Therapeutic Solutions for Rare Diseases - Corporate Overview September 23, 2019 - Investor Relations
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NASDAQ: ZGNX Therapeutic Solutions for Rare Diseases Corporate Overview September 23, 2019
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
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
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
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
FINTEPLA® (ZX008, fenfluramine)
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
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
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
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
10ZX008 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
11ZX008 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.
12ZX008 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)
13Regulatory 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
14ZX008 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
15ZX008
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
16Commercialization
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.
17Market 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
18Product 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
19MT1621 (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 2018MT1621 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
23MT1621 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
24MT1621 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 (pMT1621 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
26Diagnosis 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
27Continuing 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
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