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Item 1. Business

2024-03-04 compared with 2023-03-06 · 403 added, 462 removed, 409 unchanged (68% of the section changed)

We are a clinical stage genetic medicines company focused on developing transformative therapies for central nervous system, or CNS, disorders with limited or no approved treatment options.

Our vision is to fulfill the promise of gene therapy by developing groundbreaking therapies that transform the lives of patients with CNS diseases.

The field of genetic medicine is rapidly expanding and we believe we have a differentiated approach to developing treatments for CNS disorders that enables us to select and advance product candidates with a higher probability of technical and regulatory success.

We have entered into a strategic research collaboration with the Trustees of the University of Pennsylvania’s, or Penn’s, Gene Therapy Program, or GTP , headed by Dr.

We are a clinical stage genetic medicines company on a mission to improve the lives of patients with neurodegenerative diseases.

Our primary focus is the development and advancement of cutting-edge, one-time gene therapies designed to target the underlying pathology of these conditions.

We believe we have developed a differentiated approach to developing treatments for central nervous system, or CNS, disorders that allows us to select and advance product candidates with a higher probability of technical and regulatory success.

Our lead clinical product candidate, PBFT02, seeks to elevate progranulin levels to restore lysosomal function and slow disease progression across a variety of neurodegenerative diseases.

PBFT02 utilizes an adeno-associated virus, or AAV1, capsid to deliver a functional granulin gene, or GRN , encoding progranulin, or PGRN, to the brain via intra cisterna magna, or ICM, administration .

The lead indication for PBFT02 is frontotemporal dementia, or FTD, caused by progranulin deficiency, or FTD- GRN .

We believe this clinical product candidate has the potential to provide patients with significantly improved outcomes given the rigorous capsid and transgene selection process, and our chosen route of ICM administration, which provides the potential for enhanced benefits due to widespread vector delivery to the brain and spinal cord and an improved safety profile compared with systemic administration due to the lower doses required.

We are currently studying PBFT02 in FTD- GRN , for which there are currently no approved disease-modifying therapies.

In addition to the continued clinical development of PBFT02 to treat FTD- GRN , we intend to pursue PBFT02 in additional adult neurodegenerative diseases where we believe increasing PGRN levels could provide benefit.

Third-party preclinical studies have shown that increased PGRN levels reduce the pathologic accumulation of TAR DNA binding protein 43, or TDP-43.

TDP-43 pathology is a hallmark of multiple neurodegenerative conditions, including FTD due to mutations in the C9orf72 gene, or FTD- C9orf72 , approximately 95% of sporadic amyotrophic lateral sclerosis, or ALS, and approximately 50% of sporadic FTD.

Additionally, we believe restoration of PGRN has the potential to modulate Alzheimer’s disease, or AD, in patients that are carriers of the GRN rs5848 single nucleotide polymorphism, or SNP.

Individuals with this polymorphism have reduced PGRN levels and are at an increased risk for AD.

In the second half of 2024, we expect to obtain regulatory feedback on the clinical pathway to treating FTD -C9orf72 and ALS patients with PBFT02.

We have a research collaboration with the Trustees of the University of Pennsylvania’s, or Penn’s, Gene Therapy Program, or GTP, headed by Dr.

James Wilson, a leader in the genetic medicines field.

We also leverage our close working relationship with Penn’s Orphan Disease Center, or ODC, to develop historical and prospective comparable natural history patient profiles for comparison to participants in interventional trials.

Through this collaboration we have assembled a strong portfolio of genetic medicine product candidates, for which we retain global rights, including our two lead clinical product candidates:

PBGM01 for the treatment of GM1 gangliosidosis, or GM1 , and PBFT02 for the treatment of frontotemporal dementia, or FTD;

and two clinical stage product candidates for which, in order to reduce operating expenses, we have stopped further clinical development and are exploring strategic alternatives:

PBKR03 for the treatment of Krabbe disease and PBML04 for metachromatic leukodystrophy, or MLD.

We have two programs in the research stage:

PBAL05 for amyotrophic lateral sclerosis, or ALS, and an unnamed program for Huntington’s disease.

We also have an exploratory research program for Temporal Lobe Epilepsy, or TLE.

We founded Passage Bio with the intent to build a differentiated CNS genetic medicines company delivering transformative therapies to patients by combining our team’s experience in rare and neurological disease development, manufacturing and commercialization with the pioneering research expertise of GTP in gene therapy.

We are purposefully focusing on rare CNS disorders for which we believe our genetic medicine approach provides distinct technical advantages based on decades of research by GTP.

GTP conducts rigorous preclinical studies to identify promising product candidates.

Our collaboration provides us with access to cutting edge capabilities and innovation in the field of genetic medicine research, including capsid engineering and next-generation capsid libraries, vector engineering, transgene design and gene therapy modalities, animal disease models and related studies for lead-optimization of product candidates.

Further, we believe our team’s deep clinical development experience in rare and neurological diseases will enable well planned clinical trials with the potential for efficient advancement to regulatory approval.

In addition, we are engaging with key opinion leaders, practitioners and patient advocacy groups in the field of rare CNS disorders who provide strategic input and help inform our clinical development activities.

We believe that our ability to execute on the above tenets provides us with product candidates that have an improved profile for clinical development and an enhanced probability of success.

We are focused on developing and commercializing disease-modifying therapies that can have a transformative impact on patients’ lives.

Utilizing our rigorous selection process, we have assembled a strong portfolio of product candidates for rare, monogenic CNS disorders.

Our first product candidate, PBGM01, utilizes a next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GLB1 gene encoding lysosomal beta-galactosidase, or β-gal, for GM1.

Our second product candidate, PBFT02, utilizes an AAV1 capsid to deliver to the brain a functional GRN gene encoding progranulin, or PGRN, for FTD caused by progranulin deficiency, or FTD-GRN.

There are currently no approved disease-modifying therapies for these diseases.

We believe our clinical product candidates have the potential to provide patients with significantly improved outcomes, given our chosen route of intra cisterna magna, or ICM, administration, the potential for enhanced benefits due to cross-correction of neighboring cells by secreted gene products, and our rigorous capsid and transgene selection process.

Our research collaboration with GTP provides us with access to one of the premier research institutions in the world for the discovery and preclinical development of genetic medicine product candidates and exclusive rights to product candidates for certain CNS disorders.

As part of this collaboration, we have exclusive rights to all discovery work and IND-enabling research for product candidates in the CNS indications that we select.

addition to our two lead clinical product candidates, we have two clinical product candidates for which, in order to reduce operating expenses, we have stopped further clinical development and are exploring strategic alternatives, two ongoing research programs, and eight remaining options available to us to license additional programs from GTP until August 2026.

We also have an exploratory research program with GTP in non-rare, non-monogenic, or large, CNS indications, currently focused on TLE, which can be expanded to other large, CNS diseases upon mutual agreement with GTP.

Further, we have exclusive rights, subject to certain limitations, to technologies resulting from the discovery program for our products developed with GTP, such as novel capsids, toxicity reduction technologies, delivery, and formulation.

We have global commercial rights to all of our current and future product candidates and believe that our approach to developing therapies for life-threatening diseases that are currently underserved presents an opportunity to efficiently advance our product candidates through clinical development, regulatory approval and ultimately to commercialization.

We are led by pioneers and experts with decades of collective experience in genetic medicines and rare disease drug development, manufacturing and commercialization.

Wilson, one of our scientific founders, is recognized as a world leader in research and development in the fields of genetic medicines and rare disease.

Wilson’s continuing relationship with our company helps guide our clinical and research programs.

We have assembled a team whose members have extensive experience in successfully developing, manufacturing and commercializing genetic medicine and rare disease products.

We have assembled a strong portfolio of genetic medicine product candidates for rare, monogenic CNS disorders characterized by high unmet medical needs.

We intend to further expand our portfolio with genetic medicine product candidates for other CNS disorders, as well as other treatment approaches as technology advances in the field.

We are purposefully focusing on neurodegenerative diseases for which we believe our genetic medicine approach provides distinct technical advantages based on decades of research by GTP.

GTP conducts rigorous discovery and preclinical studies to identify promising product candidates.

Under our research collaboration, we have exclusive development and global commercial rights to product candidates for certain rare monogenic and certain non-rare, non-monogenic, or large, CNS disorders, subject to certain limitations.

We also have access to platform technologies related to development of novel capsids, toxicity reduction technologies, and optimization approaches for delivery and formulation for product candidates in the CNS indications that we select.

We have progressed four product candidates sourced from our research collaboration with GTP to the clinical stage of development and have eight remaining options to license additional programs from GTP until August 2026.

In December 2023, we announced updated strategic priorities, which include:

continuing clinical development of PBFT02 to treat FTD- GRN ;

pursuing PBFT02 in additional adult neurodegenerative diseases, including FTD- C9orf72 , ALS and AD;

continuing the Huntington’s disease preclinical program being executed through our collaboration with GTP;

and pursuing potential out-licensing opportunities for clinical-stage pediatric programs in GM1 gangliosidosis, or GM1, Krabbe disease, and metachromatic leukodystrophy, or MLD.

We have assembled a portfolio of gene therapy product candidates with the potential to address multiple neurodegenerative diseases.

Our development programs consist of:

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3 license options were previously exercised, and rights were subsequently returned to the University of Pennsylvania.

† Program includes ongoing natural history study of infantile and juvenile GM1 gangliosidosis patients

PBGM01 for the treatment of GM1

We are currently developing PBGM01, which utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GLB1 gene encoding β-galactosidase (or β-gal) for infantile GM1.

Infantile GM1 is the most common and severe form of GM1, in which patients have mutations in the GLB1 gene that produce little or no residual β-gal enzyme activity.

β-gal is an enzyme that catalyzes the first step in the natural degradation of GM1 ganglioside as well as other glycan substrates.

Reduced β-gal activity results in the accumulation of toxic levels of GM1 ganglioside in neurons throughout the brain, causing rapidly progressive neurodegeneration, with a life expectancy of two to ten years.

Currently, there are no disease-modifying therapies approved for the treatment of GM1.

Early onset infantile GM1 is characterized by onset in the first 6 months of life, while late onset infantile GM1 is characterized by onset between 6 and 24 months.

We believe PBGM01 could provide patients with significantly improved outcomes.

preclinical studies we observed meaningful transgene expression in both the CNS and in peripheral organs affected in GM1.

We are conducting clinical trials using an ICM method of administration, which involves an injection at the craniocervical junction.

We have an active Investigational New Drug application, or IND, from the U.S.

Food and Drug Administration, or FDA, and approved clinical trial authorizations, or CTAs, in multiple countries for PBGM01, and we are actively proceeding with our Imagine-1 Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBGM01 in patients with a diagnosis of early and late infantile GM1.

We have completed dosing of the initial four cohorts in our Imagine-1 Trial.

This includes a total of eight patients, as follows:

Cohort 1 for late infantile GM1 treated with low dose PBGM01, Cohort 2 for late infantile GM1 treated with high dose PBGM01, Cohort 3 for early infantile GM1 treated with low dose PBGM01, and Cohort 4 for early infantile GM1 treated with high dose PBGM01.

In December 2022 and February 2023, we reported interim safety and biomarker data for the first three cohorts of our Imagine-1 trial.

The safety data showed that PBGM01 was well tolerated with no serious adverse events and no evidence of dorsal root ganglion toxicity or complications related to the ICM injection.

We observed a dose-dependent increase in β-gal activity in the cerebral spinal fluid, or CSF, coupled with a dose-dependent decrease in CSF levels of GM1 ganglioside.

We also reported meaningful improvement in a subset of patients across developmental areas in assessments utilizing the Vineland II and Bayley III scales, performed by caregivers and trained healthcare providers, respectively.

The data suggests that stage of disease may be a determinant in treatment outcomes.

We expect to report initial safety and biomarker data from patients in Cohort 4 in the middle of 2023.

A key objective of the initial phase of the Imagine-1 trial is to determine the optimal dose for the confirmatory phase of the study.

Based on the favorable safety profile of PBGM01 observed to date, the observed dose-response in key biomarkers, such as CSF b -gal activity and GM1 ganglioside levels, and that our preclinical studies showed no safety signals at doses higher than currently being evaluated in the ongoing clinical trial, we plan to treat additional patients in the Imagine-1 trial at higher doses of PBMG01 than the doses of PBGM01 administered to date in Cohorts 1 to 4.

Following regulatory review, we expect to dose the first patient at a higher dose of PBGM01 in the second half of 2023.

The FDA has granted Orphan Drug Designation, or ODD, Rare Pediatric Disease Designation, or RPDD, and Fast Track Designation, to PBGM01 for the treatment of GM1.

The European Commission has granted Orphan designation and Advanced Therapy Medicinal Product, or ATMP, designation for PBGM01.

† US/EU prevalence per third-party sources

PBFT02 for the treatment of FTD-GRN

We are currently developing PBFT02, which utilizes an AAV1 capsid to deliver a functional copy of the granulin gene, or GRN, encoding for human progranulin, or PGRN, for the treatment of frontotemporal dementia caused by progranulin deficiency, or FTD-GRN.

We are currently developing PBFT02, which utilizes an AAV1 capsid to deliver a functional copy of GRN encoding for PGRN, for the treatment of FTD- GRN .

FTD- GRN is an inheritable form of FTD in which patients have mutations in the GRN gene, causing a deficiency in PGRN.

PGRN is a complex and highly conserved protein thought to have multiple roles in cell homeostasis, neurodevelopment, and inflammation.

Emerging evidence suggests that PGRN deficiency in FTD and other neurodegenerative disorders may contribute to lysosomal dysfunction.

Evidence suggests that PGRN deficiency in FTD and other neurodegenerative disorders may contribute to lysosomal dysfunction.

Currently, there are no disease-modifying therapies approved for the treatment of FTD- GRN .

Based on findings in preclinical studies, we believe that PBFT02 may provide FTD- GRN patients with significantly improved outcomes.

We selected the AAV1 capsid and ICM administration for PBFT02 because this approach led to extensive and robust expression of human PGRN throughout the brain and spinal cord of non-human primates, or NHPs, and due to the higher PGRN levels in CSF using AAV1 as compared with other serotypes tested.

ICM administration of AAV1 to NHPs resulted in supraphysiologic CSF levels of human PGRN compared to levels in healthy human subjects’ CSF, and in excess of levels achieved in NHPs with AAVhu68 or AAV5.

We have an active IND from the FDA and approved CTAs in multiple countries for PBFT02, which allows us to proceed with our upliFT-D Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBFT02 in patients with a diagnosis of early symptomatic FTD-GRN.

In August 2022, we dosed the first patient in our upliFT-D trial.

We expect to report initial safety and biomarker data from patients in Cohort 1 in the second half of 2023.

The FDA has granted ODD and Fast Track Designation to PBFT02 for the treatment of FTD-GRN and the European Commission granted Orphan designation for PBFT02.

We selected the AAV1 capsid and ICM administration for PBFT02 because this approach led to extensive and robust expression of human PGRN throughout the brain and spinal cord of non-human primates, or NHPs, and due to the higher PGRN levels in cerebral spinal fluid, or CSF, achieved using AAV1 as compared with other serotypes tested.

ICM administration of AAV1 to NHPs resulted in supraphysiologic CSF levels of human PGRN when compared with CSF levels in healthy human subjects, and in excess of levels achieved in NHPs with AAVhu68 or AAV5.

We have an active IND from the U.S.

Food and Drug Administration, or FDA, and approved clinical trial authorizations, or CTAs, in multiple countries for PBFT02.

We are conducting our upliFT-D trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBFT02 in patients with a diagnosis of symptomatic FTD- GRN .

We reported initial safety and biomarker data from three patients in Cohort 1 of our upliFT-D trial in December of 2023.

In this trial, Dose 1 of PBFT02 treatment resulted in supraphysiologic levels of CSF PGRN with concentrations ranging from 10.7 to 17.3 ng/mL at 30 days post-treatment (n=3), exceeding the range found in healthy adult controls of 3.3 to 8.2 ng/mL (n=61).

In the first patient to reach 6-months post PBFT02 administration, CSF PGRN remained at supraphysiologic levels with a concentration of 27.3 ng/mL.

By contrast, following PBFT02 treatment plasma PGRN levels were unaltered, remaining similar to baseline concentrations and below levels found in healthy adult controls throughout the available follow-up period across all three patients.

As previously reported, Patient 1, who received a low level of immunosuppression (60 mg oral prednisone daily for 60 days), per the initial trial protocol, experienced two serious adverse events, or SAEs, that were both asymptomatic and

likely consistent with an immune response.

Following Patient 1, the protocol was amended to increase the steroid regimen.

Dose 1 of PBFT02 was generally well-tolerated in patients 2 and 3, who received an enhanced steroid regimen (1,000 mg IV methylprednisolone on days 1-3 followed by 60 mg oral prednisone for 60 days).

In these two patients, no SAEs were reported, all treatment emergent adverse events, or AEs, were mild to moderate in severity, and there was no evidence of a clinically significant immune response, hepatotoxicity, or safety-related imaging findings in either patient.

In all three patients, there was no evidence of dorsal root ganglion toxicity, as measured by nerve conduction studies, and no complications were observed related to the intra-cisterna magna administration procedure.

We intend to treat two additional patients at Dose 1 in Cohort 1, with no required delay between these patients, to further study the safety and pharmacodynamic effects of PBFT02 at this dose.

We expect to initiate dosing of Cohort 2 FTD- GRN patients in the upliFT-D trial in the first half of 2024, report six-month safety and biomarker data from Cohort 1 patients in the second half of 2024, and report 12-month follow-up data from Cohort 1 patients and initial safety and biomarker data from Cohort 2 patients in the first half of 2025.

The FDA has granted Orphan Drug Designation, or ODD, and Fast Track Designation to PBFT02 for the treatment of FTD- GRN and the European Commission granted Orphan designation for PBFT02.

PBFT02 for the treatment of FTD-C9orf72 and ALS

We intend to pursue PBFT02 in additional adult neurodegenerative diseases where we believe supraphysiologic PGRN levels could provide benefit.

This approach stems from PGRN’s pleiotropic cellular effects including the regulation of microglial activation and lysosomal function, and in particular its potential to ameliorate TDP-43 pathology.

TDP-43 is a ribonucleic acid / deoxyribonucleic acid, or RNA/DNA, binding protein that normally resides in the nucleus where it regulates gene expression, RNA splicing, RNA trafficking, and mRNA turnover.

Cytoplasmic TDP-43 pathology is a hallmark of multiple neurodegenerative conditions including FTD- GRN , FTD- C9orf72 , approximately 95% of sporadic ALS, and approximately 50% of sporadic FTD.

In these disorders, hyperphosphorylated TDP-43 accumulates in the cytoplasm of cell bodies and dendritic processes of neurons and glia, suggesting that loss of TDP-43's normal nuclear function contributes to the neurodegenerative process.

The potential for benefit of increased PGRN in disorders with TDP-43 pathology has been demonstrated by third-party preclinical studies in mice and zebrafish which showed that increased PGRN levels reduced TDP-43 pathology and associated toxicities.

We anticipate that elevating neuronal PGRN levels in diseases with TDP-43 pathology may provide significant benefits to patients.

We expect to obtain regulatory feedback on the clinical pathway to treating FTD- C9orf72 and ALS patients with PBFT02 in the second half of 2024.

PBFT02 for the treatment of AD

We believe that elevating PGRN levels has the potential to improve the course of AD in patients who carry the GRN rs5848 single nucleotide polymorphism, or GRN SNP.

The GRN SNP is associated with reduced PGRN levels and is present within approximately 30% of the population.

Its presence has been shown to confer an increased risk for AD onset.

Within symptomatic AD patients, GRN SNP carriers not only have lower levels of PGRN, but also higher levels of CSF tau, which correlates with increased AD pathology in the brain and more rapid disease progression.

Third party preclinical studies in animal models have demonstrated that low levels of PGRN may exacerbate AD pathology and, conversely, high levels of PGRN may reduce AD pathology.

We plan to initiate preclinical studies in AD to extend these initial observations.

Other Clinical Product Candidates

We have two clinical product candidates, PBKR03 and PBML04, for which, in order to reduce operating expenses, we have stopped further clinical development and are exploring strategic alternatives for these assets.

We have three additional clinical product candidates, PBGM01, PBKR03 and PBML04.

In order to reduce operating expenses, we have stopped further clinical development and are pursuing out-licensing opportunities for these product candidates.

PBGM01 utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GLB1 gene encoding β-galactosidase (or β-gal) for infantile GM1.

Infantile GM1 is the most common and severe form of GM1, in which patients have mutations in the GLB1 gene that produce little or no residual β-gal enzyme activity.

b -gal is an enzyme that catalyzes the first step in the natural degradation of GM1 ganglioside as well as other glycan substrates.

Currently, there are no disease-modifying therapies approved for the treatment of GM1.

Early onset infantile GM1 is characterized by onset in the first 6 months of life, while late onset infantile GM1 is characterized by onset between 6 and 24 months.

We have an active IND from the FDA and approved CTAs in multiple countries for PBGM01 to support our Imagine-1 trial, a two-part international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBGM01 in patients with a diagnosis of early and late infantile GM1.

Part 1 of the Imagine-1 trial is a dose escalation study exploring three doses of PBGM01 in six cohorts of GM1 patients, three with early infantile GM1 and three with late infantile GM1, and is currently ongoing.

We have completed dosing of the initial two dose levels, cohorts 1 to 4, and began dosing of our third and highest dose level in the fifth cohort, for late infantile GM1, and sixth cohort, for early infantile GM1.

To date, the safety data showed that PBGM01 was well tolerated with no SAEs related to study treatment and no evidence of dorsal root ganglion toxicity or complications related to the ICM injection.

In both, early and late infantile GM1 patients, we observed a dose-dependent increase in β-gal activity in the CSF coupled with a dose-dependent decrease in CSF levels of GM1 ganglioside.

Furthermore, at the second dose level, GM1 ganglioside achieved normal adult levels at one-year post-dose.

In December 2023, we announced that we have paused enrollment of additional patients into the Imagine-1 trial and that we are pursuing potential out-licensing opportunities for this asset.

PBKR03 utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GALC gene encoding the hydrolytic enzyme galactosylceramidase to treat Krabbe disease.

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This results in the accumulation of galactolipids such as psychosine, resulting in widespread death of myelin-producing cells in the CNS and in the peripheral nervous system, or PNS.

We have an active IND from the FDA and approved CTAs in multiple countries for PBKR03 to support our GALax-C Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBKR03 in patients with a diagnosis of infantile Krabbe disease.

In March 2022, we dosed the first patient in our GALax-C Trial.

In November 2022, we announced plans to stop further clinical development of PBKR03 in order to reduce operating expenses, and are exploring strategic alternatives for this asset.

We currently have an active IND from the FDA.

Our GALax-C trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBKR03 in patients with a diagnosis of infantile Krabbe disease, was terminated and we have stopped further clinical development of PBKR03, in order to reduce operating expenses, and are pursuing potential out-licensing opportunities for this asset.

PBML04 utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional arylsulfatase A gene, or ARSA , encoding the ARSA enzyme, to treat Metachromatic Leukodystrophy, or MLD.

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When the ARSA enzyme is lacking, sulfatides accumulate in lysosomal storage deposits in microglia, oligodendrocytes, and Schwann cells, leading to widespread demyelination.

Our preclinical data in ARSA -/- mice and in NHPs support the ability of PBML04 administration into CSF to result in dose-dependent increases in brain and CSF levels of functional human ARSA enzyme, leading to improved biochemical, histopathological, behavioral, survival endpoints, and with no safety or toxicity signs up to the highest tested dose in NHPs.

Preclinical findings were presented by GTP in 2021.

Our preclinical data in ARSA -/- mice and in NHPs support the ability of PBML04 administration into CSF to result in dose-dependent increases in brain and CSF levels of functional human ARSA enzyme, leading to improved biochemical, histopathological, behavioral, and survival endpoints, and with no safety or toxicity signs up to the highest tested dose in NHPs.

In April 2022, we submitted an IND for PBML04 to support clinical development in MLD.

On May 20, 2022, the FDA cleared our IND application for PBML04, which supports PBML04-001, an international, multi-center, open-label, single-arm clinical trial of PBML04 in patients with a diagnosis of late onset infantile MLD.

In November 2022, we announced plans to stop further clinical development of PBML04 in order to reduce operating expenses, and are exploring strategic alternatives for this asset.

On May 20, 2022, the FDA cleared our IND application for PBML04, which supports PBML04-001, a multi-center, open-label, single-arm clinical trial of PBML04

in patients with a diagnosis of late onset infantile MLD.

We have not initiated clinical development of PBML04, in order to reduce operating expenses, and are pursuing potential out-licensing opportunities for this asset.

Research Programs

We have two programs in preclinical research stages under our license agreement with Penn:

PBAL05 for ALS and, an unnamed program for Huntington’s disease.

PBAL05 is targeting patients with ALS who have a gain-of-function mutation in the C9orf72 gene.

Our unnamed program is focused on the treatment of Huntington’s disease, a repeat expansion disorder.

Beyond this portfolio, through our research collaboration with GTP, we also have the option to license programs for eight additional new indications in CNS diseases along with certain rights and licenses to new gene therapy technologies developed by Penn, such as novel capsids, toxicity reduction technologies and delivery and formulation.

We also have an exploratory research program with GTP for larger non-monogenic indications, currently focused on TLE, which can be expanded to other large CNS diseases upon mutual agreement with GTP.

We are a genetic medicines company focused on developing transformative therapies for CNS disorders with limited or no approved treatment options.

Our vision is to fulfill the promise of gene therapy by developing groundbreaking therapies that transform the lives of patients with CNS diseases.

To achieve our vision, we have assembled a world-class team whose members have decades of collective experience in genetic medicines and rare disease drug development and commercialization.

We leverage this experience, to develop treatments that improve outcomes for patients with serious, life-threatening CNS diseases.

Patients are considered every step of the way, in every decision we make.

We have one unnamed preclinical research program through our license agreement with GTP, which is exploring multiple potential treatment targets for Huntington’s disease.

Beyond this program, through our research collaboration with GTP, we also have the option to license programs for eight additional new indications in CNS diseases along with certain rights and licenses to new gene therapy technologies developed by GTP, such as novel capsids, toxicity reduction technologies, and approaches to optimize delivery and formulation.

Other Research Programs

We have a preclinical research program, PBAL05, under our license agreement with Penn for patients with ALS who have a gain-of-function mutation in the C9orf72 gene.

We also have a program under our exploratory research program with GTP for Temporal Lobe Epilepsy, or TLE.

In order to reduce operating expenses, we have paused development of both of these programs.

We are a genetic medicines company on a mission to improve the lives of patients with neurodegenerative diseases.

Our primary focus is the development and advancement of cutting-edge, one-time therapies designed to target the underlying pathology of these conditions.

To achieve our vision, we have assembled a world-class team whose members have decades of collective experience in drug development and commercialization.

We leverage this experience as we strive to develop treatments that benefit patients with neurodegenerative conditions and their families.

Patients are considered in every decision we make.

Key elements of our strategy include:

• Focus on underserved indications for which we can have a transformative impact on patients’ lives.

We believe that genetic medicine has the potential to have a transformative impact on CNS disorders, and on patients’ lives, by providing them with a treatment for life-threatening diseases with limited or no approved treatment options.

• Rapidly advance our clinical product candidates through clinical development and commercialization.

We leverage our collaboration with GTP, as well as our internal capabilities, to select optimal product candidates for each indication based on extensive preclinical data, including animal data and disease-specific animal models and biomarkers, thus enhancing the probability of clinical success of our product candidates.

Our goal is to select candidates that have the potential to address high unmet clinical needs and have transformative therapeutic effects for patients.

If our clinical trials are successful, we plan to meet with regulatory authorities to discuss expedited regulatory approval strategies.

• Advance and expand our pipeline by identifying and developing additional product candidates into the clinic.

We believe our differentiated drug development approach as well as our internal and partnered research capabilities may allow us to address a broad range of CNS disorders, thus expanding our pipeline.

Through our collaboration with GTP, we are continuing to develop additional genetic medicine product candidates targeting life-threatening CNS disorders.

We have two lead clinical product candidates, two clinical product candidates for which we have stopped further clinical development in order to reduce operating expenses and are exploring strategic alternatives for these assets, and three additional programs advancing through the research or discovery stage.

We also have the option to license eight additional CNS indications from GTP until May 2026.

• Focus on neurodegenerative indications for which we can have a transformative impact on patients’ lives.

We believe that genetic medicines have the potential to significantly change the course of neurodegenerative diseases and to transform patients’ lives, by providing patients with one-time disease modifying treatments for life-threatening conditions with limited or no approved treatment options.

• Advance PBFT02 for the treatment of FTD- GRN .

Based on the initial clinical data for PBFT02 in FTD- GRN , we are prioritizing the execution of the ongoing upliFT-D study, with the goal of advancing this program to the registrational phase.

We believe this clinical product candidate has the potential to provide patients with significantly improved outcomes, given our initial observations of supraphysiologic CSF PGRN levels in patients after PBFT02 administration and the improvements in pathology seen in preclinical studies at these PGRN levels .

• Broaden the application of PBFT02 by exploring its potential in additional neurodegenerative indications .

Based on initial clinical data for PBFT02 in FTD- GRN and evidence supporting progranulin’s role in neurodegeneration, we are exploring the therapeutic potential of PBFT02 in multiple diseases, including FTD- C9orf72 , ALS and AD.

We believe that our differentiated approach of advancing one genetic medicine candidate to treat multiple indications is a cost-effective strategy due to shared research and development costs, streamlined regulatory processes, and the opportunity for diversified revenue streams.

• Extend existing and establish new relationships with patients and patient advocacy groups.

Patients are at the core of what we do.

We have been engaging with them and with their advocacy groups since our inception and have acquired an intimate understanding of how we can positively impact their lives.

We have been engaging with patients, their families, and their advocacy

groups since our inception and have acquired an intimate understanding of how we can positively impact their lives.

These relationships deeply inform us as we develop and ultimately seek to commercialize our product candidates.

Our relationship with Penn’s ODC, which is currently performing a natural history study for GM1 that we are funding, represents an example of our strategy, and has been helping us to engage effectively with patients.

We have a collaboration with Invitae to facilitate genetic testing and support early identification of GM1 through Invitae’s Detect Lysosomal Storage Disorders, as well as provide clinical trial information to physicians and patients, and have partnered with InformedDNA to offer free genetic counseling and testing for adults who have been diagnosed with FTD.

• Continue to develop proprietary manufacturing capabilities.

We also have agreements with third-party providers to offer genetic testing and counseling to adults who have been diagnosed with FTD at no cost to the patient.

• Continue to leverage our robust manufacturing capabilities.

We believe the quality, reliability and scalability of our genetic medicine manufacturing techniques and know-how will be a critical advantage to our long-term success.

We have established robust in-house analytical and process development operations to support ongoing and future manufacturing operations.

We have also advanced our manufacturing and testing technology platforms;

our in-house laboratory is equipped with state-of-the-art analytical capabilities, capable of assay development and validation, clinical product testing, and process and product development to support viral vector manufacturing.

We also have the internal manufacturing

and quality expertise to oversee external manufacturing and supply chain operations provided by third party strategic relationships, such as Catalent Maryland, a unit of Catalent Biologics, Inc, or Catalent.

We also have access to a manufacturing suite through Catalent where we have successfully produced GMP material for our clinical programs.

This facility is capable of producing sufficient supplies to conduct our planned clinical trials and, supply initial commercial launch of our current clinical product candidates, if approved.

• Selectively enter into new discovery relationships with premier research institutions and expand our existing collaboration.

We will continue to foster our well-established relationship with Penn, and potentially enter into new collaborations to build or advance our pipeline.

We will look to nurture our genetic medicine technology capabilities by keeping abreast of advances in next-generation capsid development, promoter selection, transgene design, gene silencing and gene editing, which will help us to engineer optimal product profiles to address life-threating CNS disorders characterized by high unmet medical needs.

We have also advanced our manufacturing and testing technology platforms and our in-house laboratory is equipped with state-of-the-art analytical capabilities for assay development and validation, clinical product testing, and process and product development to support viral vector manufacturing.

We also have the internal manufacturing and quality expertise to oversee external manufacturing and supply chain operations provided by third party strategic relationships, such as Catalent Maryland, a unit of Catalent, Inc., or Catalent.

We believe Catalent is capable of producing enough supplies to support our planned clinical trials and initial commercial launch of our current clinical product candidate, if approved .

• Continue to leverage our existing collaboration with GTP and s electively enter into new discovery relationships with premier research institutions.

We will continue to leverage our well-established relationship with GTP and explore other potential collaborations to build or advance our pipeline, contingent on the prioritization of operating expenses .

Genetic Medicine Background

Each person’s genetic material, or genome, consists of deoxyribonucleic acid, or DNA, in sequences of genetic code called genes.

Each person’s genetic material, or genome, consists of DNA in sequences of genetic code called genes.

The DNA in the human genome contains approximately three billion nucleotide base pairs, and small changes, or mutations, routinely occur in the base pairs.

A mutation in a single gene can alter the amount or activity of the protein expressed by the gene, causing deformities and disease.

Currently, there are estimated to be over 10,000 diseases caused by a genetic abnormality in a single gene.

These are also known as monogenic diseases.

Based on research commissioned by us, we believe there are at least 790 rare monogenic CNS diseases, with few currently approved disease modifying treatments for any rare monogenic CNS diseases.

In addition, gene therapy can also be applied to correct biological pathways that are not necessarily inherited or associated with one defective gene.

Currently, there are estimated to be over 10,000 diseases caused by a genetic abnormality in a single gene, which are also known as monogenic diseases.

One gene therapy approach is to introduce into cells a new, fully functional version of a defective or missing gene.

This approach is the basis for our FTD- GRN program.

In addition, gene therapy can also be applied to correct dysfunctional biological pathways that are not necessarily inherited or associated with one defective gene.

This approach aims to reduce the expression of pathological proteins or increase the production of corrective biological targets.

This is the basis for the programs that target non-hereditary conditions such as TLE.

The development of molecular therapeutics to modulate human gene expression and correct disease-causing genetic defects had its advent several decades ago, and with advances in science and a deeper understanding of human genetics it has expanded to include a broader range of genetic medicines with the potential to modulate gene expression through additional molecular mechanisms.

These transformative genetic medicines include gene therapy (delivery of an external gene to replace a defective gene), gene silencing (delivery of a DNA or ribonucleic acid, or RNA, based therapeutic that modulates the transcription or translation of an injurious gene product), gene editing (delivery of a DNA or RNA-based therapeutic that corrects the expression of targeted genes) and combinations of these therapeutic modalities.

This is the basis for our programs that target conditions such as FTD- C9orf72 , ALS, and AD.

The development of molecular therapeutics to modulate human gene expression and correct disease-causing genetic defects had its advent several decades ago, and with advances in science and a deeper understanding of human genetics it has expanded to include a broad range of genetic medicines with the potential to modulate gene expression through diverse molecular mechanisms.

These transformative genetic medicines include gene therapy (delivery of an external gene to replace the normal function of a defective gene), gene silencing (delivery of a DNA or RNA-based therapeutic that modulates the transcription or translation of an injurious gene product), gene editing (delivery of a DNA or RNA-based therapeutic that corrects the expression of targeted genes) and combinations of these therapeutic modalities.

We believe that this expanded molecular biological tool box will provide new therapeutics with the potential to deliver highly potent and safe interventions across a diverse set of CNS diseases, offering several advantages, including:

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• Potential to target mechanisms that have not been effectively or safely modulated by traditional small molecule or protein-based therapeutics.

The inherent specificity of genetic medicines for unique nucleic acid sequences can provide a high therapeutic index resulting from high potency and the potential to deliver adequate doses while avoiding off-target safety liabilities.

The inherent specificity of genetic medicines for unique

nucleic acid sequences can provide a high therapeutic index resulting from high potency and the potential to deliver adequate doses while avoiding off-target safety liabilities.

• Efficient delivery of transformative therapeutics.

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These disorders are generally life-threatening to patients.

There is a significant need for genetic

medicines that can target these disorders.

Our initial programs focus on rare, monogenic CNS disorders because they offer a compelling opportunity for the effective application of genetic medicines.

There is a significant need for genetic medicines that can target these disorders.

Our lead clinical program, upliFT-D, is focus ed on a rare, monogenic CNS disorder , FTD- GRN , because it offer s a compelling opportunity for the effective application of a genetic medicine, by correcting the progranulin deficiency that results from disease-causing mutations in the GRN gene.

We are also exploring the potential for our progranulin gene therapy candidate, PBFT02, to target other degenerative disorders, such as FTD- C9orf72 , ALS, and AD, where increasing progranulin levels in the central nervous system could provide benefit .

The field of genetic medicine is rapidly expanding and we believe we have developed a differentiated approach to developing treatments for CNS disorders that allows us to select and advance product candidates with a higher- probability of technical and regulatory success.

Our gene therapy product candidates use AAV, a small, non-pathogenic virus that is genetically engineered to function as a delivery vehicle, or vector.

In our current clinical programs, the AAV is administered to a patient to introduce a healthy copy of a mutated gene, or the transgene, to the cells in a process referred to as transduction.

Our current approaches use AAVs to deliver either a (i) replacement non-mutant transgene, or (ii) a combination of a microRNA, known as miRNA, to reduce expression of a mutant transgene, and a replacement non-mutant transgene.

In our current clinical program s , the AAV is administered to a patient to introduce a healthy copy of a gene, or the transgene, to the cells in a process referred to as transduction.

Our current approaches use AAVs to deliver a wild type transgene to either (i) restore expression of a fully functional version of a mutated gene or to (ii) overexpress a gene product.

The components of an AAV gene therapy vector include the therapeutic gene that makes up the DNA payload, or the transgene, the outer viral shell that encloses the DNA payload, or the capsid, and any promotors added to the vector to boost expression of the transgene.

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The core tenets of our approach include a rigorous process for selecting product candidates, mitigation of early development risk through relationships with leading researchers and academic institutions, and mitigation of clinical development risk through deep relationships with patient advocacy groups, key opinion leaders and practitioners.

Together, these relationships allow us to directly benefit from decades of collective experience, the latest technologies and contemporary perspectives from patients and their experiences.

Rigorous Process for Selecting Product Candidates

In selecting our product candidates, we focus initially on optimizing transduction and expression of transgenes in the indication-specific target tissues.

Together, these relationships allow us to directly benefit from decades of collective experience, the latest technologies and contemporary perspectives from patients.

In selecting our product candidates, we are focusing initially on optimizing transduction and expression of transgenes in the indication-specific target tissues.

This involves prioritizing the following principles:

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Identifying the optimal route of administration for AAV gene therapy is critical to achieving safe and effective levels of transgene expression in the targeted location in the CNS.

The optimal route of administration for CNS treatments should also leverage the immuno-privileged aspects of the CNS to reduce the potential effects of neutralizing antibodies, or NAbs, on AAV capsids, which are often faced by gene therapy product candidates.

We evaluate preclinical studies and other data to decide the preferred route of administration on a program-by-program basis.

For our existing clinical product candidates, we believe that ICM administration is the optimal route of administration as compared to other potential delivery mechanisms due to its diffuse delivery distribution, potential for improved biodistribution to the brain and spinal cord and transduction, and lower expected toxicity.

Administration through ICM can also reduce the potential impact of NAbs as compared with intravenous administration.

We believe that by using ICM we can achieve comparable protein expression at lower dosages than would be required by other administration routes.

The optimal route of administration for CNS treatments should also leverage the immuno-privileged aspects of the CNS to reduce the potential for deleterious effects of neutralizing antibodies, or NAbs , on the biodistribution of AAV capsids .

We evaluate preclinical stud y outcomes and other data to decide the preferred route of administration on a program-by-program basis.

For our clinical stage product candidate s , we believe that ICM administration is the optimal route of administration as compared to other potential delivery mechanisms due to its potential to provide widespread biodistribution to the brain and spinal cord .

Further, when compared with systemic and other intra-thecal administration routes, we can achieve comparable protein expression at lower dosages, and thereby also lower the potential for toxicit ies.

The potential for an impact from NAbs is also reduced .

• Capsid, transgene, and promoter selection:

For each of our programs, we conduct rigorous studies to select the capsid, transgene, and promoter to use for our product candidate.

For each clinical program, we conduct rigorous studies to select the capsid, transgene, and promoter to use for our product candidate.

We identify the optimal AAV gene therapy for each of our indications depending on the target indication, our goal of CNS and/or PNS transduction, and the target brain regions and cell types.

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• Cross-correction:

Our existing clinical product candidates exploit the cross-correction mechanism by which secreted gene product from transduced cells is taken up by non-transduced neurons.

We believe this cross-correction mechanism can help overcome the limits of vector biodistribution and CNS transduction inefficiency that are characteristic of other genetic medicine approaches, and ultimately drive clinical benefit.

Our existing clinical-stage product candidate exploits the cross-correction mechanism by which secreted gene product from transduced cells is taken up by non-transduced neurons.

• Effective use of biomarkers:

Our development program targets must have measurable, predictive biomarkers to inform early and efficient clinical development decisions.

These include pharmacodynamic biomarkers to confirm achievement of target levels of transduction and gene expression, and disease activity and progression biomarkers to confirm downstream effects on the underlying disease pathophysiology.

Mitigation of Early Development Risk of Programs Prior to IND submission

We have a strategic research collaboration with GTP, which is led by our co-founder and Chief Scientific Advisor, Dr.

Wilson, and which we believe positions us at the forefront of gene therapy research.

This collaboration provides us with access to differentiated discovery technology and expertise that informs the basis of our product candidate selection and subsequent development.

Our strategic research collaboration with GTP provides us with access until August 2026 to one of the premier gene therapy research institutes in the world for the discovery and preclinical development of gene therapy product candidates and exclusive rights to certain CNS disorders, including next-generation AAV capsid technology and vector engineering, and state-of-the art preclinical animal studies, including NHP models.

Through GTP’s staff, we have access to cutting edge expertise and capabilities in gene therapy research and preclinical development.

Our collaboration with GTP allows us to choose programs that have been or will be validated through extensive testing in preclinical disease models, and once selected, to collaborate with GTP on further preclinical optimization of our product candidate, such as vector choice, transgene construct and route of administration.

We believe this collaboration improves our probability of technical and regulatory success in developing product candidates that provide transformative clinical benefits.

Once we select a particular CNS indication for further development, GTP, with our close involvement and oversight, embarks on a rational discovery and development program to design product candidates that may provide improved clinical benefit.

We usually evaluate transduction efficiency and biodistribution using multiple different capsids in NHPs to select the capsid best suited for the targeted indication.

GTP also works to optimize the delivery method used for each product candidate by balancing delivery, efficacy, safety, host immunity and ease of administration.

We believe the translational preclinical characterization provided by GTP, including the use of NHP models for vector screening and toxicology, reduces the early-stage development risk of our product candidates.

Mitigation of Clinical Development Risk through Our Relationship with Penn’s ODC

We also have a strong relationship with Penn’s ODC.

As part of our research collaboration with GTP, we have access to Penn’s ODC’s insights and capabilities in the study of rare diseases.

We leverage our close working relationship with Penn’s ODC to develop historical and prospective external data for each disease for use in building comparable patient profiles of participants in interventional trials.

Penn’s ODC is currently performing a natural history study for GM1 funded by us.

Our Product Candidates

Overview of GM1

GM1 is a rare and often life-threatening monogenic recessive lysosomal storage disease that results in progressive damage to both the CNS and the peripheral tissues.

The infantile form of the disease is characterized by onset in the first two years of life with symptoms including hypotonia (reduced muscle tone), progressive CNS dysfunction leading to deafness, blindness, enlarged liver and spleen, rigidity and progressive skeletal dysplasia that leads to restrictive lung disease and aspiration pneumonia.

Early onset infantile GM1, or Type I, is characterized by onset in the first six months of life, while late onset infantile GM1, or Type IIa, is characterized by onset between six and 24 months.

The disease rapidly progresses, with a life expectancy of less than two years for early infantile GM1 and five to ten years for late infantile GM1.

GM1 is caused by recessive mutations in the GLB1 gene, which encodes lysosomal acid β-gal, an enzyme that catalyzes the first step in the natural degradation of GM1 ganglioside as well as other glycan substrates.

Reduced β-gal activity results in the accumulation of toxic levels of GM1 ganglioside in neurons throughout the brain, causing rapidly progressing neurodegeneration.

GM1 manifests as a continuum of clinical severity, ranging from infants with earlier onset and more severe and rapidly progressive disease to those with later juvenile or adult onset, slower progression and less severe manifestations.

The United States incidence of GM1 has been estimated to be approximately 1 in 100,000 live births, with infantile GM1 representing approximately 62.5% of such cases.

No states include GM1 in mandatory infant screening.

We engaged a third-party data-analytics firm to conduct an analysis of a variety of de-identified electronic medical records.

Based on this analysis, we estimate the incidence of infantile GM1 to be approximately 1.4 in 100,000 live births.

Currently, there are no approved disease-modifying therapies available.

Supportive treatment options include the use of feeding tubes or ventilators for infants with GM1.

Program selection

We chose GM1 as one of our initial lead programs because it met our criteria for rare, monogenic CNS disorders in which we believe we can develop product candidates with a higher probability of technical and regulatory success that will substantially impact on the lives of severely underserved patients.

Several key factors supported the decision to focus on GM1 for AAV gene therapy, as described below.

• Cross-correction :

Following treatment with PBGM01, we expect that newly synthesized functional β-gal will be secreted by transduced cells and provide a source of secreted proteins that could be taken up by surrounding non-transduced and other wise enzyme-deficient cells.

This cellular cross-correction could therefore lead to enzyme replacement broad ly throughout the CNS and peripheral organ s .

• Biomarkers :

There are known biomarkers in GM1 that are measurable and available to assist in drug development.

o β -gal activity.

Reduced β-gal activity is a hallmark of GM1 and treatment with PBGM01 is expected to restore this activity.

To this end, β-gal activity is being measured in CSF and blood.

o Pharmacodynamic biomarkers .

Reduced β-gal activity results in the accumulation of GM1 ganglioside and other glycan substrates in neurons throughout the brain.

These substrates may be reduced following treatment with PBGM01 and are being measured in CSF, blood, and urine.

o Disease progression biomarkers.

Recent MRI studies of infants with GM1 have shown longitudinal changes in MRI in infants with GM1 consistent with progressive brain atrophy and ventricular enlargement, suggesting that brain MRI would be a useful biomarker to detect and help verify treatment effects on disease pathophysiology.

• Preclinical validation:

We used the GLB1 knockout mouse disease model showing clinical, biological and histological manifestations of GM1 in preclinical studies.

In these studies, we observed a robust dose-related improvement in both neurological status, enzyme activity, histologic lysosomal storage pathology and survival following treatment with PBGM01.

Product Candidate Development Strategy

We have chosen the earliest and most severe form of GM1 for clinical development for several reasons.

Within GM1, infantile GM1 represents the greatest medical need, as early onset GM1 infants often do not survive past two years, and thus are in immediate need of an effective therapy.

We expect treatment-related efficacy to be measurable sooner after treatment in this more rapidly progressing form of GM1.

Patients with onset forms of GM1 later than infantile, which we define as an onset later than 24 months, are caused by less severe reductions of β-gal enzyme activity and generally demonstrate slower progression and more variable clinical courses, likely requiring larger and longer clinical trials and a broader control group.

If our initial clinical trials in infantile GM1 are successful, we intend to explore expansion of the indication with trials in later onset forms of GM1.

Our Product Candidate

We are developing PBGM01 to treat infantile GM1, with a single dose of PBGM01 by ICM administration.

PBGM01 utilizes a next-generation AAVhu68 viral vector to deliver modified DNA encoding the β-gal enzyme to a patient’s cells.

The goal of this vector and delivery approach is to increase levels of the β-gal enzyme in both the CNS and the peripheral tissues.

We selected the AAVhu68 capsid and ICM route of administration due to the superior transduction observed in cells of the CNS and peripheral organs, which are both affected in GM1 disease patients.

Based on prior capsid comparison studies, the AAVhu68 vector has the potential to provide corrective β-gal enzyme to both the CNS and peripheral tissues, which we believe gives us the potential to treat both the CNS pathologies and the peripheral manifestations observed in GM1 disease.

We believe gene replacement with PBGM01 and consequent wide brain distribution and uptake of the β-gal enzyme has the potential to greatly reduce the accumulation of GM1 gangliosides, reversing neuronal toxicity, thereby restoring developmental potential and improving the quality of life for treated patients.

We will evaluate this clinically by assessing the prevention of further developmental regression and restoration of developmental trajectories, as measured by developmental milestones using accepted clinical scales and observer-reported outcomes.

Preclinical studies

The potential for efficacy of PBGM01 is supported by preclinical findings in GLB1 knockout ( GLB1-/-) mice.

This mouse line develops several characteristics that are reminiscent of the neurological presentation of GM1, including a rapid accumulation of GM1 ganglioside in the brain shortly after birth followed by progressive motor abnormalities and a shortened survival.

Intracerebroventricular, or ICV, injection of PBGM01 in GLB1-/- mice resulted in persistent dose-dependent elevations in β-gal activity in the brain, CSF, serum, and in peripheral organs.

Increased β-gal activity was associated with increased phenotypic and histopathological benefits in the GLB1-/- mice including the resolution of pre-existing brain lysosomal storage lesions as assessed by lysosomal associated membrane protein 1, or LAMP-1, immunohistochemistry, improved neurological phenotypes in assays of clinical deficits and animals’ gait, and increased survival.

Preclinical findings were published by GTP in 2020.

NHP Toxicology Study

A 120-day good laboratory practice, or GLP, compliant toxicology study conducted in NHPs assessed the safety, tolerability, biodistribution and excretion profile of PBGM01 following ICM administration of vehicle or one of three dose levels of PBGM01.

PBGM01 vector distributed to the CSF and high levels of gene transfer were detected in the brain, spinal cord and dorsal root ganglia, or DRG.

The quantity of vector genomes detected in CNS tissues was generally dose-dependent.

PBGM01 also reached high levels in peripheral blood and liver.

Measurement of transgene expression by β-gal activity in CSF and serum was limited in NHPs by the nature of the assay, which could not distinguish between human and endogenous rhesus β-gal.

β-gal activity in the CSF and serum was detectable in animals from all dose groups 14 days after PBGM01 administration.

In the CSF, animals administered the two higher doses displayed dose-dependent increases in β-gal activity to approximately two-fold and four-fold higher than the levels in vehicle-treated controls, respectively.

There were no blood or CSF abnormalities related to PBGM01 administration except for asymptomatic, mild, and transient increases in CSF leukocytes in the majority of animals from all dose groups.

PBGM01 was well-tolerated at all doses evaluated and no adverse effects were detected on body weight or clinical, neurological, or behavioral signs.

PBGM01 vector DNA was detectable in urine and feces five days post-administration and was undetectable within 60 days.

In response to a potential AAV platform risk reported in NHPs we assayed DRG and TRG toxicity after PBGM01 administration.

Mild and transient degeneration of DRGs, TRGs, and associated sensory nerve axonopathy were observed in all dose groups;

however, these findings were not linked with any clinical or neurological abnormalities in any animals up to 120 days post-dose.

In summary, based on our preclinical studies, we believe that CSF delivery of PBGM01 has the potential to sufficiently increase β-gal levels in both the CNS and in peripheral tissues to overcome intracellular β-gal deficiency in GM1.

Clinical development

Our clinical development plan is to start with trials in infantile GM1, and if successful, explore expansion of the indication with trials in later onset forms of GM1.

We initiated patient dosing in our Imagine-1 trial, a multi-center, open-label, single-arm Phase 1/2 clinical trial of PBGM01 in patients with a diagnosis of early and late infantile GM1 in March 2021.

Primary endpoints include safety and efficacy.

Efficacy is being evaluated by the assessment of developmental milestones using accepted clinical scales and observer-reported outcomes.

Secondary outcomes include serum and CSF β-gal enzyme activity, GM1 ganglioside levels, and disease progression endpoints including evaluations using electroencephalogram, or EEG, and MRI.

The study enrolled both early and late infantile patients in separate, smaller cohorts.

Part 1 of the study includes a total of four cohorts of two patients each, with separate dose-escalation cohorts for late onset infantile GM1 patients , defined as onset prior to 24 months in age and after 6 months in age, and early onset infantile GM1 , defined as onset prior to 6 months of age .

The study is assessing an initial low dose (3.3x10˄10 genome copies/gm brain weight) that exceeds the minimum effective dose, or MED, as determined in our preclinical studies, and a 3-fold greater high dose (1.1x10˄11 genome copies/gm brain weight).

Cohorts 1 and 2 enrolled patients diagnosed with late infantile GM1 and treated them with low dose and high dose PBGM01, respectively, while Cohorts 3 and 4 enrolled patients diagnosed with early infantile GM1 and treated them with low dose and high dose PBGM01, respectively.

All patients are treated with an abbreviated course of low dose steroids.

To better understand the clinical significance of the peripheral nerve findings in NHPs, we implemented clinical monitoring in our Imagine-1 trial, consisting of both nerve conduction studies and neurological exams focused on sensory and peripheral nerve function .

There is a 60-day interval between all subjects dosed within a cohort to allow review of biomarker and safety data before dosing the next subject.

Following the dose-escalation cohorts, each patient population will be enrolled into a confirmatory cohort.

Patients will be evaluated over two years for safety and efficacy, followed by an additional 36 months of long-term follow up.

Clinical development results

We completed dosing of the initial four cohorts in our Imagine-1 trial in November 2022.

In December 2022 and February 2023, we reported interim safety and biomarker data for the first three cohorts of the trial.

The results from the interim assessment are shown below and include clinical data from the first three cohorts with follow-up from three to eighteen months based on data as of December 2022.

PBGM01 was well tolerated, with a positive safety profile, no serious adverse events, or SAEs, and all treatment-related adverse events, or AEs, were mild to moderate in severity.

There were no clinically significant changes in liver function requiring intervention and no evidence of peripheral nerve toxicity as measured by nerve conduction studies and neurological exam.

There was also a favorable immunological profile with no evidence of an immune response requiring changes to the immunosuppression regimen.

As anticipated, moderate levels of Nabs developed to capsid in blood and low levels of NAbs to capsid were also detected in CSF.

No antibodies were detected to the transgene product in either the CSF or serum.

There were also no complications related to the ICM administration.

The six patients enrolled in Cohorts 1 to 3 ranged from 6 to 31 months of age at the time of PBGM01 administration.

Across the first three cohorts, PBGM01 administration resulted in a dose-dependent increase in CSF β-gal activity with the high dose resulting in a 3.6-5.2x increase in CSF β-gal activity relative to baseline, well above levels observed in the Natural History Study being conducted by the University of Pennsylvania ODC.

In patient 1, who was observed with the longest follow-up, increased CSF β-gal activity was sustained for 12 months.

Sustained β-gal enzyme expression was also observed in blood.

GM1 Cohorts 1-3 Interim CSF b -gal Enzyme Activity

NHS patient value range based on preliminary data from University of Pennsylvania’s ODC Natural History Study (NHS) (NCT04041102);

Value range (0.3-1.81 nmol/mL/3hr, or nanomole per milliliter per 3 hours)

To assess pharmacodynamic activity in the CNS associated with b -gal activity, GM1 gangliosides levels were measured in the CSF.

GM1 gangliosides are hypothesized to mediate CNS manifestation of disease.

PBGM01 administration resulted in a dose-dependent decrease in CSF GM1 ganglioside levels for patients in the high dose cohort, showing decreases of up to 75% at six months.

GM1 ganglioside levels in the CSF were unchanged following the administration for patients in the low dose cohort.

Clinical assessments include the Bayley III and Vineland II scales, performed by trained healthcare providers and the patients caregivers, respectively.

The scales assess the developmental age of the child across a broad range of clinical parameters.

The patients treated with PBGM01 exhibited a broad range of developmental age at baseline, as assessed with the Bayley III, as well a wide range of developmental delay, which is determined by the patients chronological age minus their developmental age.

Two patients, patients 1 and 5, exhibited developmental delay of 2 and 5.5 months, respectively, which we have characterized as mild-to-moderate delay.

The remaining patients exhibited developmental delay ranging from 12 to 24 months, which we have characterized as marked delay.

Following treatment with PBGM01, we observed that patients with a lower developmental delay at dosing experienced a better clinical response to treatment, regardless of dosage level.

On both the Bayley III and the Vineland II, the two patients with mild-to-moderate developmental delay at baseline show improvement in their developmental age over time, which contrasts with the plateau and subsequent regression generally expected based on the natural history of the disease.

The remaining patients with more marked developmental delay show stabilization or limited improvement.

Based on this data, we believe that milder developmental delay at the time of dosing may be a determinant in treatment outcomes.

Cohorts 1 – 3 Interim Clinical Results:

Vineland-II and Bayley-III

*The Vineland-II is caretaker-assessed.

**The Bayley-III is based on direct observation by a neurodevelopmental specialist.

Treatment effects on brain volume and white matter integrity are being assessed using a MRI severity score, a novel scoring metric, for GM1 patients based on baseline and follow-up brain MRI scans.

The MRI severity score is based on cerebral and cerebellar atrophy, abnormalities in white matter, and signal abnormalities in the basal ganglia and hippocampi, where higher scores indicate more structural damage.

In a natural history study with six late infantile GM1 patients, the MRI severity score increased in the majority of patients over the follow up period of six months to four years, implying progression of structural damage.

In contrast, PBGM01 administration was associated with stabilization of the MRI severity score over the follow up period of six to twelve months.

While the PBGM01 data is for a shorter period of time than the natural history study data, we believe the initial trend observed, if continued, may be an important indicator of biological activity.

Cohorts 1 – 3 Interim MRI Results:

MRI Severity Score

Initial biomarker and safety data from Cohort 4 are expected to be reported in the middle of 2023.

A key objective of the initial phase of the Imagine-1 trial is to determine the optimal dose for the confirmatory phase of the study.

Based on the favorable safety profile of PBGM01 to date, the observed dose-response in key biomarkers, such as CSF b -gal activity and GM1 ganglioside levels, and that our preclinical studies showed no safety signals at doses higher than currently being evaluated in the ongoing clinical trial, we plan to treat additional patients in the Imagine-1 trial at higher doses of PBGM01 than the doses of PBGM01 administered to date in cohorts 1 to 4.

Following regulatory review, we expect to dose the first patient at a higher dose of PBGM01 in the second half of 2023.

Based on the available data in the Imagine-1 trial to date, we believe that patients with more limited developmental delay at the time of enrollment may have better outcomes.

As we consider our pivotal trial design and potential modifications to the ongoing trial, we are revising inclusion criteria to maximize the benefit-risk profile of PBGM01.

As our clinical data matures, we are planning for continued interactions with regulatory authorities to align on design of the confirmatory study and appropriate pathway to submission of a Biologics License Application, or BLA, and regulatory approval for commercialization in the United States and internationally.

Natural History Data

We are currently funding a GM1 natural history study being conducted by Penn’s ODC to collect prospective data on clinical disease progression in infantile and juvenile GM1.

This data, supplemented with data from retrospective studies, will be used to construct natural history patient profiles for comparison to the profiles of treated participants in our planned Phase 1/2 clinical trial.

Regulatory Designations

The FDA has granted ODD, RPDD, and Fast Track Designation to PBGM01 for the treatment of GM1.

The European Commission has granted Orphan designation and Advanced Therapy Medicinal Product, or ATMP, designation for PBGM01.

Clinical Supply

Through our manufacturing partners, we have manufactured the PBGM01 clinical supply and have established a clinical supply chain to support our ongoing clinical trial activities.

Overview of FTD-GRN

FTD is one of the more common causes of early-onset dementia, occurring with a median age of 55 years.

These include biomarkers to confirm achievement of target levels of transduction and gene expression, one or more downstream pharmacodynamic biomarkers to demonstrate positive functional effects on pathways involved in disease etiology, and disease activity and progression biomarkers to demonstrate effects on disease course .

We have a strategic research collaboration with GTP, which provides us with access to differentiated discovery technology and expertise and informs the basis of our product candidate selection s and subsequent development.

Our collaboration with GTP allows us to choose programs that have been, or will be, validated through extensive testing in preclinical disease models.

Once selected, we collaborate with GTP on further preclinical optimization of our product candidates, to optimize aspects including vector choice, transgene construct and route of administration.

We typically evaluate in NHPs the transduction efficiency and biodistribution of diverse capsids to select the capsid best suited for the targeted indication.

GTP also works to optimize the delivery approach for each product candidate by balancing biodistribution, efficacy, safety, host immunity, and ease of administration.

We believe that the gene therapy preclinical expertise provided by GTP, including the use of NHP models for vector screening and toxicology, improves the probability of technical and regulatory success for our collaborative pipeline programs.

Our Product Candidates – PBFT02

We are currently developing PBFT02, which utilizes an AAV1 capsid to deliver a functional copy of GRN encoding for PGRN for the treatment of FTD- GRN .

We also intend to pursue PBFT02 in additional adult neurodegenerative diseases where we believe increased PGRN levels could provide benefit .

PBFT02 for the treatment of FTD-GRN

FTD is one of the more common causes of early-onset dementia, occurring in patients with a median age of 55 years.

FTD presents as a rapidly progressive clinical syndrome and causes impairment in behavior, language, and executive function.

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Survival averages eight years after onset of symptoms.

In approximately 5% to 10% of individuals with FTD, the disease is caused by mutations in the granulin, or GRN, gene, causing a deficiency of progranulin.

PGRN is a complex and highly conserved protein thought to have multiple roles in cell biology, development and inflammation.

Emerging evidence suggests that PGRN’s pathogenic contribution to FTD and other neurodegenerative disorders relates to a critical role in lysosomal function.

In approximately 5% to 10% of individuals with FTD, the disease is caused by mutations in the GRN gene, causing a deficiency of progranulin.

PGRN is a complex and highly conserved protein that binds to multiple cell membrane receptors to generate diverse intracellular effects, including anti-inflammatory effects, growth factor and regenerative activity, and importantly, improvement in lysosomal activity.

In FTD- GRN , PGRN deficiency leads to lysosomal and microglial dysfunction, TDP-43 pathology, and ultimately neurodegeneration.

There are no disease modifying therapies approved for the treatment of FTD.

Anti-depressants have been shown to manage some behavioral symptoms.

We engaged a third-party data-analytics firm to conduct an analysis of a variety of de-identified electronic medical records.

Based on this analysis, we estimate the prevalence of FTD in the United States to be approximately 62,000.

The prevalence of FTD due to GRN mutation found in literature is 5% to 10%.

Accordingly, we estimate the prevalence of FTD-GRN deficiency in the United States to be approximately 3,000 to 6,000.

Program selection

We chose FTD-GRN as one of our initial lead programs because it meets our criteria for rare, monogenic CNS disorders in which we believe we can develop product candidates with a higher probability of technical and regulatory success:

Based on third-party data analytics and available literature, we estimate the prevalence of FTD- GRN deficiency in the United States and Europe is approximately 18,000.

Indication selection

The development of PBFT02 in FTD- GRN is facilitated by the following:

• Cross-correction:

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There are known biomarkers in FTD- GRN that are measurable and available to assist in drug development.

o Pharmacodynamic biomarkers.

o Pharmacodynamic biomarker.

PGRN is a secreted protein that can be measured in the CSF and plasma, and it has been shown to be reduced in the CSF of human GRN mutation carriers.

o Disease progression biomarkers.

We expect to be able to use recent progress in the identification of clinical disease progression biomarkers for FTD, including CSF, neuroimaging and retinal biomarkers, to facilitate clinical development by enabling early detection of treatment effects on disease pathophysiology.

We expect to be able to use recent progress in the identification of clinical disease progression biomarkers for FTD, including plasma, CSF, neuroimaging and retinal biomarkers, to facilitate clinical development by enabling early detection of treatment effects on disease pathophysiology.

• Preclinical Validation:

In our preclinical studies in GRN knockout mice, or GRN -/- mice, ICV administration of PBFT02 resulted in increased levels of PGRN in the CNS and CSF, with resolution of lysosomal storage pathology.

In our preclinical studies in GRN knockout mice, or GRN -/- mice, intracerebroventricular, or ICV, administration of PBFT02 resulted in increased levels of PGRN in the CNS and CSF, with resolution of lysosomal storage pathology.

ICM administration in NHPs, which do not have the disease phenotype, resulted in robust increases in PGRN levels in CNS and CSF.

Our Product Candidate

We are developing PBFT02 to treat patients affected with FTD-GRN with a single dose of PBFT02 by ICM administration.

We are developing PBFT02 to treat patients affected with FTD- GRN , via a single ICM administration.

PBFT02 is a gene therapy that utilizes an AAV1 viral vector to deliver a modified DNA encoding the GRN gene to a patient’s cells.

The goal of this vector and delivery approach is to provide higher than normal levels of PGRN to the CNS to overcome the progranulin deficiency in GRN mutation carriers, who have been observed to have reduced CSF PGRN levels ranging from 30% to 50% of the PGRN levels observed in normal, mutation non-carriers.

The goal of this vector construct and delivery approach is to provide higher levels of PGRN to the CNS to overcome the progranulin deficiency in GRN mutation carriers, who have reduced CSF PGRN levels ranging from 30% to 50% of those observed in normal, mutation non-carriers.

A higher level of CSF PGRN makes more PGRN available to bind to cell membrane receptors.

We selected the AAV1 capsid and ICM administration route due to the widespread and robust expression of the human PGRN transgene observed throughout the brain and spinal cord in NHP studies.

Following AAV1 administration in NHP levels of human PGRN in the CSF achieved supraphysiologic levels compared to those measured in healthy human CSF and exceeded PGRN levels observed in NHPs that received AAV5 or AAVhu68 serotypes by greater than 5 times.

Following ICM AAV1 administration in NHPs, levels of human PGRN in the CSF achieved supraphysiologic levels compared to those measured in healthy human CSF, and exceeded PGRN levels observed in NHPs that received AAV5 or AAVhu68 serotypes by greater than five times.

Preclinical studies

PBFT02 was selected as our development candidate following a study in adult NHPs which evaluated the expression of human PGRN protein in the CSF after ICM administration of four different vector constructs.

The AAV1 vector construct produced supraphysiological levels of PGRN and greater than 5 times higher than the other vectors tested, as shown below.

PBFT02 was selected as our development candidate following preclinical proof of concept studies in adult NHPs, which evaluated the expression of human PGRN protein in the CSF after ICM administration of four different vector constructs.

The AAV1.hPGRN vector construct produced supraphysiological levels of PGRN that were greater than five times higher than the AAVhu68.hPGRN and AAV5.hPGRN vectors tested, as shown below.

ICM AAV1 did not strongly transduce the liver or significantly elevate levels of circulating PGRN, which may reduce the potential for unknown peripheral effects of PGRN.

Proof of concept findings were published by GTP in 2020.

Comparison of Vector Serotypes:

Production of Human PGRN-protein in CSF of NHPs following ICM-AAV administration.

Production of Human PGRN-protein in CSF of NHPs Following ICM-AAV Administration of Human GRN Gene.

Two adult rhesus macaques per treatment received ICM AAV.hPGRN High dose, 3.0 x 10 13 GC / 3.3 x 10 11 GC/g brain) on study day 0.

Reference range for healthy adult controls’ PGRN levels in CSF (n = 61) (Passage Bio data).

In a separate NHP study, rhesus macaques were necropsied 28 days after administration of AAV1 and AAVhu68 vectors expressing a green fluorescent protein, or GFP, reporter gene, to examine differential transduction.

Ependymal cell transduction was evaluated by immunohistochemistry in multiple brain regions.

As shown in the figure below, transduction of the ependymal cells (as shown by density of darkened ependymal cells) was substantially higher in the animal treated with AAV1 (48%, n=1) as compared to the animals treated with AAVhu68 (1-2%, n=2).

In all other CNS cell types, AAV1 and AAVhu68 demonstrated similar transduction efficiency.

Ependymal Cell Transduction in NHPs Following ICM Delivery of AAV1 or AAVhu68 Vectors Expressing GFP

Representative sections showing GFP immunohistochemistry in ependymal cell layers, from rhesus macaques following ICM administration of AAVhu68.GFP or AAV1.GFP.

Scale bars = 5 mm

Based on the results from the NHP vector comparison studies, we selected AAV1 as the capsid for our PBFT02 product.

The efficacy of the AAV1 vector was assayed in a dose-ranging study in GRN -/- mice.

PBFT02 was administered via ICV delivery to adult mice at an age when lipofuscin deposition (a marker of lysosomal dysfunction), lysosomal enzyme abnormalities, and neuroinflammation were present in brain regions involved in FTD-GRN pathophysiology.

Human PGRN expression in the CSF increased in a dose-dependent manner following PBFT02 administration.

Transgene expression led to improvements in histopathologic and enzymatic changes in key brain regions in the mice, including a reduction in the accumulation of lipofuscin and reduced neuroinflammation (as shown in below figure), and elevated lysosomal hexosaminidase activity.

PBFT02 was administered via ICV delivery at one of four ascending doses or vehicle to adult mice at an age when lipofuscin deposition (a marker of lysosomal dysfunction), lysosomal enzyme abnormalities, and neuroinflammation were present in brain regions involved in FTD-GRN pathophysiology.

In this study, human PGRN expression in the CSF increased in a dose-dependent manner following PBFT02 administration.

Transgene expression led to improvements in histopathologic and enzymatic changes in key brain regions in the mice, including the cerebral cortex, hippocampus, and thalamus.

The improvements included a reduction in the accumulation of lipofuscin and reduced neuroinflammation (as shown in the thalamus in the figure below), and elevated lysosomal hexosaminidase activity .

PBFT02 Improved Lysosomal Dysfunction and Inflammation in a Mouse Model of Granulin Deficiency

Markers of lysosomal dysfunction (lipofuscin autofluorescence) and inflammation (CD68 immunohistochemistry) in the thalamus of Grn -/- mice 90 days after PBFT02 administration.

Staining in brain sections of PBFT02-treated Grn -/- mice was compared with vehicle-treated WT and Grn -/- mice.

Both markers were elevated in Grn -/- mice at the time of treatment (baseline).

Data are mean +/- standard error of the mean, or SEM.

*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, one-way ANOVA followed by Tukey’s multiple comparison test.

Abbreviations:

-/-, gene knockout;

ANOVA, analysis of variance;

CSF, cerebrospinal fluid;

ICV, intra-cerebroventricular;

SEM, standard error of the mean;

WT, wild type.

NHP Toxicology Study

A 90-day GLP compliant toxicology study conducted in NHPs assessed the safety, tolerability, biodistribution and excretion profile of PBFT02 following ICM administration at three dose levels.

There were no blood or CSF abnormalities related to PBFT02 administration except for asymptomatic, mild, and transient increases in CSF leukocytes in the majority of animals .

PBFT02 was well-tolerated at all doses evaluated and no adverse effects were detected on body weight or clinical, neurological, or behavioral signs.

Vector distributed to the CSF and high levels of gene transfer were detected in the brain, spinal cord and DRG at Day 90.

The quantity of vector genomes detected in CNS tissues was generally dose-dependent.

PBFT02 also reached significant concentrations in the peripheral blood, liver and spleen.

PBFT02 vector DNA was detectable in urine and feces 5 days post-administration and was undetectable within 60 days.

A 90-day GLP compliant toxicology study was conducted in NHPs to assess the safety, tolerability, biodistribution and excretion profile of PBFT02 following ICM administration at three dose levels.

No blood or CSF abnormalities related to PBFT02 administration were observed except for asymptomatic, mild, and transient increases in CSF leukocytes in the majority of animals.

PBFT02 was shown to be well-tolerated at all doses evaluated and no adverse effects were detected on body weight or clinical, neurological, or behavioral signs.

Vector distributed to the CSF and high levels of gene transfer were detected in the brain, spinal cord and dorsal root ganglia, or DRG, at day 90.

The quantity of vector genomes detected in CNS tissues was generally dose-dependent, as shown in the figure below .

Vector Biodistribution 90 Days After ICM Administration of PBFT02 to NHPs

Tissues were collected at necropsy from adult NHPs 90 days after a single ICM administration of PBFT02 at doses indicated (n=3/group) and from vehicle- (ITFFB-) treated NHPs (n=2) as a control.

Each bar represents mean PBFT02 vector genomes detected per μg of DNA.

Error bars represent the SEM.

Dashed line represents limit of detection of assay.

PBFT02 was also shown to reach significant concentrations in the peripheral blood, liver and spleen.

PBFT02 vector DNA was detectable in urine and feces five days post-administration and was undetectable within 60 days.

Human PGRN was detectable in CSF and serum in all animals by 7 to 14 days after PBFT02 administration, peaking between days 14 to 28.

Responses were generally dose dependent and resulted in supraphysiologic PGRN levels after the 2 highest doses.

Responses were generally dose dependent and resulted in supraphysiologic PGRN levels after the two highest doses.

Expression declined by day 60, correlating with the appearance of antibodies against the human transgene product, which are not expected to develop in haploinsufficient patients with FTD- GRN .

Mild to minimal grade transient degeneration of DRGs and TRGs, and associated sensory nerve axonopathy, were observed in all PBFT02 dose groups.

Dose Dependent Effects of PBFT02 on CSF level of Progranulin in NHPs

Adult rhesus macaques received ICM PBFT02 (n = 3/dose) or vehicle (n =2) on study day 0.

CSF was sampled 14 days post-dose

Mild to minimal grade transient degeneration of DRG, trigeminal root ganglia, or TRG, and associated sensory nerve axonopathy, were observed in NHPs after all PBFT02 dose groups.

These histopathologic observations were not linked with any clinical or neurological abnormalities in any animals up to 90 days’ post-dose.

One PBFT02-treated animal exhibited a peripheral nerve conduction impairment in the median nerve, as detected by bilateral reductions in sensory nerve action potential, or SNAP, amplitudes on Day 28 and Day 90, that appeared to be treatment related as severe axon loss and endoneurial fibrosis were detected at necropsy.

One PBFT02-treated animal exhibited a peripheral nerve conduction impairment in the median nerve, evident from bilateral reductions in sensory nerve action potential, or SNAP, amplitudes on day 28 and day 90, that appeared to be treatment related as severe axon loss and endoneurial fibrosis were detected at necropsy.

PBFT02-induced SNAP changes and sensory neuron degeneration were not associated with any clinical or neurological abnormalities in any animals up to 90 days post-dose.

In summary, our preclinical studies demonstrated that CSF delivery of PBFT02 has the potential to safely increase extracellular PGRN levels in the CNS up to supraphysiologic levels and has the potential to improve histopathologic and enzymatic changes in key brain regions associated with FTD.

Clinical development

Our clinical development plan is to treat FTD-GRN with a single dose of PBFT02 via ICM administration, with our initial clinical trial focused on early symptomatic FTD patients who have the GRN mutation.

This trial is expected to be a two-cohort dose-escalation trial, with three subjects per cohort, and with a potential for a third higher-dose cohort, if considered necessary based on the results of the first two cohorts .

The planned starting dose (3.3x10˄10 genome copies/gm brain weight) will exceed the MED in the GRN knockout mouse model, with planned escalation to a higher dose (1.1x10˄11 genome copies/gm brain weight) .

Our clinical development plan is to treat FTD- GRN patients with a single dose of PBFT02 via ICM administration.

Our initial clinical trial is focused on symptomatic FTD patients who have the GRN mutation and, if successful, we plan to expand into presymptomatic stage of disease.

We have initiated our upliFT-D trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBFT02 in patients with a diagnosis of symptomatic FTD-GRN.

This trial is a two-cohort dose-escalation trial, with three to five subjects per cohort, and with a potential for a third higher-dose cohort, if considered necessary based on the results of the first two cohorts.

The dose for Cohort 1 (3.3x10 10 genome copies/gm brain weight) exceeds the minimum effective dose in the GRN knockout mouse model, with possible escalation to a higher dose (up to 1.1x10 11 genome copies/gm brain weight);

however, the dose for Cohort 2 has not yet been determined.

The primary endpoint of the trial is to assess safety and tolerability over 60 months.

To better understand the clinical significance of the peripheral nerve findings in NHPs, we implemented clinical monitoring in our uplift-D interventional trial, consisting of both nerve conduction studies and neurological exams focused on sensory and peripheral nerve function.

Secondary endpoints are to assess change from baseline to 24 months on biomarkers, including CSF and plasma progranulin levels, biomarkers of neurodegeneration and disease progression, and on clinical outcomes as measured by the Clinical Dementia Rating, or CDR, for improving evaluation of patients with frontotemporal lobar degeneration, or FTLD, or CDR ® , plus NACC FTLD, and other neurocognitive assessments.

To better understand the clinical significance of the peripheral nerve findings in NHPs, we implemented clinical monitoring, consisting of both nerve conduction studies and neurological exams focused on sensory and peripheral nerve function.

Secondary endpoints are to assess change from baseline to 24 months on biomarkers, including CSF and plasma PGRN levels, biomarkers of lysosomal function, neurodegeneration and disease progression, and on clinical outcomes as measured by the Clinical Dementia Rating plus National Alzheimer’s Coordinating Center with Frontotemporal Lobar Degeneration, or CDR ® plus NACC FTLD, and other neurocognitive assessments.

Interim analyses are planned for certain biomarkers starting at one month post dosing and for clinical outcomes beginning at one year post dosing.

The independent data monitoring committee, or IDMC, will review 30-day biomarker data and safety data for each subject in a cohort.

All subjects will be followed for a total of five years to monitor safety and selected biomarker and efficacy measures.

The independent data monitoring committee, or IDMC, will review 30-day biomarker data and 60-day safety data for each subject in a cohort.

We have an ongoing dialogue with IDMC regarding dose selection for Cohort 2 and will make this decision in consultation with the IDMC.

All subjects will be evaluated over two years for safety and efficacy, followed by an additional 36 months of long-term follow-up.

A scientific advice meeting with MHRA was held in November 2020, providing feedback on our proposed protocol.

Feedback was also obtained from other regulatory agencies outside the United States.

In August 2022, we dosed the first patient in our upliFT-D trial.

We expect to report initial safety and biomarker data from patients in Cohort 1 in the second half of 2023.

Depending on the results from the initial cohorts, we plan to obtain input from regulatory agencies on the requirements to submit for regulatory approval for commercialization in the United States and internationally.

Clinical development results

We reported initial safety and biomarker data from three patients in Cohort 1 in December of 2023.

Dose 1 of PBFT02 treatment resulted in supraphysiologic levels of CSF PGRN with concentrations ranging from 10.7 to 17.3 ng/mL at 30 days post-treatment (n=3), which is greater than 2 to 3-fold higher than the mean CSF PGRN levels observed in healthy adult controls (mean 4.8 ng/mL;

median 4.7 ng/mL;

range 3.3 to 8.2 ng/mL;

In the first patient to reach six months post PBFT02 administration, CSF PGRN remained at supraphysiologic levels with a concentration of 27.3 ng/mL.

The results exceeded our expectations based on what was observed in preclinical NHP studies.

CSF Progranulin Levels Following Administration of PBFT02 Dose 1

Reference range for healthy adult controls’ PGRN levels in CSF (3.28 – 8.15 ng/mL, n = 61) (Passage Bio data)

CSF= Cerebrospinal Fluid

CSF Progranulin Concentration (ng/mL) Following Administration of PBFT02 Dose 1

D30 = day 30 post-dose;

D180 = day 180 post-dose;

N/A = not available

ICM administration of PBFT02 has not been demonstrated to alter circulating PGRN levels.

Plasma PGRN levels were similar to baseline concentrations and remained below levels found in healthy adult controls throughout the available follow-up period across all three patients.

Thus, it appears that PGRN levels were increased only in the central nervous system, where elevated levels have the potential to correct the neurodegeneration associated with PGRN haploinsufficiency.

Plasma Progranulin Levels Following Administration of PBFT02 Dose 1

Lower limit of normal of reference range for healthy adult controls’ PGRN levels in plasma (91.6 – 372.4 ng/mL, n = 56) (Passage Bio data)

As previously reported, Patient 1, who received a low level of immunosuppression (60 mg oral prednisone daily for 60 days), per the initial trial protocol, experienced two SAEs during week eight that were both asymptomatic and likely consistent with an immune response.

The SAEs included hepatotoxicity, as manifest by an increase in liver function tests, and venous sinus thrombosis.

Notably, the increase in liver function tests was not associated with an increase in total or direct bilirubin levels, and quickly resolved following treatment with IV methylprednisolone.

Patient 1 declined further treatment and withdrew consent for the trial at week 10, and no additional follow-up is available.

Following Patient 1, the protocol was amended to increase the steroid regimen to include 1,000 mg IV methylprednisolone on days 1-3 followed by 60 mg oral prednisone for 60 days post treatment, as well as additional safety monitoring.

With this modified immunosuppression regiment, Dose 1 of PBFT02 was generally well-tolerated in patients 2 and 3, who received the enhanced steroid regimen (1,000 mg IV methylprednisolone on days 1-3 followed by 60 mg oral prednisone for 60 days).

In all three patients, there was no evidence of dorsal root ganglion toxicity, as measured by nerve conduction studies, and no complications were observed related to the ICM administration procedure.

The table below summarizes the safety data as of February 14, 2024 for the three patients treated with PBFT02 Dose 1.

Safety and Tolerability of Initial Three Patients Treated with PBFT02 Dose 1

1 Day minus one refers to the day prior to dosing.

2 Days 14-21 LFT elevations were mild and self-resolved;

days 51-55 LFT elevations:

ALT 16x upper limit of normal (ULN), AST 4x ULN, alkaline phosphatase 2x ULN, GGT 10x ULN;

total bilirubin was normal.

Resolving with methylprednisolone at time of patient study withdrawal.

liver function test;

serious adverse event

In December 2023, we announced our plans to treat two additional patients at Dose 1, with no required delay between these patients, to further study the safety and pharmacodynamic effects of PBFT02 at this dose.

Regulatory designations and Clinical Trial Approvals

We have an active IND from the FDA and approved CTAs in multiple countries for PBFT02, which allows us to proceed with our upliFT-D trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBFT02 in patients with a diagnosis of symptomatic FTD- GRN .

The FDA has granted ODD and Fast Track Designation to PBFT02 for the treatment of FTD- GRN and the European Commission granted Orphan designation for PBFT02.

Clinical Supply

Through our manufacturing partners, we have manufactured the PBFT02 clinical supply to support ongoing clinical trial activities.

Other Research Programs

We have two additional programs in candidate selection or discovery stages of preclinical research, in collaboration with GTP.

These include PBAL05 for ALS and our unnamed program for Huntington’s disease.

Overview of C9orf72 ALS - PBAL05

C9orf72-mediated Amyotrophic Lateral Sclerosis, or C9orf72 ALS, is an adult-onset, rapidly progressing neurodegenerative disease characterized by dysfunction and death of upper and lower motor neurons leading to progressive weakness, loss of motor function, and death typically within three to five years of disease onset.

Most cases of ALS are sporadic with an unknown etiology, but approximately 10% of patients have autosomal

dominantly inherited forms.

We are focusing on C9orf72-mediated ALS, since mutations in the C9orf72 gene are the most common mutation found in ALS patients including both familial (approximately 40% of familial ALS cases) and sporadic ALS cases (approximately 8% of sporadic ALS patients carry C9orf72 mutations), accounting for approximately 11% of all ALS cases.

In 2021, the total number of prevalent C9orf72 ALS cases was estimated to be approximately 4,500 worldwide.

In these cases, the disease is caused by a hexanucleotide repeat expansion in the first intron of C9orf72.

The pathogenic mechanism of C9orf72 mutations is not yet proven, but three potential mechanisms predominate, which are toxic gain of function arising from deposition of transcribed atypical dipepetide repeat proteins, and/or deposition of mutant ribonucleic acid, or RNA, and/or loss of function of endogenous proteins.

Our approach is to use a single AAV vector to deliver a miRNA and a codon-optimized miRNA-resistant C9orf72 transgene combination, to both deplete normal and mutant mRNA within cells with the miRNA and to replace with functional wildtype human transgene.

This program is currently at the discovery stage.

Unnamed Research Program

With GTP we have one additional specified research program, to develop a genetic medicine to treat Huntington’s disease.

This program, initiated in 2021, is currently in the discovery stage.

Beyond this portfolio, through our research collaboration with GTP, we also have the option to license programs for eight additional indications.

Exploratory Research Program

We have an exploratory research program with GTP with the goal of developing genetic medicines for non-rare CNS disorders.

The program is currently focused on treatment-resistant TLE, and can be expanded to other large CNS diseases upon mutual agreement with GTP.

PBFT02 for the treatment of FTD-C9orf72 and ALS

Preclinical data suggests that increased neuronal PGRN may reduce TDP-43 pathology, which is a hallmark of multiple neurodegenerative conditions .

This includes FTD- C9orf72 and approximately 95% of sporadic ALS , which are indications that we are actively pursuing.

TDP-43 is a ribonuclear protein with multiple transcriptional and post-transcriptional functions.

In TDP-43 pathology disorders, hyperphosphorylated TDP-43 abnormally

accumulates in the cytoplasm of cell bodies and dendritic processes of neurons and glia, rather than its typical localization in the nucleus.

Neuronal dysfunction and degeneration have been linked with loss of TDP-43’s normal nuclear functions and with toxicity of insoluble cytoplasmic TDP-43.

Third-party preclinical studies demonstrated that TDP-43 pathology and associated toxicities may be reduced by increasing PGRN levels.

The potential for a beneficial effect of PGRN in TDP-43-associated neurodegenerative disorders has been shown in mice and zebrafish.

In a transgenic mouse model expressing human mutant TDP-43, overexpression of PGRN reduced cytoplasmic accumulation of insoluble TDP-43, reduced axonopathy in the spinal cord, and slowed disease progression, leading to prolonged survival.

In zebrafish models in which mutant TDP-43 expression induced motor neuron degeneration, depleting PGRN expression resulted in worsened axonopathy.

In contrast, overexpression of PGRN rescued the TDP-43-associated motor neuron degeneration in the zebrafish.

Following from these animal model observations, we postulate that elevating neuronal PGRN levels in diseases with TDP-43 pathology may provide significant benefits to patients.

We expect to obtain regulatory feedback on the clinical pathway to treating FTD- C9orf72 and sporadic ALS patients with PBFT02 in the second half of 2024.

PBFT02 for the treatment of AD

We believe that elevating PGRN levels has the potential to improve the course of AD in patients who are carriers of the GRN SNP.

The GRN SNP is associated with reduced PGRN levels.

It is present within approximately 30% of the population where its presence confers an increased risk for AD onset.

Within AD patients, presence of the GRN SNP and reduced PGRN levels translates into more rapid disease progression.

This is accompanied by higher levels of CSF tau, which correlate with increased AD pathology in the brain.

Third party preclinical studies in animal models have demonstrated that low levels of PGRN may exacerbate AD pathology and, conversely, high levels of PGRN may reduce AD pathology.

We plan to initiate preclinical studies in AD to extend these initial observations.

PBFT02 Clinical Supply

Through our manufacturing partners, we have manufactured the PBFT02 clinical supply to support completion of the ongoing Phase 1/2 clinical study in FTD- GRN as well as initiate dosing in one additional indication.

Other Active Research Programs

We have a program in collaboration with GTP to develop a genetic medicine to treat Huntington’s disease.

This program is currently in the discovery stage.

Beyond this, through our research collaboration with GTP, we also have the option to license programs for eight additional CNS indications.

Manufacturing

Gene therapy manufacturing is a critical factor in the successful development and commercialization of novel genetic medicines, and to that end, we have established internal CMC capabilities to support our vector manufacturing and production platform and we have a relationship with Catalent, a contract development and manufacturing organization, or CDMO, for our initial manufacturing needs.

Gene therapy manufacturing is a critical factor in the successful development and commercialization of novel genetic medicines.

To that end, we have established internal chemistry, manufacturing and control, or CMC, capabilities to support our vector manufacturing and production platform, and we have a relationship with Catalent, a contract development and manufacturing organization, or CDMO, for our manufacturing needs.

We utilize a production platform approach with HEK293 mammalian cells as the substrate, triple plasmid transient transfection and single-use fixed-bed iCELLis® bioreactor system for the manufacture of our AAV product candidates.

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We believe our approach will enable rapid development, control of product quality and regulatory compliance.

We have invested significantly in our internal laboratory capabilities and infrastructure to support the manufacturing of our clinical product candidates.

Our in-house laboratory is equipped with state-of-the-art analytical and process development capabilities to support and enhance our viral vector manufacturing platform.

We have developed the internal technical and scientific capability along with the manufacturing and quality expertise to develop, transfer, and oversee vector production systems externally at commercial scale.

We believe our capabilities provide a core strategic advantage and position us to be a leading drug development company to address CNS disorders.

GTP currently provides us with the preclinical and toxicology research-grade vector supplies, while Catalent provides us with the cGMP AAV clinical supplies for our clinical trials.

The production process for our two lead clinical stage product candidates, PBGM01 and PBFT02, and for the two clinical stage product candidates for which we have stopped clinical development, PBKR03 and PBML04, has been scaled up to GMP standards at Catalent’s facility.

Clinical materials for these candidates have been manufactured.

We have a collaboration agreement with Catalent, or the Collaboration Agreement, that gives us access to a cGMP manufacturing suite .

Access to cGMP manufacturing capacity gives us the ability to meet production requirements for our current clinical product candidates supporting current and future clinical trials.

We also have a development services and clinical supply agreement, or the Manufacturing and Supply Agreement, with Catalent to support clinical scale manufacturing for our gene therapy product candidates.

We entered into a lease to support chemistry, manufacturing and controls laboratory operations for our gene therapy programs, which commenced in March 2021, in the Princeton West Innovation Campus.

In 2021, we completed our build out of this new laboratory that is initially focused on state-of-the-art analytical capabilities, assay development and validation, and clinical product testing to support both viral vector manufacturing and clinical development.

Since then, we have been able to internalize all major CMC laboratory capabilities, including process development, which will enable late-stage development and commercialization of our gene therapies.

We have advanced our manufacturing platform which can be leveraged across our clinical and pre-clinical pipeline through standardization of our manufacturing and analytical technologies.

We believe that our internal CMC capabilities provide a strategic advantage.

In 2021, we built a state-of-the-art laboratory in the Princeton West Innovation Campus, which enabled us to internalize all major CMC laboratory

capabilities, including analytical development, process development, and quality control testing.

With our strong technical expertise, we are constantly exploring new ways to improve the manufacturing process for gene therapy products.

Through internal efforts, we have developed leading-edge, robust analytical methods and an enhanced manufacturing platform that can be leveraged across our clinical and pre-clinical pipeline.

In this regard, we have filed two patent applications on new methods to improve the manufacturing of our products.

Additionally, we have established the necessary internal technical and scientific expertise to manage the external operations for clinical and commercial manufacturing.

GTP currently provides us with preclinical and toxicology research-grade vector supplies, while Catalent provides us with current good manufacturing practice, or cGMP, AAV clinical supplies for our clinical trials.

The production processes for PBFT02 and for the three clinical stage product candidates for which we have stopped clinical development, PBGM01, PBKR03 and PBML04, have been scaled up to cGMP standards at Catalent’s facility.

Clinical materials for each of these candidates have been successfully manufactured.

We have an amended and restated collaboration agreement with Catalent that governs our relationship with Catalent for the supply of cGMP capacity.

Access to cGMP manufacturing capacity gives us the ability to meet production requirements for our current and future clinical trials.

We also have an amended and restated development services and clinical supply agreement, and together with the amended and restated collaboration agreement, the Amended Catalent Agreements, with Catalent to support clinical scale manufacturing for our gene therapy product candidates.

The Amended Catalent Agreements establish a limited exclusive relationship between us and Catalent for the manufacture of bulk drug substance and drug product for PBFT02 and PBGM01 programs.

The limited exclusive relationship under the Amended Catalent Agreements converts to a non-exclusive relationship (i) in the event Catalent fails to meet certain performance standards and (ii) following certain conditional events related to the divestiture by us of either PBFT02 or PBGM01, in which case, if such events occur, we would pay Catalent certain fees.

In addition, in the event of certain transactions, we may terminate the Amended Catalent Agreements for convenience with respect to such products, in which case, we would pay to Catalent a certain termination fee.

We believe that our manufacturing capabilities provide us with the advantages of better control of drug development timelines, improved control of vector supply for a portfolio of clinical assets and improved control of product quality through the improvements of the manufacturing platform.

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We may also face competition from large and specialty pharmaceutical and biotechnology companies, academic research institutions, government agencies and public and private research institutions with genetic medicine and other therapeutic approaches.

We consider our most direct competitors with respect to PBGM01 for the treatment of GM1 to be Lysogene, S.A, or Lysogene, which is developing a gene therapy treatment administered via intracisternal magna for early and late infantile GM1.

As of February 2022, Lysogene reported having dosed three patients and enrolled a fourth patient in the safety cohort.

The National Institutes of Health is conducting a clinical trial for an IV gene therapy treatment for early and late infantile/juvenile GM1 and reported data from ten patients in October 2021.

There are also preclinical enzyme replacement therapies in preclinical development.

For the treatment of FTD, there are no approved disease-modifying therapies.

We consider our most direct competitors with respect to PBFT02 for the treatment of FTD- GRN to be Alector, Inc.

(partnered with GlaxoSmithKline), which is enrolling a Phase 3 clinical trial with a humanized anti-human sortilin monoclonal antibody for FTD-GRN, and Prevail Therapeutics Inc.

(now part of Eli Lilly & Co), which has initiated a Phase 1/2 clinical trial for a gene therapy treatment for FTD-GRN, and is expected to continue enrolling through 2023.

Several other companies, including AviadoBio Ltd, Applied Genetic Technologies Corporation (recently acquired by Syncona Limited), and Orchard Therapeutics plc, are conducting preclinical research using gene therapy approaches to treat FTD-GRN patients.

AviadoBio Ltd has reported the planned initiation of a phase 1/2 trial in 2023.

(partnered with GlaxoSmithKline), which is conducting a Phase 3 clinical trial with a humanized anti-human sortilin monoclonal antibody for FTD- GRN , and Prevail Therapeutics Inc.

(now part of Eli Lilly & Co), which is conducting a Phase 1/2 clinical trial for a gene therapy treatment for FTD- GRN .

AviadoBio began enrolling their Phase 1/2 gene therapy trial in patients with FTD- GRN in the second half of 2023.

Additional companies, including Kyowa Kirin Co., Ltd.

and QurAlis Therapeutics, are conducting preclinical research using gene therapy approaches to treat patients with FTD- GRN .

Denali Therapeutics Inc.

in partnership with Takeda Pharmaceutical Company Limited has a preclinical recombinant progranulin protein under evaluation in addition to their oral EIF2a modulator in a Phase 1 clinical trial.

in partnership with Takeda Pharmaceutical Company Limited

is conducting a Phase 1/2 clinical trial for their recombinant progranulin protein in addition to their oral EIF2a modulator already in a Phase 1 clinical trial.

VesperBio began Phase 1 enrollment for a small molecule sortilin antagonist program targeting FTD- GRN in the fourth quarter of 2023.

We are also aware of other therapeutic approaches in preclinical development that may target FTD- GRN patients.

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Competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market, if ever.

Additionally, new or advanced technologies

developed by our competitors may render our current or future product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors.

Additionally, new or advanced technologies developed by our competitors may render our current or future product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors.

License Agreement

University of Pennsylvania

We have a research, collaboration and licensing agreement, as amended, or the Penn Agreement, with Penn, for research and development collaborations and exclusive license rights to patents for certain products and technologies.

Under the Penn Agreement, we have the obligation to fund certain research relating to the preclinical development of selected products in research programs as well as the new exploratory research program in non-rare and/or non-monogenic, or large, CNS indications, initially TLE.

We also fund discovery research conducted by Penn through August 2026 and will receive exclusive rights, subject to certain limitations, to technologies resulting from the discovery program for products developed with GTP, such as novel capsids, toxicity reduction technologies and delivery and formulation improvements.

Our discovery research funding commitment is $5.0 million a year for five years, with quarterly payments of $1.3 million through June 2026.

Under the Penn Agreement we have eight remaining options available to us to commence additional licensed programs for CNS indications until August 2026.

If we were to exercise any of these remaining options, we would owe Penn a non-refundable aggregate fee of $1.0 million, with $0.5 million per product indication paid immediately and another $0.5 million fee owed upon a further developmental milestone.

The Penn Agreement requires that we make payments of up to (i) $16.5 million per product candidate for rare, monogenic disorders in aggregate and (ii) $39.0 million per product candidate in the aggregate arising from the exploratory program for large CNS indications, currently TLE and such other mutually agreed upon large CNS indications.

We have a research, collaboration and licensing agreement with Penn, as amended, or the Penn Agreement, for research and development collaborations and exclusive license rights to patents for certain products and technologies.

Under the Penn Agreement, we have the option to obtain exclusive licenses to, and to fund, certain research relating to the preclinical development of selected products in research programs in rare monogenic CNS indications.

We have eight remaining options available to commence additional licensed programs for CNS indications until August 3, 2026.

The Penn Agreement includes an exploratory research program to identify targets and early product candidates in certain agreed upon non-monogenic, non-rare, or large, CNS indications.

The initial term of the exploratory research program is three years, or until August 2024, which term can be extended by mutual agreement.

During such term, we will have an exclusive right of first negotiation to include additional targets to the exploratory research program in the agreed upon large CNS indications.

Under the exploratory research program, we will have the right to further develop and commercialize any gene therapy product candidates specific for those selected targets that arise from the exploratory research programs by exercising one of our remaining eight options.

We currently do not have any active exploratory research programs.

If we were to exercise any of the remaining options, we would owe Penn a non-refundable aggregate fee of $1.0 million per product indication, with $0.5 million due upfront and another $0.5 million fee owed upon a further developmental milestone.

We also fund discovery research conducted by Penn through August 3, 2026 and will receive exclusive rights, subject to certain limitations, to platform technologies resulting from the discovery research for our products developed with GTP, such as novel capsids, toxicity reduction technologies and delivery and formulation improvements.

This funding commitment for the discovery research is $5.0 million annually, paid in quarterly increments of $1.3 million through June 2026.

The Penn Agreement requires that we make payments of up to (i) $16.5 million per product candidate for rare, monogenic disorders in the aggregate and (ii) $39.0 million per product candidate in the aggregate arising from the exploratory program for large CNS indications.

Each payment will be due upon the achievement of specific development milestone events by such licensed product for a first indication, reduced development milestone payments for the second and third indications and no development milestone payments for subsequent indications.

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The agreement will expire on a licensed product-by-licensed product and country-by-country basis upon the later of (i) the expiration of the last valid claim of the licensed patent rights that covers the exploitation of such licensed product in such country, and (ii) the expiration of the royalty period.

At any time after August 2026, we may terminate the agreement in its entirety, or for a licensed product, for convenience upon 90 days’ prior written notice to Penn.

Penn may terminate the agreement on an indication-by-indication basis if we fail to meet any diligence event and fail to timely cure such breach, or the agreement in its entirety if we fail to pay the research funding, fail to comply with applicable laws, grant a security interest in any of the licensed patent rights, fail to achieve certain financing obligations, or make certain challenges to the licensed patent rights.

Either party may terminate the agreement for the other party’s insolvency or material breach that is not cured within a specified period of time.

In addition, we will pay Penn a tiered transaction fee ranging from 1-2% of the net proceeds upon certain change of control events.

The Penn Agreement includes an exploratory research collaboration to identify targets and early product candidates in such large CNS indications.

The exploratory research program is focused on discovering targets and novel gene therapy candidates for large CNS diseases, currently focused on TLE, and that can be expanded to other large CNS diseases upon mutual agreement.

The initial term of the exploratory research program is 3 years, or until August 2024, which term can be extended by mutual agreement.

During such term we will have an exclusive right of first negotiation to include additional targets to the exploratory research program in the agreed upon large CNS indications.

Under the exploratory research program, we will have the right to further develop and commercialize any gene therapy product candidates specific for those selected targets within TLE (and any future large CNS indications that are mutually agreed upon) that arise from the exploratory research programs on

substantially the same terms of the current Penn Agreement.

In November 2022, we agreed with GTP to not continue further advancement of our exploratory research program in AD.

In addition, we will pay a tiered transaction fee of 1-2% of the net proceeds upon certain change of control events.

Penn will notify us of any patented manufacturing methods developed by GTP during the specified research term, and we have the option to obtain a non-exclusive license under those patent rights controlled by Penn for our licensed products.

On a CNS indication-by-indication basis, Penn has agreed that GTP will not collaborate with any commercial third party to develop another gene therapy product for the same indication during, or for one year following, its work for us on a given indication and licensed product.

In addition to the exclusive licenses granted to us, on a CNS indication-by-indication basis, Penn has agreed that GTP will not collaborate with any commercial third party to develop another gene therapy product for the same indication until two years after the earlier of the filing of the IND or the clearance of the IND for a licensed product in such indication.

Under the licensed Penn patent rights, Penn retains the right to conduct (and to authorize non-commercial third parties to conduct) certain educational, research, clinical and patient care activities.

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We may satisfy this obligation by achieving, for each licensed product, certain diligence events by a specified achievement date, which dates may be extended under certain circumstances.

Pursuant to the agreement, Penn will be responsible for preclinical development activities, including all IND-enabling non-clinical studies and research grade manufacturing, and other collaborative activities set forth in the plan for the funded research, and we will be responsible for regulatory strategy and operations, clinical development, GMP manufacture and commercialization of all licensed products.

Pursuant to the agreement, Penn will be responsible for preclinical development activities, including all IND-enabling non-clinical studies and research grade manufacturing, and other collaborative activities set forth in the plan for the funded research, and we will be responsible for regulatory strategy and operations, clinical development, cGMP manufacture and commercialization of all licensed products.

Intellectual Property

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Additionally, we intend to rely on regulatory protection afforded through rare drug designations, data exclusivity and market exclusivity as well as patent term extensions, where available.

Currently, our patent protection consists of patent applications that we have in-licensed from Penn under the Penn Agreement for our product candidates in our licensed indications and a patent application that we filed and solely own related to a process for manufacturing our products.

Currently, our patent protection consists of patents and patent applications that (i) we have in-licensed from Penn under the Penn Agreement for our product candidates in our licensed indications and (ii) we own solely based on internally developed processes for manufacturing our products.

The in-licensed patent applications are directed to new AAV capsids and certain defined variants, to recombinant AAV viruses, or rAAVs, capable of delivering certain genes into human cells to treat monogenic diseases of the CNS, to methods of treating those monogenic diseases with rAAV, as well as certain aspects of our manufacturing capabilities and related technologies.

Our in-licensed patent portfolio currently includes:

• a patent family with applications pending in the United States and certain foreign jurisdictions with claims directed to rAAVs having an AAVhu68 capsid.

We exclusively licensed the patent family for licensed products within our rare, monogenic field of use indications.

• two patent families with claims directed to rAAV for use in treating FTD.

The first patent family includes applications pending in fourteen jurisdictions, including the U.S., Argentina, Brazil, Canada, China, Europe, Israel, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on February 21, 2040, absent any term adjustments or extensions.

The second patent family includes applications in sixteen jurisdictions, including the U.S., Argentina, Taiwan, Brazil,

Canada, China, Europe, Israel, Japan and Korea.

Any patents that may issue from applications in this family are expected to expire on August 26, 2041, absent any term adjustments or extensions;

• a patent family with patents granted in the U.S., Europe, and South Africa and applications pending in the U.S.

and certain foreign jurisdictions with claims directed to rAAVs having an AAVhu68 capsid.

We exclusively licensed this patent family for licensed products within our rare, monogenic field of use indications.

Patents that have issued or may issue from applications in this family are expected to expire on February 27, 2038, absent any term adjustments or extensions;

• two patent families with claims directed to an rAAV containing a coding sequence of human β-gal for use in treating GM1.

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Any patents that may issue from applications in this family are expected to expire on February 1, 2041, absent any term adjustments or extensions;

• two patent families with claims directed to rAAV for use in treating FTD.

The first patent family includes applications pending in fifteen jurisdictions, including the US, Argentina Brazil, Canada, China, Europe, Israel, Japan, and Korea.

• two patent families with claims directed to rAAV for use in treating Krabbe.

The first patent family includes pending applications in fifteen jurisdictions, including the U.S., Argentina, Australia, Brazil, Canada, China, Europe, Israel, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on February 26, 2040, absent any term adjustments or extensions.

The second patent family includes applications in Argentina and Taiwan and a pending PCT application.

Any patents that may issue from applications in this family are expected to expire on August 26, 2041;

• one patent family with claims directed to rAAV for use in treating ALS.

The patent family includes applications pending in Argentina and Taiwan and a pending PCT application.

The second patent family includes pending applications in sixteen jurisdictions, including the U.S., Argentina, Australia, Brazil, Canada, China, Europe, Israel, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on May 11, 2041, absent any term adjustments or extensions;

• two patent families with claims directed to rAAV for use in treating MLD.

The first patent family includes applications pending in fifteen jurisdictions, including the U.S., Argentina, Brazil, Canada, China, Europe, Israel, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on May 24, 2040, absent any term adjustments or extensions.

The second patent family includes applications pending in Argentina and Taiwan, and a patent cooperation treaty, or PCT, application.

Any patents that may issue from applications in this family are expected to expire on January 10, 2043, absent any term adjustments or extensions.

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Our ability to stop third parties from making, using, selling, offering to sell or importing our products may depend on the extent to which we have rights under valid and enforceable patents or trade secrets that cover these activities.

With respect to our licensed intellectual property, we cannot be sure that patents will issue with respect to any of the pending patent applications to which we license rights or with respect to any patent applications that we or our licensors may file in the future, nor can we be sure that any of our licensed patents or any patents that may be issued in the future to us or our licensors will be commercially useful in protecting our product candidates and methods of manufacturing the same.

With respect to our owned or licensed intellectual property, we cannot be sure that patents will issue

with respect to any of the pending patent applications to which we own or license rights or with respect to any patent applications that we or our licensors may file in the future, nor can we be sure that any of our licensed patents or any patents that may be issued in the future to us or our licensors will be commercially useful in protecting our product candidates and methods of manufacturing the same.

Moreover, we may be unable to obtain patent protection for certain of our product candidates generally, as well as with respect to certain indications.

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The Federal Food, Drug, and Cosmetic Act, or the FDC Act, and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.

Biological products used for the prevention, treatment, or cure of a disease or

condition of a human being are subject to regulation under the FDC Act, except the section of the FDC Act which governs the approval of New Drug Applications, or NDAs.

Biological products used for the prevention, treatment, or cure of a disease or condition of a human being are subject to regulation under the FDC Act, except the section of the FDC Act which governs the approval of New Drug Applications, or NDAs.

Biological products, such as gene therapy products, are approved for marketing under provisions of the Public Health Service Act, or PHSA, via a BLA.

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subjects and subsequent protocol amendments must be submitted to the FDA as part of the IND.

The FDA may order the temporary or permanent discontinuation of a clinical trial at any time, or impose other sanctions, if it believes that the clinical trial either is not being conducted in accordance with FDA regulations or presents an unacceptable risk to the clinical trial subjects.

presents an unacceptable risk to the clinical trial subjects.

The trial protocol and informed consent information for subjects in clinical trials must also be submitted to an institutional review board, or IRB, for approval.

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After the FDA evaluates the BLA and completes any clinical and manufacturing site inspections, it issues either an approval letter or a complete response letter.

A complete response letter generally outlines the deficiencies in the BLA submission and may require substantial additional testing, or information, in order for the FDA to reconsider the application for approval.

A complete response letter generally outlines the deficiencies in the BLA submission and may require substantial additional testing, or information, in order for the FDA to

reconsider the application for approval.

If, or when, those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the BLA, the FDA will issue an approval letter.

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Changes to some of the conditions established in an approved BLA, including changes in indications, product labeling, manufacturing processes or facilities, require submission and FDA approval of a new BLA or BLA supplement before the change can be implemented.

supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures and actions in reviewing BLA supplements as it does in reviewing BLAs.

A BLA supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures and actions in reviewing BLA supplements as it does in reviewing BLAs.

Additional Standard for Gene Therapy Products

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In such cases, the FDA generally intends to determine whether two gene therapy products are different on a case-by-case basis.

During the seven-year marketing exclusivity period, the FDA may not approve any other applications to market a biological product containing the same principal molecular structural features for the same indication, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity.

During the seven-

year marketing exclusivity period, the FDA may not approve any other applications to market a biological product containing the same principal molecular structural features for the same indication, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity.

A product can be considered clinically superior if it is safer, more effective or makes a major contribution to patient care.

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in general, the disease must affect fewer than 200,000 such individuals in the U.S.;

the NDA or BLA must be deemed

eligible for priority review;

the NDA or BLA must be deemed eligible for priority review;

the NDA or BLA must not seek approval for a different adult indication (i.e., for a different disease/condition);

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Competitors may use this publicly available information to gain knowledge regarding the progress of clinical development programs as well as clinical trial design.

Pediatric Information

Under the Pediatric Research Equity Act, or PREA, NDAs or BLAs or supplements to NDAs or BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective.

The FDA may grant full or partial waivers, or deferrals, for submission of data.

Unless otherwise required by regulation, PREA does not apply to any biological product with

orphan product designation except a product with a new active ingredient that is a molecularly targeted cancer product intended for the treatment of an adult cancer and directed at a molecular target determined by FDA to be substantially relevant to the growth or progression of a pediatric cancer.

Additional Controls for Biologics

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Once a BLA is approved, a product will be subject to certain post-approval requirements.

For instance, the FDA closely regulates the post-approval marketing and promotion of biologics, including standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities and

promotional activities involving the Internet.

Biologics may be marketed only for the approved indications and in accordance with the provisions of the approved labeling.

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In the United States, biotechnology company activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare & Medicaid Services, or CMS, other divisions of the U.S.

Department of Health and Human Services (e.g., the Office of Inspector General and the Office for Civil Rights), the U.S.

Department of Health and Human Services, or HHS (e.g., the Office of Inspector General and the Office for Civil Rights), the U.S.

Department of Justice, or DOJ, and individual U.S.

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The civil monetary penalties statute imposes penalties against any person or entity who, among other things, is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.

federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.

Federal false claims laws, including the federal civil False Claims Act, prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.

As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S.

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Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.

In addition, several states have enacted legislation requiring pharmaceutical and biotechnology companies to

establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical and biotechnology companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.

In addition, several states have enacted legislation requiring pharmaceutical and biotechnology companies to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical and biotechnology companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.

Certain local jurisdictions also require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures.

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Different pricing and reimbursement schemes exist in other countries.

In the EU, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers.

In the European Union, or EU, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers.

Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed.

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The marketability of any product candidates for which regulatory approval is received for commercial sale may suffer if the government and other third-party payors fail to provide coverage and adequate reimbursement.

In addition, emphasis on managed care in the United States has increased and is expected to continue to increase the pressure on healthcare pricing.

addition, emphasis on managed care in the United States has increased and is expected to continue to increase the pressure on healthcare pricing.

Coverage policies and third-party reimbursement rates may change at any time.

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Healthcare reform proposals recently culminated in the enactment of the Inflation Reduction Act, or IRA, which will eliminate, beginning in 2025, the coverage gap under Medicare Part D by significantly lowering the enrollee maximum out-of-pocket cost and requiring manufacturers to subsidize, through a newly established manufacturer discount program, 10% of Part D enrollees’ prescription costs for brand drugs below the out-of-pocket maximum, and 20% once the out-of-pocket maximum has been reached.

The IRA will also allow HHS to negotiate the selling price of certain drugs and biologics that CMS reimburses under Medicare Part B and Part D (excluding drugs and biologics that are designated and approved for only one rare disease or condition), although only high-expenditure single-source biologics that have been approved for at least 11 years (7 years for drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.

The negotiated prices, which will first become effective in 2026, will be capped at a statutory ceiling price.

Beginning in October 2022 for Medicare Part D and January 2023 for Medicare Part B, the IRA will also penalize drug manufacturers that increase prices of Medicare Part D and Part B drugs at a rate greater than the rate of inflation.

The IRA will also allow HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D.

Only high-expenditure single-source biologics that have been approved for at least 11 years (seven years for drugs) can qualify for negotiation, with the negotiated price taking effect two years after the selection year.

Negotiations for Medicare Part D products begin in 2024 with the negotiated price taking effect in 2026, and negotiations for Medicare Part B products begin in 2026 with the negotiated price taking effect in 2028.

In August 2023, HHS announced the ten Medicare Part D drugs and biologics that it selected for negotiations, and by October 1, 2023, each manufacturer of the selected drugs signed a manufacturer agreement to participate in the negotiations.

HHS will announce the negotiated maximum fair prices by September 1, 2024, and this price cap, which cannot exceed a statutory ceiling price, will come into effect on January 1, 2026.

A drug or biological product that has an orphan drug designation for only one rare disease or condition will be excluded from the IRA’s price negotiation requirements, but loses that exclusion if it has designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation.

The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation.

The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

Manufacturers that fail to comply with the IRA may be subject to various penalties, some significant, including civil monetary penalties.

The IRA also extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

These provisions are taking effect progressively starting in 2023, although they may be subject to legal challenges.

For example, the provisions related to the negotiation of selling prices of high-expenditure single-source drugs and biologics have been challenged in multiple lawsuits.

Thus, while it is unclear how the IRA will be implemented, it will likely have a significant impact on the pharmaceutical industry and the pricing of our products and product candidates.

It is unclear to what extent other statutory, regulatory, and administrative initiatives will be enacted and implemented in the future.

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Our Mission and Our Employees

At Passage Bio, our mission is to discover and develop transformative therapies for CNS disorders with limited or no approved treatment options, while also building strong relationships with the communities we serve.

At Passage Bio, our mission is to improve the lives of patients with neurodegenerative diseases, while also building strong relationships with the communities we serve.

We embrace collaboration, discipline and efficiency, while welcoming fresh ideas and stimulating personal development.

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they are relying on us

● Committ to Excellence

● Commit to Excellence

o We apply leading-edge science and technology to develop gene therapies for our patients

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o We have an unrelenting focus on quality

● Make and impact

● Make an Impact

o We act with a sense of urgency;

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o We care about our community and strive to be good citizens

● Suceed together

o We’re all part of the solution and help each other be successful

● Succeed Together

o We are all part of the solution and help each other be successful

o We innovate by challenging the status quo, taking appropriate risk and encouraging diversity of thought

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Given the highly competitive nature of our industry and the importance of recruitment and retention to our success, we strive to provide our employees with what we believe is a very competitive and comprehensive total rewards package of compensation, benefits and services.

This package includes at or above-market pay, healthcare benefits for employees and family members, life insurance benefits, short and long-term disability benefits, generous paid time off benefits, parental leave, bereavement leave, flexible work schedules, a 5% employer match of employee contributions to our sponsored retirement plans, and an annual stipend for employees to spend on professional development.

This package includes competitive market pay, healthcare benefits for employees and family members, life insurance benefits, short and long-term disability benefits, generous paid time off benefits, parental leave, bereavement leave, flexible work schedules, a 5% employer match of employee contributions to our sponsored retirement plans, and an annual stipend for

employees to spend on professional development.

Additionally, we also offer every full-time employee the benefit of equity ownership in our Company through our equity plans.

Our principal executive office is located in Philadelphia, Pennsylvania, where we lease a total of approximately 37,000 square feet of office space, which commenced in February 2021 and will expire in December 2031, subject to our option to extend the term of the lease by up to two additional five-year terms .

We also lease approximately 62,000 square feet of laboratory space at the Princeton West Innovation Campus in Hopewell, New Jersey.

This lease has a 15-year term from the lease commencement date of March 2021.

We have the option to extend the term of the lease by up to two additional five-year terms.

The compensation and benefits program is governed by our board of director’s Compensation Committee.

Specifically, the Compensation Committee, with advice from an independent executive compensation consulting firm, determines compensation for the Chief Executive Officer and other executive officers, which includes an evaluation of market rates for all components of compensation.

Our Compensation Committee and an independent executive compensation consulting firm also evaluate and recommend the framework of compensation and benefit plans, as it relates to discretionary non-equity incentive plans and equity incentive plans, for non-executive officers.

For non-executive officers, we utilize a third-party resource to evaluate market rates for base compensation.

Legal Proceedings

From time to time, we may be involved in legal proceedings arising in the ordinary course of our business.

We are not presently a party to any legal proceedings that, in the opinion of management, would have a material adverse effect on our business.

We are currently a defendant in litigation with a former employee in the Court of Common Pleas of Philadelphia County (Commerce Division), or the Court, relating to a claim of breach of contract and violation of the Pennsylvania Wage Payment and Collection Law.

The plaintiff claims that, pursuant to an alleged settlement agreement reached on February 3, 2020, we agreed to issue plaintiff 150,000 shares of our common stock and that such shares would not be subject to the reverse stock split implemented by us in connection with our initial public offering on February 14, 2020.

The plaintiff’s claim is for an amount in the mid-single digit millions of dollars.

We disagree with the allegations that there was ever a binding settlement agreement or that any shares would not be subject to the reverse stock split, and we believe the plaintiff’s claim is without merit.

In October 2023, the Court denied both the Company’s and the plaintiff’s motions for summary judgement and therefore we anticipate that this matter will go to trial in 2024.

We intend to vigorously defend against these claims, and believe we have strong arguments to prevail in the litigation.

There can be no assurance that we will prevail on our claims.

Other than the above, we are not presently a party to any legal proceedings that, in the opinion of management, could have a material adverse effect on our business.

Regardless of outcome, litigation can have an adverse impact on us due to defense and settlement costs, diversion of management resources, negative publicity and reputational harm, and other factors.

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We were incorporated under the laws of the State of Delaware in July 2017 under the name Passage Bio, Inc.

Our principal executive office is located at Two Commerce Square, 2005 Market Street, 39th Floor, Philadelphia, PA, 19103, and our telephone number is (267) 866-0311.

Our principal executive office is located at One Commerce Square, 2005 Market Street, 39th Floor, Philadelphia, Pennsylvania, 19103, and our telephone number is (267) 866-0311.

Our website address is www.passagebio.com.

The information contained on, or that can be accessed through, our website is not part of, and is not incorporated by reference into, this prospectus.

The information contained on, or that can be accessed through, our website is not part of, and is not incorporated by reference into, this Annual Report.

Available Information

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business