/

Developing

Breakthrough

Genetic Medicines for

Rare CNS Diseases

JEFFERIES HEALTHCARE CONFERENCE 2019

/

Company Overview

Developing life transforming genetic medicines for the

treatment of rare monogenic CNS diseases

- Portfolio of 5 indications with option to license an additional 7 indications

Partnership with the University of Pennsylvania Gene Therapy Program

- Proven best-in-class AAV technology and know-how, with 8 INDs filed in the orphan disease space

- Includes capsids from the next generation platform

- GTP will conduct IND-enabling preclinical work through an SRA and Passage Bio will be responsible for clinical development, regulatory, manufacturing and commercialization

Partnership with Penn’s Orphan Disease Center to support clinical

development and commercial deployment

- Create patient registries

- Conduct natural history studies

- Engage with KOLs and patient alliances

2

HEADQUARTERED IN

Philadelphia, PA

RECENTLY COMPLETED

$115.5M Series A

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Deep Pipeline of Rare Monogenic CNS Disease Therapies*

3

INDICATION GENE DISCOVERY IND ENABLINGCLINICAL

DEVELOPMENT

Lead Programs

GM1 GLB1 1H 2020

FTD PGRN 1H 2020

Krabbe Disease GALC 2H 2020

Other Programs

Program 4 2021

Program 5 2021

*Option to license 7 additional indications

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Passage Bio Management Team and BOD

4

Jill Quigley

COO & GENERAL COUNSEL

Pharmasset, NPS Pharma, Shire, Nutrinia

BOARD OF DIRECTORS

Tachi YamadaBoard Chair, Frazier

Saqib IslamCEO of SpringWorks

Stephen SquintoInterim CEO and

OrbiMed Venture Partner

Carl GordonOrbiMed Advisors

Patrick HeronFrazier

Tom WoiwodeVersant Ventures

Stephen Squinto, Ph.D

INTERIM CEO

Regeneron, Alexion co-founder, OrbiMed Venture Partner

Jim Wilson, M.D., Ph.D.

CHIEF SCIENTIFIC ADVISOR

Director, Gene Therapy Program and Orphan Disease Center

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Focused on Building through Partnership

5

▪ Strong preclinical translational science and regulatory capabilities.

▪ At the cutting edge of AAV research for 20+ years

▪ AAV manufacturing expertise

▪ Deep orphan drug development and commercialization know-how.

▪ Ability to select and prioritize existing programs and nominate new programs for research.

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Passage Bio: Access to Best-in-Class AAV Technology

and Know-How

6

GTP Lab Know-How

▪ Access to next-gen manufacturing strategies

▪ Fully-integrated capabilities

▪ 6-12 months from vector concept to in vivo animal PoC

▪ Unique regulatory insight due to participation in multiple applications of the platform

▪ 8 INDs filed for rare orphan diseases

Next-Gen Vectors

▪ Improved tissue / cell-type targeting translating to reduced toxicity

▪ Higher efficiency of transduction, allowing for improved efficiency and reduced COGS

▪ Lower rate of pre-existing neutralizing Abs

Best-In-Class Capabilities

▪ ~300 researchers working on novel vectors, capsids and clinical applications

▪ On-site GLP toxicology and small scale vector manufacturing

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Our Unique Therapeutic Development Process

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DISCOVERY CLINIC COMMERCIALIZATION

▪ All pre-clinical and IND-enabling studies

▪ Support for GLP toxicology

▪ Development of next generation capsids

▪ All clinical development, regulatory strategy and commercialization activities

Patient registries, natural history studies, KOL and patient engagement

PASSAGE BIO RECEIVES

▪ Licenses to 5 initial programs

▪ Exclusive option to license 7 additional programs utilizing next generation capsids

PENN RECEIVES

▪ Upfront payment

▪ Royalties and milestones

▪ Sponsored research agreement funding

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INDICATION Passage Bio

Passage Bio Optimal Vector and Delivery Route Selection

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Intraparenchymal IV Lumbar ICV ICM

Delivery LimitedLimited /

Very High DosesLimited Diffuse Diffuse

Toxicity High Systemic Low High Low

AAV Abs Impact Limits efficacy No Impact No Impact No Impact

Procedure RoutineInterventional

Radiologist

Interventional

Radiologist

Utilize best delivery route

SELECT OPTIMAL AAV

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Development Pipeline

9

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Type 1 GM1 Gangliosidosis Overview

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▪ Autosomal recessive genetic disorder, cause by inactivating mutation of the lysosomal enzyme β-galactosidase (GLB1)

▪ Abnormal upregulation of lysosomal enzymes in serum

▪ Extensive brain storage lesions

▪ Gait abnormalities by 4 months of age, developmental regression by 6 months

▪ Rapid progression with mortality by ~2 years of age

▪ No disease modifying therapies currently available

▪ The estimated worldwide incidence of infantile GM1 gangliosidosis is 0.5–1:100,000 live births

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Pharmacology Study in GLB1-/-

Mice Brain HEX Activity

11 *p < 0.05, **p<0.01 Kruskal-Wallis test/Dunn’s test

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Infantile GM1 Natural History Study

CONFIDENTIAL12

STUDY 1:

Infantile NHS, onsite assessments required

STUDY 2:

Infantile registry/web-based portal

AGE RANGE All ages All ages

INCLUSION

CRITERIA

• Diagnosis of type 1 GM1 gangliosidosis

• Documented symptom onset before

12 months of age

• Documentation of homozygous GLB1

gene deletion or mutation and GLB1

activity < lower limit of normal.

• Documented symptom onset by

6 months of age with hypotonia on

exam or history elicited from

parent/caregiver

ENDPOINTS • Survival, Bayley Score, and all FIH

exploratory endpoints

• Parent reported outcomes (survival,

feeding tube placement, seizure

onset and frequency, Vineland-II,

PedsQL)

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Overview of Frontotemporal Dementia (FTD)

Caused by Progranulin Mutations

▪ FTD typically presents around age 60-70

- A subset of familial forms of FTD is caused by mutations that lead to a deficiency in progranulin

- Average survival 8 yrs. from symptom onset

▪ Shrinking of the frontal and temporal lobes of the brain

- Causes impairment of executive function, language and/or social interaction

▪ No disease modifying therapies currently available

▪ Goal of therapy: restore CSF PGRN levels to normal

▪ 20,000-30,000 patients with FTD (between the ages of 45-64)1

13

1Knopman 2011

FLAIR. Marked frontal and temporal atrophy +

periventricular white matter lesions

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Frontotemporal Dementia PGRN

Preclinical Program

Evaluated potential to achieve therapeutic expression levels in a large animal model

▪ Proprietary AAV vector expressing human PGRN administered ICM to 2 rhesus macaques

▪ Necropsy 35 days post injection

▪ CSF PGRN levels reached 5-10x those of normal human subjects

▪ No abnormalities noted on weekly physical exam or daily observations

▪ No significant abnormalities noted on weekly CBC/chem, LFTs, CSF analysis

▪ No brain pathology

14Two adult rhesus macaques were treated with ICM AAV on study day 0.

Human PGRN was measured in CSF by ELISA..

0 10 20 30 40

0.1

1

10

100

Day

RA2981

RA2982

Healthy Subjects

0.1

1

10

100

AAV Treated NHPs

CS

F P

GR

N (

ng

/mL

)

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Krabbe Disease Overview

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▪ Autosomal recessive lysosomal storage disease caused by mutations in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC)

▪ Global incidence: 1 in 100,0001

▪ Destroys the myelin of nerve cells in the brain and throughout the nervous system

▪ Early infantile Krabbe disease2

▪ Most severe, 60–70% of diagnoses

▪ Symptoms develop before 6 months of age

▪ Survival is ~2 years

▪ Late infantile Krabbe disease3

▪ 10–30% of diagnoses

▪ Onset between 7-12 months of age

▪ Survival is ~5 years

▪ No disease modifying therapies currently available

1Escolar et al., 2016, Wasserstein et al., 20162Escolar et al., 2006, Duffner et al., 20113Duffner et al., 2012

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Krabbe Disease Preclinical Program

▪ Route: ICM in pre-symptomatic Krabbe dogs (3 weeks of age)

▪ Humane endpoint reached in vehicle treated controls (hindlimb severe paresis, urinary incontinence, head tremors, ataxia)

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Glia: Affected sham treated Oligo: Affected littermate ICM

Insert Video 2: Oligo treated 19 weeksInsert Video 1: Cortex sham 12 weeks

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iCELLis: Superior GMP Manufacturing Platform

▪ Fully-integrated bioreactor system

▪ Provides excellent cell growth conditions

for adherent cells

▪ Can handle large clinical and

commercial-scale volumes at reduced

operational costs

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Upcoming Milestones

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2020 2021

GM1Clinical Development

Krabbe DiseaseClinical Development

Program 4Clinical Development

FTDClinical Development

Program 5Clinical Development

Pediatric Indications

Adult Indications

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Company Overview

Developing life transforming genetic medicines for the

treatment of rare monogenic CNS diseases

- Portfolio of 5 indications with option to license an additional 7 indications

Partnership with the University of Pennsylvania Gene Therapy Program

- Proven best-in-class AAV technology and know-how, with 8 INDs filed in the orphan disease space

- Includes capsids from the next generation platform

- GTP will conduct IND-enabling preclinical work through an SRA and Passage Bio will be responsible for clinical development, regulatory, manufacturing and commercialization

Partnership with Penn’s Orphan Disease Center to support clinical

development and commercial deployment

- Create patient registries

- Conduct natural history studies

- Engage with KOLs and patient alliances

19

HEADQUARTERED IN

Philadelphia, PA

RECENTLY COMPLETED

$115.5M Series A

/

Developing

Breakthrough

Genetic Medicines for

Rare CNS Diseases

JEFFERIES HEALTHCARE CONFERENCE 2019