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Item 1. Business

2025-03-04 compared with 2024-03-04 · 278 added, 335 removed, 477 unchanged (56% of the section changed)

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.

Our primary focus is the development and advancement of cutting-edge, one-time gene therapies designed to target critical underlying pathologies in 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 .

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

PBFT02 is a gene replacement therapy that utilizes an adeno-associated virus serotype 1, 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 .

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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.

Additionally, we believe restoration of PGRN has the potential to modulate Alzheimer’s disease, or AD, in patients who are carriers of the PGRN-lowering 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.

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.

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.

We have received positive regulatory feedback on the clinical pathway to treating FTD- C9orf72 patients and ALS patients with PBFT02.

We are proceeding with clinical development of PBFT02 in FTD- C9orf72 patients and plan to initiate dosing in the first half of 2025.

On July 31, 2024, we entered into a series of sublicense agreements with Gemma Biotherapeutics, Inc., or Gemma, a newly formed genetic medicines company co-founded by Dr.

James Wilson in connection with the outlicensing of PBGM01 for the treatment of GM1 gangliosidosis, or GM1, PBKR03 for the treatment of Krabbe disease, and PBML04 for the treatment of metachromatic leukodystrophy, or MLD, collectively the Outlicensed Programs, and such agreements, the Gemma Sublicenses.

Pursuant to the Gemma Sublicenses, we will receive (i) initial payments of an aggregate of $10.0 million for licenses and clinical product supply;

(ii) up to an additional $10.0 million contingent on the completion by Gemma of certain business milestones;

(iii) up to an additional $114.0 million in development and commercial milestone payments;

and (iv) single digit royalties as a percentage of annual worldwide net sales in exchange for sublicenses to relevant intellectual property, transfer of regulatory dossiers and transfer of clinical trial materials and product supply related to the Outlicensed Programs.

Pursuant to the Gemma Sublicenses, Gemma will also be responsible for all payments due to the Trustees of the University of Pennsylvania, or Penn, under the Penn License Agreement, as further described below, related to the Outlicensed Programs.

We also entered into a transition services agreement with Gemma, or the Transition Services Agreement, as amended by the First Amendment to the Transition Services Agreement, dated January 31, 2025, pursuant to which, we will provide transitional services at cost to Gemma through May 31, 2025, unless terminated earlier, and be entitled to reimbursement for transitional services performed retroactively from March 1, 2024, related to the transfer of the Outlicensed Programs.

As of December 31, 2024, we have collected $5.0 million in initial payments and $3.2 million in transition services payments under these agreements.

Subsequent to December 31, 2024, we have received an additional $0.5 million in transition services payments.

We also entered into a research, collaboration and license agreement with Gemma, or the Gemma Collaboration Agreement, pursuant to which (i) Gemma will conduct certain preclinical and Investigational New Drug, or IND, enabling work for our active research program in Huntington’s disease and a currently paused research program in Temporal Lobe Epilepsy, or TLE, which were previously being conducted by Penn under the Penn Agreement and (ii) Gemma will grant us options to conduct new research programs in four new CNS indications.

We refer to the Gemma Sublicenses, the Transition Services Agreement, and the Gemma Collaboration Agreement, collectively, as the Outlicense Transaction Agreements.

As a result of the Outlicense Transaction Agreements, we also entered into an Amended and Restated Research, Collaboration and License Arrangement with Penn as of July 31, 2024, or the Penn License Agreement, to (i) terminate our funding of discovery research;

(ii) terminate the research and exploratory research programs being conducted by Penn;

(iii) terminate the remaining options we had to select new research programs in the CNS field;

and (iv) terminate the transaction fee due to Penn as a result of certain corporate transactions.

Prior to the execution of the Outlicense Transaction Agreements, we progressed four product candidates from preclinical to clinical stage development and had one active preclinical program in Huntington’s disease through our research collaboration with Penn’s Gene Therapy Program, or GTP.

This collaboration provided access to differentiated scientific expertise for the conduct of rigorous preclinical studies to generate promising product candidates.

Gemma is comprised of a core research team from GTP and is continuing the same approach to preclinical development to support the continued development of our preclinical Huntington’s disease program.

We have a gene therapy pipeline with the potential to address multiple neurodegenerative diseases.

Our development programs consist of:

* 8 additional CNS pipeline license options remain;

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

† 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 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.

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 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 currently developing PBFT02, a gene replacement therapy 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 caused by reductions in PGRN production due to mutations in the GRN gene.

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

In FTD- GRN , PGRN deficiency results in lysosomal dysfunction, neuroinflammation, and neurodegeneration.

Currently, there are no disease-modifying therapies approved for the treatment of FTD- GRN , and we estimate the prevalence of FTD- GRN in the United States and Europe is approximately 18,000, based on available literature.

Supported by 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 vector delivery throughout the brain and spinal cord of non-human primates, or NHPs, and due to the higher PGRN levels in cerebrospinal fluid, or CSF, achieved using AAV1 as compared with other serotypes tested.

ICM administration of AAV1 to NHPs resulted in elevated 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 application from the U.S.

Food and Drug Administration, or the 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.

In January 2025, we reported biomarker data from patients in our upliFT-D trial who received Dose 1 of PBFT02 (3.3e10 genome copies/g estimated brain weight, or 4.50e13 total genome copies).

Dose 1 of PBFT02 resulted in robust and durable increases in CSF PGRN levels, with concentrations increasing from below 3.0 ng/mL at baseline to 8.0 to 17.3 ng/mL at 30 days post-treatment (n=6), 13.2 to 27.3 ng/mL at six months post-treatment (n=4), and 22.3 to 34.0 ng/mL at 12 months post-treatment (n=2).

CSF PGRN levels generally plateaued by 6 months post-treatment and have remained durable through the longest available follow-up of 18 months post-treatment (n=1).

These levels of CSF PGRN are higher than the range found in healthy adult controls of 3.3 to 8.2 ng/mL (mean=4.8 ng/mL;

In contrast, following PBFT02 administration, plasma PGRN levels were unaltered, remaining similar to baseline concentrations and below levels found in healthy adult controls.

Dose 1 of PBFT02 also resulted in an average 13% decrease in plasma neurofilament light chain, or NfL, levels, a biomarker associated with disease progression, compared to baseline at 12 months post-treatment (n=2).

This reduction in plasma NfL after PBFT02 administration contrasts with an expected increase in plasma NfL levels of approximately 29% per year among untreated, symptomatic FTD- GRN patients, according to published natural history data (Saracino 2021).

As of December 2024, interim safety highlights from Dose 1 of PBFT02 in FTD- GRN patients (n=7) included:

● In five of seven patients, all treatment emergent adverse events were mild to moderate in severity.

● Two of seven patients experienced a total of three serious adverse events.

Patient 1 experienced the asymptomatic serious adverse events of venous sinus thrombosis, or VST, and hepatotoxicity, leading to a revised immunosuppression regiment in all subsequent patients (1,000 mg IV methylprednisolone on days 1-3 followed by 60 mg oral prednisone through day 60).

Patient 7 also experienced the serious adverse event of VST, which was asymptomatic and completely resolved prior to day 30 following treatment with anticoagulants.

Patient 7 had no evidence of hepatotoxicity, immune response, or other laboratory abnormalities.

● No evidence of clinically significant immune responses in any patient who received the revised immunosuppression regimen.

● No evidence of dorsal root ganglion toxicity, as measured by nerve conduction studies, and no complications during ICM administration were observed across any of the seven treated patients.

● Patients treated (n=7) range from 1 – 18 months post-dose.

Given the robust PGRN expression observed among patients who received Dose 1 of PBFT02, and to allow for dose exploration and support the program regulatory strategy, we are evaluating Dose 2, which is 50% lower than Dose 1, in subsequent FTD- GRN patients.

We expect to deliver on the following related to our upliFT-D trial for PBFT02 for the treatment of FTD- GRN :

● Report 12-month follow-up data from Dose 1 and interim safety and biomarker data from Dose 2 in the second half of 2025;

● Seek regulatory feedback on registrational trial design in the first half of 2026.

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.

We are also evaluating PBFT02 for the treatment of additional adult neurodegenerative diseases where we believe elevated PGRN levels could provide benefits.

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.

In these disorders, hyperphosphorylated TDP-43 accumulates in the cytoplasm of cell bodies and dendritic processes of neurons and glia.

Experimental evidence suggests that loss of TDP-43's normal nuclear function contributes to neurodegenerative processes.

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.

We have initiated preclinical studies to extend these initial observations.

We received positive regulatory feedback on the clinical pathway to treating FTD- C9orf72 with PBFT02 in the ongoing upliFT-D trial and amended the upliFT-D clinical trial protocol to include two cohorts of FTD- C9orf72 patients to be enrolled sequentially.

Each cohort will consist of three to five symptomatic FTD patients with C9orf72 gene mutations and patients will initially receive Dose 2 PBFT02.

We expect to initiate dosing of FTD- C9orf72 patients in the first half of 2025.

There are no disease modifying therapies approved for the treatment of FTD- C9orf72 .

Based on available literature, we estimate the prevalence of FTD- C9orf72 in the United States and Europe is approximately 21,000.

Similarly, we received positive regulatory feedback on the clinical pathway to treating ALS with PBFT02.

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.

The GRN SNP has an allele frequency of approximately 30% and is associated with reduced PGRN levels.

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

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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.

We have initiated preclinical studies in AD to further explore the potential for benefit from elevated levels of PGRN.

PBFT02 Clinical Supply

Through our partners, we have manufactured the PBFT02 clinical supply to support completion of the ongoing Phase 1/2 clinical trial in FTD- GRN and FTD- C9orf72 , and initiation of a registrational study in FTD- GRN .

Other Clinical Product Candidates

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.

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 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.

Krabbe disease is an autosomal recessive lysosomal storage disease caused by mutations in the GALC gene, which provides instructions for making an enzyme called galactosylceramidase, which breaks down certain fats, including galactosylceramide and psychosine.

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 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.

MLD is a rare, autosomal recessive lysosomal storage disease caused by mutations in the ARSA gene, resulting in little or no functional activity of the ARSA enzyme, which is essential for the degradation of sphingolipid cerebroside-3-sulfate, or sulfatide.

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, 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, 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 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.

As of July 31, 2024, we out-licensed our clinical stage pediatric programs in GM1 (PBGM01), Krabbe disease (PBKR03), and MLD (PBML04) as part of the Outlicense Transaction Agreements.

Active Research Programs

We have one unnamed preclinical research program through the Gemma Collaboration Agreement (which was previously conducted by Penn under the Penn Agreement) for which we are exploring multiple potential treatment targets for Huntington’s disease.

Beyond this program, through the Gemma Collaboration Agreement, we also have the option to license programs for four additional new indications in CNS diseases from Gemma.

Paused Research Programs

We have a research program through the Gemma Collaboration Agreement for TLE, which was previously conducted by Penn under the Penn Agreement.

In order to reduce operating expenses, we have paused development of this program.

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

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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 .

We believe this product candidate has the potential to provide FTD- GRN patients improved clinical outcomes, given our initial observations of robust and durable elevations in CSF PGRN levels and early evidence of reductions in plasma NfL, a disease progression biomarker, in patients after PBFT02 administration .

• 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.

We believe that our 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 patients, their families, and 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.

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 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 .

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

• Build upon our strong manufacturing and analytical foundation.

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

We have combined broad in-house expertise with an outsourced model for execution.

The strategy enables innovation in manufacturing testing and process development while maintaining operational efficiency.

Our internal manufacturing and quality experts oversee external manufacturing and supply chain operations provided by third-party strategic relationships, such as Catalent Maryland, a unit of Catalent, Inc.

acquired by Novo Holdings A/S, or Catalent.

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

• Continue to leverage our existing research and s electively enter into new research relationships.

We will continue to leverage existing research collaborations and explore other potential collaborations to

build or advance our pipeline, contingent on the prioritization of operating expenses .

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.

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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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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.

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

Typically, we compare multiple capsids in NHPs to identify the capsid best suited for each program.

• Cross-correction:

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.

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 cells.

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 will ultimately drive clinical benefit.

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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

We have a strategic research collaboration with Gemma, which provides us with access to differentiated discovery technology and expertise and informs the basis of our product candidate selections and subsequent preclinical development through to IND status.

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

These activities include developing of payload constructs, evaluating efficacy in cells and in relevant animal models of disease, selecting the optimum capsid and route of administration for the targeted indication, and evaluating transduction efficiency, biodistribution, safety and tolerability of lead candidates in NHPs.

We believe that the gene therapy preclinical expertise provided previously by GTP, and by Gemma moving forward, improves the probability of technical and regulatory success of our clinical programs for PBFT02 indications, for our Huntington’s disease preclinical program, and for future pipeline programs.

Our Lead Program – 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.

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

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.

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

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

PBFT02 is a gene replacement 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 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 CNS PGRN, resulting in CSF levels ranging from 30% to 50% of those observed in normal, mutation non-carriers.

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.

ICM AAV1 administration in NHPs resulted in superior levels of human PGRN in CSF compared with other AAV vectors, exceeding PGRN levels observed in NHPs that received AAV5 or AAVhu68 serotypes by greater than five fold.

Indication Selection

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• Preclinical Validation:

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.

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 reduced lysosomal storage pathology and neuroinflammation.

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 , 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 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 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 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.

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

Comparison of Vector Serotypes:

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

Production of Human PGRN-protein in CSF of NHPs Following ICM-Administration of Different AAVs with Human GRN Gene Payload

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).

Healthy adult sample range of 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.

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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.

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

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.

In this study, human PGRN expression in the CSF increased in a dose-related 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.

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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.

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

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

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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 .

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

Vector Biodistribution 90 Days After ICM Administration of PBFT02 to NHPs

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Dashed line represents limit of detection of assay.

Abbreviations:

Cerv, cervical;

DRG, dorsal root ganglion;

FCX, frontal cortex;

Hipp, hippocampus;

Lumb, lumbar;

PCX, parietal cortex;

OCX, occipital cortex;

TCX, temporal cortex;

Thor, thoracic;

TRG, trigeminal root ganglion.

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 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 .

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

Human PGRN was detectable in CSF and serum in all animals by 7 to 14 days after PBFT02 administration, showing dose-related levels of human PGRN that peaked between days 14 to 28.

Expression declined from day 14, correlating with the appearance of antibodies against the human transgene product which are not expected to develop in haploinsufficient patients with FTD- GRN .

Dose-Related Increases in CSF Progranulin in NHPs Following ICM PBFT02 Administration

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

CSF was sampled 14 days post-dose

CSF 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.

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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.

We 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 .

The FTD- GRN portion of the trial is a three-cohort dose-escalation trial, with three to five subjects per cohort.

Dose 1 (3.3x10 10 genome copies/gm brain weight, or 4.50x10 13 total genome copies) was administered to five patients in Cohort 1 and the first two patients in Cohort 2.

In January 2025, we disclosed plans to introduce Dose 2, which is 50% lower than Dose 1 and exceeds the minimum effective dose in the Grn -/- mouse model.

Dose 2 will be administered to the remaining patients in Cohort 2 and to all patients in Cohort 4 (FTD- C9orf72 ).

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, 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.

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 change in 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 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.

Upon completion of a cohort, the independent data monitoring committee, or IDMC, will review available biomarker and safety data from each subject in the cohort.

All subjects 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 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.

In January 2025, we reported interim biomarker data from six patients in our upliFT-D trial who received Dose 1 of PBFT02 (P1 through P6 in figures below).

Dose 1 of PBFT02 resulted in robust and durable increases in CSF PGRN levels, with concentrations increasing from below 3.0 ng/mL at baseline to 8.0 to 17.3 ng/mL at 30 days post-treatment (n=6), 13.2 to 27.3 ng/mL at 6 months post-treatment (n=4), and 22.3 to 34.0 ng/mL at 12 months post-treatment (n=2).

CSF PGRN levels generally plateaued by 6 months post-treatment and have remained durable through the longest available follow-up of 18 months post-treatment (n=1).

These levels of CSF PGRN are higher than the range found in healthy adult controls of 3.3 to 8.2 ng/mL (mean=4.8 ng/mL;

In contrast, following PBFT02 treatment, plasma PGRN levels were unaltered, remaining similar to baseline concentrations and below levels found in healthy adult controls.

CSF Progranulin Levels Following Administration of PBFT02 Dose 1

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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.

Plasma NfL levels were 13% lower than baseline on average at 12 months (n=2) post-treatment.

In contrast, in untreated symptomatic FTD- GRN patients, plasma NfL levels are expected to increase by approximately 29% per year, according to published natural history data.

Plasma NfL Annual Rate of Change

1 Natural history:

15 symptomatic FTD-GRN patients;

average time since diagnosis 2.9 years (Saracino et al, 2021).

Average time since diagnosis in PBFT02 patients 2 years (n=2).

NfL, neurofilament light chain

Safety and Tolerability

The serious adverse events included hepatotoxicity, as manifest by an increase in liver function tests, and VST.

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.

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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.

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.

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.

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.

With this modified immunosuppression regimen, Dose 1 of PBFT02 was generally well-tolerated in patients 2 through 6.

In these five patients, no serious adverse events were reported, all treatment emergent adverse events 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.

As previously reported, following treatment, Patient 7 experienced one serious adverse event of VST that was asymptomatic and completely resolved prior to day 30 following treatment with anticoagulants.

This patient had no evidence of hepatotoxicity, immune response or other laboratory abnormalities and remains enrolled in the clinical study as of data evaluation on December 31, 2024.

In all seven 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.

Clinical Development Plan Guidance

In January 2025, we announced our plans to treat the remaining patients in Cohort 2 of the upliFT-D trial at Dose 2.

We expect to report 12 month safety and biomarker data from Dose 1 patients and interim safety and biomarker data from Dose 2 patients in the second half of 2025.

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

We expect to seek regulatory feedback on registrational trial design in the first half of 2026 .

Regulatory Designations and Clinical Trial Approvals for PBFT02

The FDA has granted Orphan Drug Designation to PBFT02 for FTD, which would include the treatment of FTD genetic subtypes like FTD- GRN and FTD- C9orf72 , and Fast Track Designation to PBFT02 for the treatment of FTD- GRN.

Similarly, the European Commission granted Orphan designation for PBFT02 for FTD, which includes FTD- GRN and FTD- C9orf72 .

Manufacturing

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.

We are using a well-characterized production platform that has been used for both commercial and clinical AAV products and product candidates.

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

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.

We have a well-established relationship with Catalent for process development, manufacturing, supply chain, and analytical testing.

Additionally, we plan to expand our outsourced analytical testing capabilities to support future program development needs.

For our current clinical drug product, 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.

We have completed internal process development and the scale-up of a high-productivity, GMP-ready suspension-based manufacturing process for PBFT02 at 200-liter scale.

This process is substantially more efficient than the current adherent-based process, with improved yield and the potential of a lower cost of goods.

In addition, we have developed and received initial positive feedback from the FDA on the suitability of a potency assay for the release of PBFT02 for late-stage clinical studies and commercialization.

These two achievements position the PBFT02 program for late-stage development.

We have an amended and restated collaboration agreement with Catalent that governs our relationship with Catalent for the supply of current Good Manufacturing Practices, or cGMP, capacity.

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

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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.

The outlicense of GM1 to Gemma under the Outlicense Transaction Agreements, and subsequent business decisions implemented by Gemma in their sole discretion, could be considered an event related to the divesture of GM1 under the Amended Catalent Agreements and require us to make payment of certain fees to Catalent, for which fees are immaterial.

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.

We also anticipate that we will continue to make significant investments to further optimize our manufacturing capabilities and platforms to produce high-quality, cost-effective AAV vectors and we will continue to make investments in process and analytical sciences, internally or with third parties, to evaluate and develop manufacturing process improvements that may increase the productivity and efficiency of our manufacturing platform processes .

Other Active Research Programs

Beyond this program, as a result of the Gemma Collaboration Agreement, we also have the option to license programs for four additional CNS indications.

The biotechnology and pharmaceutical industries, including the genetic medicines field, are characterized by rapidly changing technologies, competition and a strong emphasis on intellectual property.

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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 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.

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

(part of Eli Lilly & Co), which is conducting a Phase 1/2 clinical trial for an ICM administered gene therapy treatment for FTD- GRN and AviadoBio Ltd, which is conducting a Phase 1/2 intrathalamic gene therapy trial in patients with FTD- GRN .

AviadoBio Ltd entered into an exclusive option and licensing agreement with Astellas in October 2024.

Alector, Inc.

(partnered with GSK plc) is conducting a Phase 3 clinical trial with a humanized anti-human sortilin monoclonal antibody for FTD- GRN .

Additional companies, including Kyowa Kirin Co., Ltd.

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

and QurAlis Corporation, are conducting preclinical research using genetic medicine approaches to treat patients with FTD- GRN .

Denali Therapeutics Inc.

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.

in partnership with Takeda Pharmaceutical Company Limited, is conducting a Phase 1/2 clinical trial for their recombinant progranulin protein.

Vesper Bio ApS began enrollment of a Ph1b/2a study of a small molecule sortilin antagonist in asymptomatic GRN mutation carriers in January 2025.

We are also aware of other therapeutic approaches in preclinical development that may target FTD- GRN patients, including the Arkuda Therapeutics small molecule progranulin enhancer program.

Johnson & Johnson exercised their exclusive option to acquire the Arkuda lysosomal function enhancer portfolio in January 2025.

to PBFT02 for the treatment of FTD- C9orf72 , our clinical stage competitors are Transposon Therapeutics, Inc., which is conducting a Phase 2 trial with a small molecule autophagy modulator for FTD- C9orf72 , and Alector, Inc.

(partnered with GSK plc) which conducted a Phase 2 clinical trial for latozinemab in FTD- C9orf72 .

There are other approaches in preclinical development for the treatment of FTD- C9orf72 .

In addition to the GRN and C9orf72 targeted therapies, there are two other clinical stage programs targeting the TDP-43 pathway.

Many of our potential competitors, alone or with their strategic partners, have substantially greater financial, technical and other resources than we do, such as larger research and development, clinical, marketing and manufacturing organizations.

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University of Pennsylvania

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.

As a result of the Outlicense Transaction Agreements, we restructured our research, collaboration and licensing agreement with Penn, as amended, previously the Penn Agreement and now referred to as the Penn License Agreement.

Pursuant to the Penn License Agreement, as of July 31, 2024, we (i) terminated the funding of discovery research programs;

(ii) terminated the research and exploratory research programs;

(iii) terminated the remaining eight options we had for future CNS indications;

(iv) terminated the transaction fee payable to Penn in the event of certain corporate transactions;

and (v) retained our current exclusive and non-exclusive licenses to our programs in FTD, GM1, Krabbe and MLD and certain platform technologies resulting from the discovery programs that we funded.

For our licensed programs in FTD, GM1, Krabbe and MLD, the Penn License Agreement requires that we make payments of up to $16.5 million per product candidate.

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.

In addition, on a product-by-product basis, we are obligated to make up to $55.0 million in sales milestone payments on each licensed product based on annual sales of the licensed product in excess of defined thresholds.

Upon successful commercialization of a product using the licensed technology, we are obligated to pay to Penn, on a licensed product-by-licensed product and country-by-country basis, tiered royalties (subject to customary reductions) in the mid-single digits on annual worldwide net sales of such licensed product.

In addition, we are obligated to pay to Penn a percentage of sublicensing income, ranging from the mid-single digits to low double digits, for sublicenses under the Penn Agreement.

In addition, on a product-by-product basis, we are obligated to make up to $55.0 million in sales milestone payments on each licensed product based on annual worldwide net sales of the licensed product in excess of defined thresholds.

Pursuant to the Gemma Sublicenses, Gemma is responsible for the payments to Penn related to the Outlicensed Programs.

Upon successful commercialization of a product using the licensed technology, we are obligated to pay to Penn, on a licensed product-by-licensed product and country-by-country basis, tiered royalties (subject to customary reductions) a percentage in the mid-single digits on annual worldwide net sales of such licensed product.

In addition, other than the Gemma Sublicenses, we are obligated to pay to Penn a percentage of sublicensing income, ranging from the mid-single digits to low double digits, for sublicenses under the Penn License Agreement.

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.

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.

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.

Under the Penn Agreement, we are obligated to use commercially reasonable efforts to develop, obtain regulatory approval for, and commercialize at least one licensed product for each of the licensed indications for prophylactic, diagnostic and therapeutic uses in humans.

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, cGMP manufacture and commercialization of all licensed products.

Pursuant to the Gemma Sublicenses, Gemma is responsible for the payments to Penn related to the Outlicensed Programs.

Gemma - Research, Collaboration and License Agreement

In connection with the transfer of the Outlicensed Programs, on July 31, 2024, we entered into the Gemma Collaboration Agreement.

Pursuant to the Gemma Collaboration Agreement, (i) Gemma will conduct certain preclinical and IND-enabling work for our active research program in Huntington’s disease and a currently paused research program in TLE, which were previously being conducted by Penn under the Penn Agreement and (ii) Gemma will grant us options to conduct mutually agreed research programs in four new CNS indications.

The Gemma Collaboration Agreement requires that we make payments of up to (i) $16.5 million per product candidate in the aggregate for Huntington’s disease and any future CNS indications available to us under our four options and (ii) $39.0 million per product candidate in the aggregate arising from the research program for TLE.

Upon successful commercialization of a product using the licensed technology, we are obligated to pay to Gemma, on a licensed product-by-licensed product and country-by-country basis, tiered royalties (subject to customary reductions) in the mid-single digits percentage on annual worldwide net sales of such licensed product.

In addition, we are obligated to pay to Gemma a percentage of sublicensing income, ranging from the mid-single digits to low double digits, for sublicenses under the Gemma Collaboration Agreement.

If we were to exercise any of the four options, we would owe Gemma 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.

Gemma - Sublicense Agreements and Transition Services Agreement

In connection with the transfer of the Outlicensed Programs to Gemma, we have entered into the Gemma Sublicenses, pursuant to which, we will receive (i) initial payments of an aggregate of $10.0 million for licenses and clinical product supply;

(ii) up to an additional $10.0 million contingent on the completion by Gemma of certain business milestones;

(iii) up to an additional $114.0 million in development and commercial milestone payments;

In addition, Gemma is responsible for all payments to Penn related to the Outlicensed Programs under the Penn License Agreement.

In addition, we entered into the Transition Services Agreement, as amended by the First Amendment to the Transition Services Agreement, dated January 31, 2025, pursuant to which, we will provide transitional services at cost to Gemma through May 31, 2025, unless terminated earlier, and be entitled to reimbursement for transitional services performed retroactively from March 1, 2024, related to the transfer of the Outlicensed Programs.

As of December 31, 2024, we have collected $5.0 million in initial payments and $3.2 million in transition services payments under these agreements.

Subsequent to December 31, 2024, we have received an additional $0.5 million in transition services payments.

Intellectual Property

Our commercial success depends in part on our ability to obtain and maintain proprietary and/or intellectual property protection in the United States and other countries for our current product candidates and future products, as well as our core technologies, including our manufacturing know-how.

Our commercial success depends in part on our ability to obtain and maintain proprietary and/or intellectual property protection in the United States and other countries for our current product candidate and future products, as well as our core technologies, including our manufacturing know-how.

We strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to the development of our business by seeking, maintaining, and defending our intellectual property, whether developed internally or licensed from third parties.

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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 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.

Currently, our patent protection consists of patents and patent applications that (i) we have in-licensed from Penn under the Penn Agreement for product candidates in our licensed indications and (ii) we solely own based on the internally developed processes for manufacturing or analyzing our product candidate as well as use of the product candidate in relation to certain neurodegenerative diseases.

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:

• 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.

Our in-licensed patent portfolio currently includes two patent families with claims directed to rAAV for use in treating FTD.

The first patent family includes applications pending in 14 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.

The second patent family includes applications in 16 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.

The first patent family includes pending applications 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 September 30, 2039, absent any term adjustments or extensions.

The second patent family includes applications pending in sixteen 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 1, 2041, absent any term adjustments or extensions;

• 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 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.

We also have options under the Penn Agreement to add additional intellectual property to our existing license, as described in the section “License Agreement”.

The in-licensed patent portfolio further includes seven patent families with pending or issued claims directed to rAAV and its use in the treatment of GM1, Krabbe, or MLD.

The patent families have been sublicensed to Gemma under our sublicense agreements with Gemma in connection with the outlicense of PBGM01 for the treatment of GM1, PBKR03 for the treatment of Krabbe, and PBML04 for the treatment of MLD.

We have options under the Penn Agreement and the Gemma Collaboration Agreement to add additional intellectual property to our existing license, as described in the section “License Agreement”.

Our patent portfolio, which we solely own, includes one patent family with claims directed to the method of purifying rAAV.

The patent family includes a patent cooperation treaty and a Taiwanese application.

Any patents that may issue from applications in this family are expected to expire on October 6, 2043, absent any term adjustments or extensions.

The term of individual patents may vary based on the countries in which they are obtained.

Generally, patents issued from applications filed in the United States are effective for 20 years from the earliest effective non-provisional filing date.

In addition, in certain instances, a patent term can be extended to recapture a portion of the term effectively lost as a result of FDA regulatory review period.

In addition, in certain instances, a patent term can be extended to recapture a portion of the term effectively lost as a result of an FDA regulatory review period.

The restoration period cannot be longer than five years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval.

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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 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.

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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Failure to comply with applicable U.S.

requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to file NDA/BLAs and to approve pending NDAs or BLAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.

requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to file NDA/BLAs and/or to approve pending NDAs or BLAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.

Biological product development for a new product or certain changes to an approved product in the United States typically involves preclinical laboratory and animal tests, the submission to the FDA of an IND which must become effective before clinical testing may commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought.

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Preclinical tests include laboratory evaluation of product chemistry, formulation, and toxicity, as well as animal studies to assess the characteristics and potential safety and efficacy of the product.

The conduct of the preclinical tests must comply with federal regulations and requirements, including Good Laboratory Practices.

The conduct of the preclinical tests must comply with federal regulations and requirements, including Good Laboratory Practices, an international standard meant to ensure the presence of a standard quality system under which laboratory work and non-clinical studies are conducted, recorded and archived.

The results of preclinical testing are submitted to the FDA as part of an IND along with other information, including information about product chemistry, manufacturing and controls, and a proposed clinical trial protocol.

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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.

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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The FDA may also refer applications for novel biologic products, or biologic products that present difficult questions of safety or efficacy, to be reviewed by an advisory committee—typically a panel that includes clinicians, statisticians and other experts—for review, evaluation, and a recommendation as to whether the BLA should be approved.

The FDA is not bound by the recommendation of an advisory committee, but generally follows such recommendations.

The FDA is not bound by the recommendation of the advisory committee, but generally follows such recommendations.

Before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

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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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An approval letter authorizes commercial marketing and distribution of the biologic with specific prescribing information for specific indications.

As a condition of BLA approval, the FDA may require a risk evaluation and mitigation strategy, or REMS, to help ensure that the benefits of the biologic outweigh the potential risks to patients.

As a condition of BLA approval, the FDA may require a Risk Evaluation and Mitigation

Strategy, or REMS, to help ensure that the benefits of the biologic outweigh the potential risks to patients.

A REMS can include medication guides, communication plans for healthcare professionals, and elements to assure a product’s safe use, or ETASU.

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In addition to the regulations discussed above, there are a number of additional standards that apply to clinical trials involving the use of gene therapy.

FDA has issued various guidance documents regarding gene therapies, which outline additional factors that FDA will consider at each of the above stages of development and relate to, among other things:

The FDA has issued various guidance documents regarding gene therapies, which outline additional factors that the FDA will consider at each of the above stages of development and relate to, among other things:

the proper preclinical assessment of gene therapies;

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and measures to observe delayed adverse effects in subjects who have been exposed to investigational gene therapies when the risk of such effects is high.

For instance, FDA usually recommends that sponsors observe all surviving subjects who receive treatment using gene therapies that are based on adeno-associated virus vectors in clinical trials for potential gene therapy-related delayed adverse events for a minimum 5-year period.

FDA does not require the long-term tracking to be complete prior to its review of the BLA.

For instance, the FDA usually recommends that sponsors observe all surviving subjects who receive treatment using gene therapies that are based on adeno-associated virus vectors in clinical trials for potential gene therapy-related delayed adverse events for a minimum 5-year period.

The FDA does not require the long-term tracking to be complete prior to its review of the BLA.

Orphan Drug Designation

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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.

Orphan drug exclusivity does not prevent the FDA from approving a different drug or biological product for the same disease or condition, or the same biological product for a different disease or condition.

Orphan drug exclusivity does not prevent the FDA from approving a different drug or biological product for the

same disease or condition, or the same biological product for a different disease or condition.

Among the other benefits of Orphan Drug Designation are tax credits for certain research and a waiver of the BLA user fee.

Rare Pediatric Disease Priority Review Voucher Program

Under the Rare Pediatric Disease Priority Review Voucher program, the FDA may award a priority review voucher to the sponsor of an approved marketing application for a product that treats or prevents a rare pediatric disease.

The voucher entitles the sponsor to priority review of one subsequent marketing application.

A voucher may be awarded only for an approved rare pediatric disease product application.

A rare pediatric disease product application is an NDA or BLA for a product that treats or prevents a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years;

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 not seek approval for a different adult indication (i.e., for a different disease/condition);

the product must not contain an active ingredient that has been previously approved by the FDA;

and the NDA or BLA must rely on clinical data derived from studies examining a pediatric population such that the approved product can be adequately labeled for the pediatric population.

Before NDA or BLA approval, the FDA may designate a product in development as a product for a rare pediatric disease.

To receive a rare pediatric disease priority review voucher, a sponsor must notify the FDA, upon submission of the NDA or BLA, of its intent to request a voucher.

If the FDA determines that the NDA or BLA is a rare pediatric disease product application, and if the NDA or BLA is approved, the FDA will award the sponsor of the NDA or BLA a voucher upon approval of the NDA or BLA.

The FDA may revoke a rare pediatric disease priority review voucher if the product for which it was awarded is not marketed in the U.S.

within 365 days of the product’s approval.

The voucher, which is transferable to another sponsor, may be submitted with a subsequent NDA or BLA and entitles the holder to priority review of the accompanying NDA or BLA.

The sponsor submitting the priority review voucher must notify the FDA of its intent to submit the voucher with the NDA or BLA at least 90 days prior to submission of the NDA or BLA and must pay a priority review user fee in addition to any other required user fee.

The FDA must take action on an NDA or BLA under priority review within six months of receipt of the NDA or BLA.

On December 27, 2020, the Rare Pediatric Disease Priority Review Voucher program was reauthorized as part of the Consolidated Appropriations Act, 2021 allowing a product that is designated as a product for a rare pediatric disease prior to September 30, 2024 to be eligible to receive a rare pediatric disease priority review voucher upon approval of a qualifying NDA or BLA prior to September 30, 2026.

It is unclear whether this program will continue to be reauthorized beyond the current sunset date in September 2024.

Fast Track Designation and Priority Review

The FDA is required to facilitate the development, and expedite the review, of drugs that are intended for the treatment of a serious or life-threatening disease or condition for which there is no effective treatment and which demonstrate the potential to address unmet medical needs for the condition.

Fast track Designation may be granted for products that are intended to treat a serious or life-threatening disease or condition for which there is no effective treatment and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition.

Such Fast Track Designation may be granted for products that are intended to treat a serious or life-threatening disease or condition for which there is no effective treatment and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition.

Fast Track Designation applies to both the product and the specific indication for which it is being studied.

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Biosimilarity sufficient to reference a prior FDA-approved product requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.

Biosimilarity must be shown through analytical trials, animal studies, and a clinical trial or trials, unless the Secretary of Health and Human Services waives a required element.

Biosimilarity must be shown through analytical trials, animal studies, and a clinical trial or trials, unless the

Secretary of Health and Human Services waives a required element.

A biosimilar product may be deemed interchangeable with a previously approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

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A reference biologic is granted 12 years of exclusivity from the time of first licensure, or BLA approval, of the reference product, and no application for a biosimilar can be submitted for four years from the date of licensure of the reference product.

The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) eighteen months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar’s application has been approved if a patent lawsuit is ongoing within the 42-month period.

The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) 18 months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar’s application has been approved if a patent lawsuit is ongoing within the 42-month period.

Post-Approval Requirements

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The term remuneration has been interpreted broadly to include anything of value.

The Anti- Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and/or formulary managers on the other.

The Anti- Kickback

Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and/or formulary managers on the other.

There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.

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HIPAA requires covered entities to limit the use and disclosure of protected health information to specifically authorized situations, and requires covered entities to implement security measures to protect health information that they maintain in electronic form.

Among other things, HITECH made HIPAA’s security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.

connection with providing a service on behalf of a covered entity.

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

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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.

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

In 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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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.

HHS announced the negotiated maximum fair prices on August 15, 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.

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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.

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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None of our employees are represented by a labor union or covered by collective bargaining agreements, and we believe our relationship with our employees is good.

In January 2025, the Company’s board of directors approved a restructuring plan that included a reduction of 55% in the Company’s workforce.

The Company’s restructuring plan is described more fully in Note 15 to our financial statements found elsewhere in this Form 10-K.

Our Mission and Our Employees

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Our Commitment to Diversity, Equity and Inclusion

We are committed to creating and maintaining a diverse, equitable and inclusive workplace where all of our employees can thrive in an environment that values differences, provides equal opportunities and embraces different backgrounds and perspectives.

different backgrounds and perspectives.

We treat all individuals with respect and dignity and provide all of our employees with fair treatment based on merit.

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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 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.

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From time to time, we may be involved in legal proceedings arising in the ordinary course of 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.

We are a defendant in litigation with a former employee, who filed a lawsuit in the Court of Common Pleas of Philadelphia County asserting claims for breach of contract and violation of the Pennsylvania Wage Payment and Collection Law.

The plaintiff, who was terminated from his employment in 2019, contended that we entered into a binding settlement agreement in February 2020 under which he was to receive shares of company stock and additional compensation.

Specifically, he contended that before the announcement of our initial public offering in February 2020, he was promised 150,000 shares of stock as part of the settlement, and that those shares were not subject to the reverse stock split that was implemented for all shareholders.

We responded that the shares offered in settlement negotiations in 2020 were to be subject to the reverse split, and that had the settlement been finalized, the plaintiff would have been entitled to 33,836 shares.

A trial in this case was held in October 2024.

The jury found that an agreement was reached, but it agreed with us that any shares to be awarded to the plaintiff were subject to the reverse split.

The jury awarded damages in an amount that was roughly equal to what we contended had been offered to the plaintiff before the initial public offering.

Both sides then challenged the verdict, and on December 12, 2024, the judge who presided over the trial delivered a judgment in our favor, finding that no binding agreement was reached and that the plaintiff was not entitled to recover any damages.

On December 23, 2024, the plaintiff filed an appeal with the Superior Court of Pennsylvania, which is currently pending.

The Company intends to continue to defend against this claim.

Other than the above, we are not presently a party to any legal proceedings that, in the opinion of management, would, if decided against us, 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.

10 unchanged sentences

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