Global Leadership in Genetic MedicineJefferies Healthcare Conference

Geoffrey McDonough MD | CEONew York | 6 June 2019

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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

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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

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Capsid enables AAV delivery but limits clinical utility

AAV genome

Durable episomal expression

AAV capsid

Delivery

Systemic immunity Transgenes <4.7kbHigh cost/low capacity

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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

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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

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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)

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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…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

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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

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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

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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

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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

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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