Developing Breakthrough Genetic Medicines for Rare CNS Diseases SEPTEMBER 2019 /
Company Overview $225.5M Developing life transforming genetic medicines for the treatment of rare monogenic CNS diseases RAISED SINCE LAUNCH - Portfolio of 6 indications with option to license an additional 6 indications - Lead programs in GM1, FTD and Krabbe disease to enter clinic in 2020 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 HEADQUARTERED IN Philadelphia, PA - Create patient registries - Conduct natural history studies - Engage with KOLs and patient alliances 2 /
Deep Pipeline of Rare Monogenic CNS Disease Therapies* CLINICAL INDICATION GENE DISCOVERY IND ENABLING DEVELOPMENT Named Programs GM1 GLB1 1H 2020 FTD PGRN 1H 2020 Krabbe Disease GALC 2H 2020 CMT2A MFN2 2021 Unnamed Programs Program 4 2021 Program 5 2021 3 / *Option to license 7 additional indications
Focused on Building through Partnership ▪ Deep orphan drug development ▪ Strong preclinical translational and commercialization know-how science and regulatory capabilities ▪ Ability to select and prioritize ▪ At the cutting edge of AAV research existing programs and nominate for 20+ years new programs for research ▪ AAV manufacturing expertise ▪ Fully-integrated capabilities 4 /
Our Unique Therapeutic Development Process DISCOVERY COMMERCIALIZATION CLINIC ▪ ▪ All pre-clinical and IND-enabling studies All clinical development, regulatory strategy and commercialization activities ▪ Support for GLP toxicology ▪ Development of next generation capsids Patient registries, natural history studies, KOL and patient engagement PENN RECEIVES PASSAGE BIO RECEIVES ▪ ▪ Upfront payment Licenses to 6 initial programs ▪ ▪ Royalties and milestones Exclusive option to license 6 additional programs utilizing next generation capsids ▪ Sponsored research agreement funding 5 /
Passage Bio Optimal Vector and Delivery Route Selection SELECT OPTIMAL AAV Passage Bio Utilize best delivery route INDICATION Intraparenchymal IV Lumbar ICV ICM Limited / Delivery Limited Limited Diffuse Diffuse Very High Doses Toxicity High Systemic Low High Low AAV Abs Impact Limits efficacy No Impact No Impact No Impact Interventional Interventional Procedure Routine Radiologist Radiologist 6 /
Development Pipeline 7 /
Type 1 GM1 Gangliosidosis Overview ▪ 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 8 /
Pharmacology Study in GLB1 -/- Mice Brain HEX Activity *p < 0.05, **p<0.01 Kruskal- Wallis test/Dunn’s test 9 /
Infantile GM1 Natural History Study STUDY 1: STUDY 2: Infantile NHS, onsite assessments required Infantile registry/web-based portal AGE RANGE All ages All ages • • INCLUSION Diagnosis of type 1 and 2 GM1 gangliosidosis Documented symptom onset by CRITERIA 6 months of age with hypotonia on • Documented symptom onset before exam or history elicited from 12 months of age parent/caregiver • Documentation of homozygous GLB1 gene deletion or mutation and GLB1 activity < lower limit of normal. • • ENDPOINTS Survival, Bayley Score and all FIH Parent reported outcomes (survival, exploratory endpoints feeding tube placement, seizure onset and frequency, PedsQL) 10 / CONFIDENTIAL
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 FLAIR. Marked frontal and temporal atrophy + periventricular white matter lesions 1 Knopman 2011 11 /
Frontotemporal Dementia PGRN Preclinical Program AAV Treated NHPs Healthy Subjects Evaluated potential to achieve therapeutic expression levels in a large animal model 100 100 RA2981 ▪ Proprietary AAV vector expressing human PGRN CSF PGRN (ng/mL) administered ICM to 2 rhesus macaques RA2982 10 10 ▪ Necropsy 35 days post injection ▪ CSF PGRN levels reached 5-10x those 1 1 of normal human subjects ▪ No abnormalities noted on weekly physical exam or daily observations 0.1 0.1 0 10 20 30 40 ▪ No significant abnormalities noted on weekly Day CBC/chem, LFTs, CSF analysis ▪ No brain pathology Two adult rhesus macaques were treated with ICM AAV on study day 0. 12 / Human PGRN was measured in CSF by ELISA..
Krabbe Disease Overview ▪ Autosomal recessive lysosomal storage disease caused by mutations in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC) ▪ Global incidence: 1 in 100,000 1 ▪ Destroys the myelin of nerve cells in the brain and throughout the nervous system ▪ Early infantile Krabbe disease 2 ▪ Most severe, 60 – 70% of diagnoses ▪ Symptoms develop before 6 months of age ▪ Survival is ~2 years ▪ Late infantile Krabbe disease 3 ▪ 10 – 30% of diagnoses ▪ Onset between 7-12 months of age ▪ Survival is ~5 years ▪ No disease modifying therapies currently available 1 Escolar et al., 2016, Wasserstein et al., 2016 2 Escolar et al., 2006, Duffner et al., 2011 3 Duffner et al., 2012 13 /
Krabbe Large Animal Model: Brain MRI 8 weeks Post-Treatment * Wild type control – Krabbe vehicle #2 – Krabbe AAV ICM #2 – hypointense WM (normal = hyperintense WM (arrows), normal (hypo) to iso WM black WM) – clear corpus cortical atrophy (star), dilated signal. No atrophy. Normal callosum (arrow) ventricle (arrowhead), corpus ventricle and normal corpus callosum (myelinated WM callosum band between 2 hemispheres) is not visible 14 /
Dedicated cGMP Manufacturing Suite ▪ Dedicated manufacturing in Harmans, MD under strategic partnership agreement with Paragon Gene Therapy ▪ cGMP suite to support future clinical and commercial production for Passage therapies ▪ Expected to be operational in second half of 2020 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 15 /
Passage Bio Management Team and BOD Stephen Squinto, Ph.D. INTERIM CEO BOARD OF DIRECTORS Regeneron, Alexion co-founder, OrbiMed Venture Partner Tachi Yamada Patrick Heron Jill Quigley Board Chair, Frazier Frazier COO & GENERAL COUNSEL Saqib Islam Tom Woiwode Pharmasset, NPS Pharma, Shire, Nutrinia CEO of SpringWorks Versant Ventures Alex Fotopoulos Stephen Squinto Liam Ratcliffe CHIEF TECHNICAL OFFICER Interim CEO and Access Industries OrbiMed Venture Partner Ultragenyx, Momenta Pharmaceutical, Biogen Carl Gordon Jim Wilson, M.D., Ph.D. OrbiMed Advisors CHIEF SCIENTIFIC ADVISOR Director, Gene Therapy Program and Orphan Disease Center 16 /
Upcoming Milestones Pediatric Indications CMT2A Program 5 GM1 Krabbe Disease Clinical Development Clinical Development Clinical Development Clinical Development 2020 2021 FTD Program 6 Clinical Development Clinical Development Adult Indications 17 /
Company Overview $225.5M Developing life transforming genetic medicines for the treatment of rare monogenic CNS diseases RAISED SINCE LAUNCH - Portfolio of 6 indications with option to license an additional 6 indications - Lead programs in GM1, FTD and Krabbe disease to enter clinic in 2020 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 HEADQUARTERED IN Philadelphia, PA - Create patient registries - Conduct natural history studies - Engage with KOLs and patient alliances 18 /
Developing Breakthrough Genetic Medicines for Rare CNS Diseases SEPTEMBER 2019 /
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