Disease - Worldwide
  Year     Dx Pts. % Increase Pop. (M) % Increase Net Grwth      Year     Dx Pts. % Increase Pop. (M) % Increase Net Grwth
  2012      126          1.6%      65.7      0.6%      1.0%     2011       4167          7.9% 3,565.6       0.7%      7.1%
  2011      124          8.8%      65.3      0.5%      8.3%     2010       3863         11.4% 3,539.4       0.8%     10.6%
  2010      114          8.6%        65      0.5%      8.1%     2009       3469         15.1% 3,513.0       0.8%     14.4%
  2009      105         14.1%      64.7      0.5%     13.7%     2008       3013         14.9% 3,486.6       0.8%     14.1%
  2008       92         22.7%      64.4      0.6%     22.0%     2007       2622         18.3% 3,460.2       0.7%     17.5%
  2007       75         15.4%        64      0.6%     14.8%     2006       2217         20.0% 3,434.5       0.8%     19.3%
  2006       65        282.4%      63.6      0.6%   281.7%      2005       1847         61.2% 3,408.3       0.8%     60.4%
  2005       17         30.8%      63.2      0.8%     30.0%     2004       1146       144.9% 3,382.2        0.8%   144.1%
  2004       13        NA          62.7    NA                   2003        468        NA     3,356.0     NA
                                        CAGR:         32.2%                                           CAGR:          30.7%

Source: The French Pompe Registry                             Source: Sanofi-Genzyme Fabry Registry
Enzyme replacement approval in France in 2006                 Initial U.S. enzyme replacement approval in U.S. in 2003

27
Continuing momentum in the year ahead
     Upcoming Milestones                                                                      Anticipated Date

     •   FINTEPLA: US NDA and EU MAA submissions in Dravet syndrome                              Q1 2019

     •   FINTEPLA: Exclusive distribution agreement for FINTEPLA in Japan (Nippon Shinyaku)      Q1 2019

     •   FINTEPLA: US FDA Type A meeting following RTF letter                                    Q2 2019

     •   FINTEPLA: Complete enrollment of global Phase 3 trial in Lennox-Gastaut syndrome        H2 2019

     •   MT1621: Closing of Modis Therapeutics acquisition                                       Q3 2019

     •   FINTEPLA: NDA resubmission in Dravet syndrome                                           Q3 2019

     •   MT1621: RETRO study results at World Muscle Society Annual Congress                     Q4 2019

     •   FINTEPLA: Initiate Phase 2 study in multiple rare epilepsies (including Doose)          Q4 2019

     •   FINTEPLA: Top-line results of Phase 3 trial in Lennox-Gastaut syndrome                  Q1 2020

     •   MT1621: FDA Type B / EMA meetings to confirm paths to approval                          Q1 2020

28
29
     Updated September 13, 2019
You can also read
NEXT SLIDES ... Cancel