Global Leadership in Genetic MedicineJefferies Healthcare Conference
Geoffrey McDonough MD | CEONew York | 6 June 2019
2
Durable expression
Therapeutic precision
Re-dosing + titrationScalable to treat millions
Our mission: global genetic medicines
SMALL MOLECULES BIOLOGICS GENETIC MEDICINEGENETIC MEDICINE
Durable expression
Therapeutic precision
Re-dosing + titration
Scalable to treat millions
3
Closed-end DNA: new vector, broad delivery, global scale
Scalable to millions of patients
cGMP-ready biologics manufacturing
High level, durable episomal expression
Large transgene capacity
Re-dosablegene therapy
Delivery to multiple tissues
Retina and liver are first therapeutic areas
4
Capsid enables AAV delivery but limits clinical utility
AAV genome
Durable episomal expression
AAV capsid
Delivery
Systemic immunity Transgenes <4.7kbHigh cost/low capacity
5
ceDNA is similar to AAV but double stranded, capsid-free
Large scale biologics manufacturing
Re-dosable
Large transgenes
Durable episomal expression
ceDNA (closed-ended DNA)
Translocation to nucleus
6
LocalDelivery
ceDNA can be formulated to access multiple tissues
Large scale biologics manufacturing
Re-dosable
Large transgenes
Durable episomal expression
ceDNA (closed-ended DNA)
Translocation to nucleus
Systemic Delivery
7
3 month rat sub-retinal (luciferase): ceDNA vs plasmid DNA
Durable, high expression in retina
DAYS PAST DOSE
AVG
RAD
IAN
CE (p
/s/c
m2 )
ceDNA (un-injected eye)
ceDNA (injected eye)
INJECTED EYE UN-INJECTED EYE
ceD
NA
Plas
mid
DN
A
plasmid DNA (injected eye)
plasmid DNA (un-injected eye)
8
Durable expression in liver
DAY 14 DAY 160
Unattenuated expression out to 160 days
0 50 100 150 200105
106
107
108
Study Day
Tota
l Fl
ux (p
hoto
ns/s
ec) PolyC
Luc ceDNA
9
Liver expression increases with repeat dosing
LNPceDNA 1mg/kgLNPceDNA 0.5mg/kgLNPceDNA 0.1mg/kgLNP Only
re-dose 10mg/kg
Repeat Dosing
17X
re-dose 3mg/kg7X
Tota
l Flu
x (p
/s)
10
High expression with ceDNA constructs for FVIII, FIX
75% activity
Hemophilia A (hydrodynamic)
D a y 3
D a y 7
D a y 3
D a y 7
D a y 3
D a y 7
D a y 3
D a y 7
-0 .2
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
F V III
FV
III
ex
pre
ss
ion
(I
U/m
L)
V e h ic leL S P 1 -F 8 -v 1L S P 1 -F 8 -v 2L S P 3 -F 8 -v 3
L L O Q
U L O Q
25% activity
Hemophilia B (hydrodynamic)
Da
y 3
Da
y 7
Da
y 3
Da
y 7
Da
y 3
Da
y 7
0 . 0 0
0 . 0 5
0 . 1 0
0 . 1 5
0 . 2 0
0 . 2 5
Pla
sm
a F
IX (
IU/m
L)
L L O Q
U L O Q
V e h i c l e
c e D N A - L S P 1
c e D N A - L S P 2
FIX
11
Correction of PHE levels in PKU model with hydrodynamic delivery
0 5 10 150
25
50
75
100
% PHE Change
Study Day
% P
HE
(rel
. to
100%
)
PolyCceDNA #1ceDNA #2
Reduction of serum phenylalanine
75% reduction • PAH point mutant mouse model
• Single hydrodynamic dose
12
Large capacity addresses rare diseases with large genes: progressive familial intrahepatic cholestasis (PFIC)
PFIC: impairs bile metabolism, - severe pruritus and jaundice- increased cancer risk, - eventual liver failure.
Requires broad transduction of hepatocytes to halt the toxic accumulation of bile precursors
The disease The genes Expression in vitro
PFIC3 promoter allows• ↑↓ as needed• Response to bile accumulation
PFIC3 promoter PFIC3 gene UTR
900bp3.8 kb3.0 kb
HepG2 Cells
HepG2 Cells
13
Manufacturing strategy leverages the biologics blueprint
• Leverages traditional biologics manufacturing capacity
• Efficient purification 1:1 with upstream
• Upstream scale unlocks production for millions of patients
• Robust analytics set a high-bar (99%+ purity)
De-risked manufacturing platform Differentiating attributes
14
ceDNA scales unlike any current cell or gene therapy
Manufacturing Investment
Man
ufac
turin
g Sc
ale
$50M $250M $500M
100 Pts
1000 Pts
10,000 Pts
100,000 Pts
1,000,000 Pts
10,000,000 Pts
• Scale for millions of patients• Biologics CoGS• Operational flexibility
15
Disrupting existing and creating new gene therapy markets
Hemophilia A PFIC
Few
pat
ient
sM
ore
pati
ents
Small genes Large/multiple genes
Potential to treat early in life with personalized dosing
Scale to meet global demand for biologics produced in patient’s own body
Revolutionary new classes of biologics requiring large genes and large scale
Uniquely address rare diseases requiring large genes
PKU
LysosomalStorage
Disorders
Stargardt
16
Building a multi-tissue portfolio…
LOCAL EYE Stargardt
LCA10
Wet AMD
CNS
SYSTEMIC LIVER PKU
GSD1a
PFIC
Heme A
MUSCLE
Pre-clinical POC Product development
DELIVERY
DELIVERY
17
…with unique clinical development approach
Multidose Phase I could allow titration for each patient
UNIQUE CLINICAL TRIAL ENROLLMENT FEATURES
Long-term re-dosing
Could enroll patients from prior gene therapy trials
18
Experienced leadership team
GEOFF MCDONOUGH, MDPresident & CEO
MARK ANGELINO, PHDChief Operating Officer Founder
DOUG KERR, MD, PHDChief Development Officer
MATT STANTON, PHDChief Scientific Officer
WILL MCCARTHYChief Business Officer
ROBERT KOTIN, PHDHead of Discovery Scientific Founder
JENNIFER ELLIOTT, PHD, JDChief Legal Officer
SARA DEN BESTENHead of Human Resources
PHILLIP SAMAYOA, PHDStrategy & Portfolio Development, Founder
TOM GRANEY Chief Financial Officer
ANTOINETTE PAONE
Head of Regulatory Affairs
19
Strong board, scientific advisors, and investors
BOARD OF DIRECTORS
JASON RHODESChair; Partner, Atlas Venture
GEOFF MCDONOUGH, MDCEO, Generation Bio
GUSTAV CHRISTENSENChairman Morphic Therapeutics
JEFF JONAS, MDCEO, Sage Therapeutics
DONALD NICHOLSON, PHDFormer CEO, Nimbus Therapeutics
ANTHONY QUINN MD, MBBSCEO, Aeglea BioTherapeutics
CHARLIE ROWLANDFormer CEO, Aurinia Pharmaceuticals
CATHERINE STEHMAN-BREEN MDFormer CMO Sarepta
INVESTORSSCIENTIFIC ADVISORY BOARD
ANDREW SCHARENBERG, MDChair & CSO, Casebia Therapeutics
KEVIN FITZGERALD, PHDCSO, Alnylam Pharmaceuticals
ROBERT KOTIN, PHDScientific Founder, Head of Discovery GenBio
AMIT NATHWANI PHD, MDDirector of the Katharine DormandyHaemophilia Centre
RICHARD THOMPSON, MD PHDProfessor of Molecular Hepatology
ADRIAN THRASHER, PHD, MDProfessor of Paediatric; Immunology; Wellcome Trust Principal Research Fellow
Series B
$100M Series A
$15M
20
ceDNA platform capabilities
ceDNA BIOLOGY• Construct screening • Immunology• Disease models
PRODUCTION• In-house process
development • cGMP CMO partner
• Lipid nanoparticles• Polymers• Novel fusion molecules
BROAD DELIVERY
NOVEL VECTORS• Genome wide informatics• Native transgene designs• Engineered structures
21
Company priorities for 2019
cGMP manufacturing at scale
Pre-IND development for multiple candidates
FDA INTERACT meting
First INDs in 2020
Building an early development portfolio
22
Early individualized intervention for a new generationPKU
Diagnosed at birthLow birth weight, ↑PheStrict diet control
SeizuresLoss of milestonesLearning disabilitiesIrreversible brain damage
Cognitive impairmentReduced attention spanDepression, anxietyTremors, paralysis
Work impairmentPsychiatric disorders
BIRTH CHILDHOOD ADOLESCENCE ADULTHOOD
Gene therapy
ceDNATreatment at birth Titration to effect
ceDNARedosing as the liver grows
BIRTH CHILDHOOD ADOLESCENCE ADULTHOOD
ceDNAMaintenance dosing as needed
Top Related