Strategic review at Passage Bio (NASDAQ: PASG) after FDA trial guidance
Rhea-AI Filing Summary
Passage Bio, Inc. reported updated interim data from its Phase 1/2 upliFT-D trial of PBFT02 for frontotemporal dementia with GRN mutations. Patients earlier in disease progression showed reduced brain atrophy and stabilized plasma NfL levels versus natural history, while more advanced patients did not show similar improvements.
The company completed a Type C meeting where the FDA indicated a randomized controlled registrational trial would be required for PBFT02 in FTD-GRN. Citing ethical, logistical, and financial challenges, Passage Bio is evaluating next steps for PBFT02 and the broader program.
Passage Bio also initiated a review of strategic alternatives that could include mergers, acquisitions, reverse merger, asset sales, partnerships, or licensing, and engaged Wedbush PacGrow as financial advisor. The company does not plan further updates until its board approves a specific action or disclosure is otherwise required.
Positive
- PBFT02 biomarker improvements in target FTD-GRN population: Early-stage patients (global CDR 0.5–1) receiving PBFT02 showed reduced whole brain and frontotemporal cortex atrophy and stabilized plasma NfL levels versus natural history, indicating potentially disease-modifying biological activity in the intended treatment group.
Negative
- FDA requires randomized controlled registrational trial: Regulators indicated PBFT02 in FTD-GRN must be studied in a randomized controlled registrational trial, which the company describes as posing substantial ethical, logistical, and financial challenges, complicating the development path for this rare disease therapy.
- Initiation of broad strategic alternatives review: Passage Bio began evaluating strategic options including mergers, reverse mergers, asset sales, and partnerships, and cautioned there is no assurance any transaction will occur, underscoring elevated strategic and continuity risk for shareholders.
Insights
FDA demands for a randomized trial and a broad strategic review introduce significant uncertainty for Passage Bio.
Passage Bio released interim PBFT02 data showing improvements in brain atrophy and plasma NfL biomarkers for less-advanced FTD-GRN patients, suggesting biological activity in the intended target population. However, patients with more advanced disease did not show comparable benefit versus natural history data.
The FDA’s feedback that a randomized controlled registrational trial is required for PBFT02 in FTD-GRN raises the bar for approval. The company explicitly notes ethical, logistical, and financial challenges, which could constrain late-stage development options and increase both cost and execution risk for this rare disease program.
The decision to initiate a wide-ranging review of strategic alternatives, including potential mergers, asset sales, and partnerships, signals that independent continuation may be uncertain. Actual outcomes will depend on whether Passage Bio can secure a transaction or partnership that supports PBFT02’s development under the more demanding trial framework.
8-K Event Classification
Key Terms
Type C meeting regulatory
randomized controlled registrational trial regulatory
strategic alternatives financial
plasma NfL medical
frontotemporal dementia medical
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FORM
CURRENT REPORT
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Item 7.01 Regulation FD Disclosure
PBFT02 Program Updates
On April 20, 2026, Passage Bio, Inc. (the “Company”) announced updated interim data from the ongoing Phase 1/2 upliFT-D clinical trial evaluating PBFT02 for the treatment of frontotemporal dementia caused by progranulin deficiency (“FTD-GRN”) and provided regulatory and corporate updates.
Updated interim data from FTD-GRN patients treated with PBFT02
Biomarkers
| · | PBFT02-treated patients with a global Clinical Dementia Rating (“CDR”) score of 1 at baseline experienced an average of 3.1% (n=2) whole brain atrophy at 12 months, representing a 64% reduction in whole brain atrophy as compared to volumetric Magnetic Resonance Imaging (“vMRI”) analysis of global CDR 1 patients from the ALLFTD natural history data (n=7). |
| · | PBFT02-treated patients with a global CDR score of 1 at baseline experienced an average of 4.6% (n=2) frontotemporal cortex atrophy at 12 months, representing a 54% reduction in frontotemporal cortex atrophy as compared to vMRI analysis of global CDR 1 patients from the ALLFTD natural history data (n=7). |
| · | Patients who received PBFT02 showed stabilization of plasma neurofilament (“NfL”) levels at 12 months post-treatment, comparing favorably to natural history. |
| · | Plasma NfL levels among PBFT02-treated patients showed an average reduction of 1.0 pg/mL (n=6) at 12 months compared to baseline. |
| · | Untreated symptomatic FTD-GRN patients from the ALLFTD natural history data showed an average increase of 13.5 pg/mL (n=7) at 12 months compared to baseline. |
| · | Dose 1 PBFT02 (4.5e13 total genome copies) resulted in a robust and durable increase in cerebrospinal fluid (“CSF”) progranulin (“PGRN”) expression through 18 months post-treatment. |
| · | Dose 1 PBFT02 increased CSF PGRN in all patients from below 3 ng/mL at baseline to a mean of 22.8 ng/mL (n=6) at 12 months and 24.2 ng/mL (n=3) at 18 months. |
| · | Dose 2 PBFT02 (2.2e13 total genome copies) achieved comparable CSF PGRN levels as Dose 1 at six months post-treatment. |
| · | Dose 2 PBFT02 increased CSF PGRN to a mean of 8.6 ng/mL (n=2) at one month, above the upper limit of a healthy adult reference range, and 22.6 ng/mL (n=1) at six months. |
Safety (as of March 23, 2026)
| · | No new treatment-related serious adverse events (“SAEs”) reported since the Company’s previous update. |
| · | As previously disclosed, two patients who received Dose 1 PBFT02 experienced a total of three asymptomatic SAEs related to PBFT02: venous sinus thrombosis (n=2) and hepatotoxicity (n=1). |
| · | No evidence of dorsal root ganglion toxicity, as measured by nerve conduction studies, and no complications from intra-cisterna magna administration have been reported. |
Regulatory Update
The Company has completed a Type C meeting with the U.S. Food and Drug Administration (“FDA”) to seek guidance on key elements of a potential future registrational trial of PBFT02 for FTD-GRN patients. Based on the feedback received, the FDA has indicated that a randomized controlled registrational study design is required for PBFT02 in this indication. In light of the ethical, logistical, and financial challenges posed by a randomized controlled registrational trial, the Company is evaluating potential next steps in the clinical development of PBFT02 in FTD-GRN and FTD-C9orf72 in the upliFT-D trial.
Corporate Update
The Company has initiated a review of strategic alternatives to maximize shareholder value. These strategic alternatives may include merger or acquisition transactions, a reverse merger, a sale of assets of the Company, strategic partnerships, licensing opportunities, or other potential paths. The strategic review is underway, and the Company does not intend to provide updates until the Company’s board of directors approves a specific action or otherwise determines that disclosure is appropriate or required. There can be no assurance that the process will result in any such transaction.
The Company has engaged Wedbush PacGrow as a financial advisor to assist in the strategic review process.
The information in this Item 7.01, including Exhibits 99.1 and 99.2 to this Current Report on Form 8-K, shall not be deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section or Sections 11 and 12(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”). The information contained in this Item 7.01 and in the accompanying Exhibits 99.1 and 99.2 shall not be incorporated by reference into any other filing under the Exchange Act or under the Securities Act, except as shall be expressly set forth by specific reference in such filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. | Description | |
| 99.1 | Passage Bio, Inc. press release, dated April 20, 2026. | |
| 99.2 | Corporate Presentation, dated April 20, 2026. | |
| 104 | Cover Page Interactive Data File (formatted as Inline XBRL). |
Forward-Looking Statements
This Current Report on Form 8-K contains “forward-looking statements” within the meaning of, and made pursuant to the
safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our evaluation of strategic
alternatives, the entry into or completion of any strategic alternative transaction, our expectations about timing and execution of anticipated
milestones, including the progress of clinical studies and the availability of clinical data from such trials; enrollment timing; timing
of engagement with, and feedback from, regulatory authorities; our expectations about our collaborators’ and partners’ ability
to execute key initiatives; our expectations about our cash runway; the ability of our product candidates to treat their respective target
CNS disorders; and the potential development of other product candidates. These forward-looking statements may be accompanied by such
words as “aim,” “anticipate,” “believe,” “continue,” “could,” “should,”
“target,” “estimate,” “expect,” “forecast,” “goal,” “intend,”
“may,” “might,” “plan,” “potential,” “possible,” “will,” “would,”
and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ
materially from those reflected in such statements, including: uncertainties inherent in the strategic review process, our ability to
identify and consummate a suitable strategic alternative, our ability to develop and obtain regulatory approval for our product candidates;
the timing and results of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately
manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory
authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates;
the occurrence of adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated
in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure
to protect and enforce our intellectual property, and other proprietary rights; our dependence on collaborators and other third parties
for the development and manufacture of product candidates and other aspects of our business, which are outside of our full control; risks
associated with current and potential delays, work stoppages, or supply chain disruptions; and the other risks and uncertainties that
are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commission
(“SEC”), and other reports as filed with the SEC. Passage Bio undertakes no obligation to publicly update any
forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future
developments or otherwise.
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| PASSAGE BIO, INC. | ||
| Date: April 20, 2026 | By: | /s/ Kathleen Borthwick |
| Kathleen Borthwick | ||
| Chief Financial Officer | ||
Exhibit 99.1
PASSAGE BIO REPORTS UPDATED INTERIM DATA FROM UPLIFT-D TRIAL AND PROVIDES REGULATORY AND CORPORATE UPDATES
PBFT02 administration resulted in improvements in two disease progression biomarkers, as compared to natural history, reducing brain atrophy and stabilizing plasma NfL levels
FDA feedback from recent Type C meeting indicated a randomized controlled registrational trial will be required for PBFT02 in FTD-GRN
The Company initiated a strategic review process intended to maximize shareholder value
PHILADELPHIA – April 20, 2026 – Passage Bio, Inc. (NASDAQ: PASG), a clinical stage genetic medicines company focused on improving the lives of patients with neurodegenerative diseases, today reported updated data from the ongoing Phase 1/2 upliFT-D clinical trial evaluating PBFT02 for the treatment of frontotemporal dementia (FTD) with granulin (GRN) mutations. In addition, the Company shared feedback from a recent Type C meeting with the United States Food and Drug Administration (FDA) on the likely registrational pathway for PBFT02 in FTD-GRN. The Company has also announced it has engaged Wedbush PacGrow as a financial advisor and has initiated a review of strategic alternatives to maximize shareholder value.
Will Chou, M.D., president and chief executive officer of Passage Bio commented, “the data shared today suggest that PBFT02 may slow neurodegeneration in patients with FTD-GRN, with improvements observed in both brain atrophy and plasma neurofilament levels, two well-established biomarkers of disease progression. Further, we continue to observe durable and robust elevations in progranulin, the target protein, and are encouraged by the emerging data from Dose 2 patients, which indicate that this lower dose level can achieve similar progranulin expression as observed with Dose 1, our higher dose.”
Dr. Chou continued, “As we look towards late-stage development of the program, we recently completed a Type C meeting with the FDA to gain feedback on the design of a future registrational trial for PBFT02 in FTD-GRN. Despite the rare, underserved nature of this devastating disease and the availability of robust natural history data, FDA did not support a single-arm trial design for this indication and instead indicated that a randomized controlled trial would be required for registrational purposes. In light of this outcome and the associated ethical, logistical, and financial challenges, we are currently evaluating potential next steps for the PBFT02 clinical development program and for the company.”
Updated interim upliFT-D data from FTD-GRN patients treated with PBFT02:
Brain Atrophy as Measured by Volumetric Magnetic Resonance Imaging (vMRI)
Patients earlier in their disease progression (global score of 1 at baseline on the Clinical Dementia Rating scale, or CDR) who received PBFT02 exhibited reduced rates of whole brain atrophy and frontotemporal cortex atrophy compared to natural history data from patients at the same stage of disease progression. In contrast, patients with more advanced disease progression (global CDR score of 2 at baseline) showed no improvements on either atrophy measure versus natural history data from a comparable global CDR 2 population. Patients with global CDR scores of 0.5 and 1 at baseline are the intended target population for PBFT02, and patients with global CDR scores of 2 or greater have been excluded from future enrollment in the ongoing upliFT-D study.
Whole Brain Atrophy
| · | PBFT02-treated patients with a global CDR score of 1 at baseline experienced a 64% reduction in whole brain atrophy at 12 months, on average, as compared to vMRI analysis of untreated global CDR 1 patients from the ALLFTD natural history data. |
| o | PBFT02-treated global CDR 1 patients (n=2): 3.1% atrophy at 12 months |
| o | ALLFTD natural history global CDR 1 sample (n=7): 8.7% atrophy at 12 months |
Frontotemporal Cortex Atrophy
| · | PBFT02-treated patients with a global CDR score of 1 at baseline experienced a 54% reduction in frontotemporal cortex atrophy at 12 months, on average, as compared to vMRI analysis of untreated global CDR 1 patients from the ALLFTD natural history data. |
| o | PBFT02-treated global CDR 1 patients (n=2): 4.6% atrophy at 12 months |
| o | ALLFTD natural history global CDR 1 sample (n=7): 9.9% atrophy at 12 months |
Plasma Neurofilament (NfL)
Patients who received PBFT02 showed stabilization of plasma NfL levels at 12 months post-treatment, comparing favorably to natural history.
| · | Plasma NfL levels among PBFT02 treated patients showed an average reduction of 1.0 pg/mL (n=6) at 12 months compared to baseline. |
| · | In contrast, analysis of untreated symptomatic FTD-GRN patients from the ALLFTD natural history data showed an average increase of 13.5 pg/mL (n=7) at 12 months compared to baseline. |
Cerebrospinal Fluid (CSF) Progranulin (PGRN)
| · | Dose 1 PBFT02 (4.5e13 total genome copies) resulted in a robust and durable increase in CSF PGRN expression through 18 months post-treatment. |
| · | Dose 1 PBFT02 increased CSF PGRN in all patients from below 3 ng/mL at baseline to a mean of 22.8 ng/mL (n=6) at 12 months and 24.2 ng/mL (n=3) at 18 months. |
| · | Dose 2 PBFT02 (2.2e13 total genome copies) achieved comparable CSF PGRN levels as Dose 1 at six months post-treatment. |
| · | Dose 2 PBFT02 increased CSF PGRN to a mean of 8.6 ng/mL (n=2) at one month, above the upper limit of a healthy adult reference range, and 22.6 ng/mL (n=1) at 6 months. |
Safety (as of March 23, 2026; n=10 FTD-GRN patients and n=1 FTD-C9orf72 patient)
| · | PBFT02 continued to be generally well-tolerated, with no new treatment-related serious adverse events (SAEs) reported. |
| o | As previously disclosed, two patients who received Dose 1 PBFT02 experienced a total of three asymptomatic SAEs related to PBFT02: venous sinus thrombosis (n=2) and hepatotoxicity (n=1). |
| · | No evidence of dorsal root ganglion (DRG) toxicity and no complications from intracisterna magna (ICM) administration have been reported. |
A presentation summarizing the interim data update can be accessed on the Events and Presentations page of the Investors and News section of the Company’s website.
Regulatory & Program Update
The Company has completed a Type C meeting with the FDA to seek guidance on key elements of a future registrational trial of PBFT02 for FTD-GRN patients. Based on the feedback received, the FDA has indicated that a randomized controlled registrational study design is required for PBFT02 in this indication. A randomized controlled registrational trial poses substantial ethical concerns for patients and their families as well as logistical and financial challenges. As such, the Company is evaluating potential next steps in the clinical development of PBFT02 in FTD-GRN and FTD-C9orf72 in the upliFT-D trial.
Corporate Update
The Company has initiated a review of strategic alternatives to maximize shareholder value. These strategic alternatives may include merger or acquisition transactions, a reverse merger, a sale of assets of the Company, strategic partnerships, licensing opportunities, or other potential paths.
The strategic review is underway, and the Company does not intend to provide updates until the Board approves a specific action or otherwise determines that disclosure is appropriate or required. There can be no assurance that the process will result in any such transaction.
The Company has engaged Wedbush PacGrow as a financial advisor to assist in the strategic review process.
About Passage Bio
Passage Bio (Nasdaq: PASG) is 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 therapies designed to target the underlying pathology of these conditions. Passage Bio’s lead product candidate, PBFT02, seeks to treat neurodegenerative conditions, including frontotemporal dementia, by elevating progranulin levels to restore lysosomal function and slow disease progression.
To learn more about Passage Bio and our steadfast commitment to protecting patients and families against loss in neurodegenerative conditions, please visit: passagebio.com.
Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our evaluation of strategic alternatives, the entry into or completion of any strategic alternative transaction, our expectations about timing and execution of anticipated milestones, including the progress of clinical studies and the availability of clinical data from such trials; enrollment timing; timing of engagement with, and feedback from, regulatory authorities; our expectations about our collaborators’ and partners’ ability to execute key initiatives; our expectations about cash runway; the ability of our product candidates to treat their respective target CNS disorders; and the potential development of other product candidates. These forward-looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “continue,” “could,” “should,” “target,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “possible,” “will,” “would,” and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: uncertainties inherent in strategic review processes, such as the risk that no suitable strategic alternative will be identified or consummated; our ability to develop and obtain regulatory approval for our product candidates; the timing and results of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure to protect and enforce our intellectual property, and other proprietary rights; our dependence on collaborators and other third parties for the development and manufacture of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.
For further information, please contact:
Investors:
Stuart Henderson
Passage Bio
shenderson@passagebio.com
Passage Bio Media:
Mike Beyer
Sam Brown Inc. Healthcare Communications
312.961.2502
mikebeyer@sambrown.com
| © 2026 Passage Bio. All rights reserved. Corporate Presentation Redefining the Course of Neurodegenerative Conditions April 2026 |
| Forward-Looking Statement This presentation includes “forward-looking statements” within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectations about timing and execution of anticipated milestones, including the progress of clinical studies and the availability of clinical data from such trials; enrollment timing; timing of engagement with regulatory authorities; the potential of our product candidates versus other treatment options and clinical candidates; our expectations about cash runway; the ability of PBFT02 to treat FTD-GRN or FTD-C9orf72, and the potential development of other product candidates. These forward-looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “possible,” “will,” “would,” and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop and obtain regulatory approval for our product candidates; the timing and results of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, the timing of and our ability to obtain and maintain regulatory approvals; our expectations about the willingness of healthcare professionals to use our product candidates, the timing, or amount, the occurrence of adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure to protect and enforce our intellectual property, and other proprietary rights; our dependence on collaborators and other third parties for the development and manufacture of product candidates and other aspects of our business, which are outside of our full control; the timing, or amount, of receipt of any potential future milestone and royalty payments; risks associated with current and potential delays, work stoppages, or supply chain disruptions; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise. 2 April 2026 |
| 3 April 2026 Redefining the Course of Neurodegenerative Conditions * Based on cash, cash equivalents, and marketable securities as of December 31, 2025. Advancing clinical stage, potential best-in-class, one-time progranulin raising gene therapy for FTD Pursuing preclinical development of differentiated gene therapy approach in Huntington’s disease Cash runway expected through 1Q 2027* |
| Validating the Therapeutic Potential of PBFT02 4 April 2026 * Based on interim data. Urgent Patient Need in FTD-GRN Differentiated, Potential Best-in-Class Profile Fast Track and Orphan Drug Designation Promising data from initial clinical study of PBFT02 in FTD-GRN Genetic form of FTD caused by GRN mutations, which lead to progranulin (PGRN) deficiency No approved disease-modifying therapies One-time, gene replacement therapy Proprietary AAV1 construct Nonsurgical injection directly to cerebrospinal fluid (CSF) Durable, elevated CSF PGRN levels* |
| Significant Market Opportunity Addressing Neurodegenerative Diseases Estimated Prevalence (US and EU) 5 April 2026 Huntington’s disease5 FTD-C9orf722–4 FTD-GRN1–3 ~18K ~21K ~70K 1. Greaves CV, et al. J Neurol 2019; 266:2075-2086. 2. Galvin JE, et al. Neurology 2017; 89:2049-2056. 3. Onyike CU, et al. Int Rev Psychiatry 2013; 25:130-137. 4. Moore KM, et al. Lancet Neurol 2020; 19: 145–156. 5. Crowell et al. Neuroepi. 2021; 55:361-368. CURRENT PRECLINICAL PROGRAM CURRENT CLINICAL PROGRAM CURRENT CLINICAL PROGRAM |
| PBFT02 Frontotemporal Dementia |
| OVERVIEW • Fatal adult-onset neurodegenerative disease affecting the frontal and temporal lobes of the brain, characterized by a decline in behavior, language, and executive function • One of the most common causes of early-onset dementia worldwide, disproportionately affecting individuals aged 40–65 years CLINICAL SYMPTOMS Disease progression is rapid and degenerative, including loss of speech, loss of expression, behavioral changes, and immobility Frontotemporal Dementia (FTD): A Devastating Adult Disease On average, people with FTD live 8 years after the onset of symptoms 7 April 2026 Loss of inhibition Apathy Social withdrawal Hyperorality (mouthing of objects) Ritualistic compulsive behaviors |
| Progranulin Deficiency is the Defining Characteristic of FTD-GRN and Leads to Neurodegeneration 8 April 2026 Progranulin is critical to maintaining CNS cell homeostasis Rhinn H et al. Trends Pharmacol Sci. 2022, 43:641-652. Decrease in PGRN levels Neuronal dysfunction, pathological changes, and inflammation Vulnerability of neurons in affected regions Neurodegeneration |
| Elevated PGRN Increases Potential for Improved Cellular Function 9 April 2026 Paushter et al. Acta Neuropathol. 2018;136:1-17. Rhinn et al. Trends Pharmacol Sci. 2022; 43:641-652. Driving elevated PGRN levels in the extracellular space increases the amount of PGRN available to enter target CNS cells Able to leverage cross-correction mechanism: secreted PGRN can be taken up by non-transduced cells Progranulin is a secreted protein that binds to cell membrane receptors to affect multiple intracellular pathways • Major role is regulating intracellular lysosomal activity • Extracellular PGRN is endocytosed via multiple receptors |
| TRIAL DESIGN upliFT-D: Global Phase 1/2 Trial with PBFT02 Currently enrolling patients in Cohort 3 and Cohort 4 10 April 2026 DURATION 2 years; with additional 3 years of follow-up for safety and durability of effect PRIMARY ENDPOINTS Safety and tolerability SECONDARY ENDPOINTS Biomarkers • Progranulin (CSF, plasma) • vMRI • NfL (CSF, plasma) Clinical • CDR + NACC FTLD sum of boxes EXPLORATORY BIOMARKERS • Cathepsin D (CSF) • GFAP (CSF, plasma) • LAMP 1 (CSF) • Lys-GL1 (CSF) Multicenter Open-label Dose exploration study Phase 1/2 Complete IDMC review Dose 1: 4.5e13 GC Dose 2: 2.2e13 GC COHORT 1 (n=5) Dose 1 COHORT 2 (n=4) Dose 1 / Dose 2 COHORT 3 (n=5-10) FTD Dose 2 -GRN COHORT 4 (n=3-5) Dose 2 COHORT 5 (n=3-5) FTD-C9orf72 |
| Cisterna magna Intra-Cisterna Magna (ICM) Administration 11 April 2026 Directly deliver vector into the CSF via a single injection • Allows for broad CNS biodistribution1 • Lower doses compared to IV systemic delivery • Reduced impact of neutralizing antibodies Brief (<60 min), non-surgical, CT-guided procedure for precise delivery to the cisterna magna Procedure avoids penetration of brain tissue 1. Hinderer et. al, Hum Gene Ther. 2018; 29:15-24. |
| Key Baseline Demographics for FTD-GRN Participants* Dose 1 (n=7); Dose 2 (n=2) 12 April 2026 (n=9) PBFT02 Dose 1 Dose 2 Age, years, mean (range) 63.3 (51–71) 69.0 (66-72) Sex, n (%) Male 4 (57%) 0 Female 3 (43%) 2 (100%) FTD-GRN phenotype, n bvFTD 5 1 PPA 2 1 Disease duration at baseline, years, mean (range) 2.9 (1–5) 2.0 (1-3) PGRN, CSF, ng/mL, mean (range) 2.2 (1.5–2.9) 1.8 (1.5 – 2.0) PGRN, plasma, ng/mL, mean (range) 38.5 (22.4–89.0) 36.2 (23.6 – 48.7) NfL, plasma, pg/mL, mean (range) 43.4 (12.4–105.0) 90.4 (69.8-111) Clinical Dementia Rating Scale1 , Global (%) 1 57% 50% 2 43% 50% Clinical Dementia Rating Scale, Sum of Boxes, mean (range) 9.6 (5–17) 10.5 (6 – 15) *Data as of January 26, 2026. 1. CDR® +NACC FTLD. Dose 1: 4.5e13 GC. Dose 2: 2.2e13 GC bvFTD, behavioral variant; PPA, primary progressive aphasia. |
| Healthy adult range 0 10 20 30 40 0 3 6 9 12 15 18 CSF PGRN, ng/mL Time, Month Dose 1 Dose 2 PBFT02, at Both Dose Levels, Generated Robust Increases in CSF PGRN in FTD-GRN Patients 13 April 2026 Dose 1 • Continued durability to 18 months Dose 2 • First 2 patients with consistent Day 30 levels at high end of normal range • First M6 data: Dose 2 generating a robust PGRN response • Potential for similar target engagement as Dose 1 with half the dose/capsid load Data as of February 9, 2026. Mean +/- SEM Shading: Healthy adult sample range for CSF PGRN (range: 3.28 – 8.15 ng/mL, mean: 4.76 ng/mL, n = 61) (Passage Bio data) Dose 1: 4.5e13 GC; Dose 2: 2.2e13 GC CSF, cerebrospinal fluid; M, month. Progranulin, CSF Dose 1 N: 7 6 6 6 3 Dose 2 N: 2 2 1 |
| Brain Atrophy (as measured with vMRI) is Associated with Clinical Deterioration in FTD-GRN Natural History vMRI assesses volume of brain tissue across various regions of interest (e.g. frontal and temporal lobes) • Volume loss (atrophy) is considered to represent synaptic and cell loss in the region of interest and is a common outcome measure employed in neurodegenerative diseases • In FTD-GRN, brain atrophy begins prior to symptom onset and is most rapid after early symptom onset before slowing with disease progression1 • In a sample of 218 GRN+ individuals (asymptomatic and FTD-GRN), atrophy was strongly associated with clinical progression1 • Although longitudinal data are limited, FTD-GRN carries the most aggressive atrophy rate across genetic FTD subtypes2,3 14 1. Staffaroni 2022. 2. Gordon et al. J. Neuroimage Clin. 2021. 3. Whitwell 2015. vMRI, volumetric MRI April 2026 Our Approach: x • Analyze PBFT02-treated patients vs. ALLFTD natural history data to determine rates of whole brain and frontotemporal cortex atrophy at 12-months • Segment analysis by CDR global score at baseline (i.e., CDR global 1 only) • Passage is only known analysis to report NH brain atrophy rate by CDR score • No statistical modelling applied to data given small sample size |
| Early Biomarker Signal that PBFT02 Slowed Disease Progression in Target Population Longitudinal changes in whole brain volume1 and frontotemporal cortex volume2 have been shown to correlate with clinical changes in FTD 15 -9.9% -4.6% -14% -12% -10% -8% -6% -4% -2% 0% -8.7% -3.1% -12% -10% -8% -6% -4% -2% 0% Data as of January 26, 2026. Note: Volume is the difference between BL and 12month data, as a percentage of the baseline volume. 1. Knopman et al., 2009; Gordon et al., 2010 2. Staffaroni 2019; 3. ALLFTD: CDR 1 patients at baseline Whole Brain Atrophy Volumetric MRI 12 month change from baseline CDR 1 Natural Hx3 (n=7) CDR 1 PBFT02 (n=2) Frontotemporal Cortex Atrophy Volumetric MRI 12 month change from baseline 64% reduction of atrophy 54% reduction of atrophy April 2026 • PBFT02 global CDR 2 patients at baseline lost 9% of volume at Month 12, with no improvement vs. CDR 2 natural history • PBFT02 global CDR 2 patients at baseline lost 10% of volume at Month 12, with no improvement vs. CDR 2 natural history CDR 1 Natural Hx3 (n=7) CDR 1 PBFT02 (n=2) |
| Plasma NfL Showed Early Evidence of Improvement in a Disease Progression Biomarker vs. Natural History • Plasma NfL remains stable in treated patients at Month 12 • Absolute pNfL change from baseline is the metric to be analyzed in registrational study 16 Natural History Natural history data supported by the ALLFTD Consortium (funded by NIA and NINDS) Plasma NfL Change from Baseline at 12M (Dose 1) Data as of January 26, 2026. Mean +/- SEM PBFT02 patients (n=6, Dose 1): Mean, SD for Baseline plasma NfL (neurofilament light chain) 48.6 ± 27.0 pg/mL. Mean time since diagnosis 2.7 years. 1. Passage Bio analysis of ALLFTD natural history sample comprised of individuals with a pathogenic GRN mutation and a CDR+NACC FTLD global score between 0.5 and 2, inclusive. Mean, SD for Baseline plasma NfL 57.8 + 20.2 pg/mL. -10 -5 0 5 10 15 20 25 Plasma NfL CFB, pg/mL ALLFTD (n=7) PBFT02 (n=6) +13.5 pg/mL -1.0 pg/mL 1 April 2026 |
| PBFT02 Interim Safety Profile PBFT02 was generally well tolerated • SAEs related to PBFT02 all asymptomatic; all occurred at Dose 1 • Venous sinus thrombosis (2) • LFT increase (1) • No evidence of thrombotic microangiopathy • No evidence of dorsal root ganglion (DRG) toxicity • No complications from ICM procedure PBFT02 immune response profile • As expected, T-cell responses against AAV1 were observed in majority of participants by Day 30 • No association with any clinical findings • No responses against hPGRN • Anti-AAV1 antibodies observed in both serum and CSF by Day 30; stable out to 18 months • 1 participant experienced transient low-titer anti-hPGRN antibodies in serum only that had resolved at last testing Data as of March 23, 2026 (n=10 FTD-GRN and n=1 FTD-C9orf72 patients) 17 SAE, serious adverse event; LFT, liver function test; ICM, intracisterna magna; TEAE, treatment emergent adverse event. April 2026 N Events TEAE considered related to PBFT02 8 32 Serious TEAE unrelated to PBFT02 1 3 Serious TEAE related to PBFT02 2 3 |
| PBFT02 Offers Best-in-Class Therapeutic Potential PBFT02 Product Candidate AAV1 gene therapy delivering GRN AAV9 gene therapy delivering GRN PGRN replacement therapy via protein transport vehicle Stage of Development Phase 1/2 Phase 1/2 Phase 1/2 Route of Administration ICM (non-surgical, 1 hour procedure) Intrathalamic (neurosurgery, lengthy procedure) IV Frequency of Administration One-time One-time Chronic dosing (~every 4 weeks)1 CSF PGRN Level at 12m 22.8 ng/mL (mean; n=6) – – Durability of CSF PGRN Elevation1 Durable at 18 m (n=3) – – PBFT02 uniquely positioned to offer a one-time therapy capable of achieving highest progranulin levels 18 April 2026 Data for PBFT02 as of January 26, 2026. Information for competitor programs based on publicly available information. 1 https://memory.ucsf.edu/research-trials/dnl593#:~:text=What%20to%20Expect,garages%20for%20all%20study%20visits (accessed on Feb 12, 2026). |
| PBFT02 has Potential to Correct Underlying Pathology in FTD-GRN, FTD-C9orf72 and ALS 19 April 2026 TDP-43 pathology is a hallmark of multiple neurodegenerative diseases1 • TDP-43 mislocalizes from nucleus to cytoplasm • Forms inclusion bodies associated with neurodegeneration 1. Rhinn H et al. Trends Pharmacol Sci. 2022; 43:641-652 |
| Elevated PGRN Ameliorates TDP-43 Pathology in Preclinical Models 20 April 2026 TDP-43 pathology due to lysosomal dysfunction (GRN/ TMEM106 double knockout, DKO) reduced by AAV.hPGRN1 AAV delivered hPGRN to mouse brain TDP-43 pathology in DKO mice reduced by AAV.hPGRN Elevated PGRN reduced insoluble TDP-43 in mouse spinal cord Elevated PGRN extended survival of TDP-43 mutant mice Elevated PGRN ameliorated TDP-43 pathology and disease course in a preclinical model2 • Elevated PGRN also prevented degeneration of large axon fibers in TDP-43 mice • PGRN neuroprotection from pleiotropic effect, not single pathway 1. Reich et al. Sci Transl Med. 2024; 16(750); 2. Beel et al. Mol Neurodegen. 2018: 13:55.; Laird et al. PLoS One 2010; 5:e13368. DKO, double gene knockout; GRN, granulin gene; PGRN, progranulin; TDP-43, transactive response DNA binding protein 43 kDa † PGRN increased to >2x endogenous levels |
| • AAV delivery of functional GRN gene to express new PGRN, increasing levels both intra- and extra-cellularly • Preserves all natural pathways to properly traffic PGRN intracellularly where it is needed • ICM route of administration enables low doses of AAV and broad CNS biodistribution • Non-surgical, brief procedure (< 60 minutes) • Potential for a one-time therapy for patients • Durable elevation of CSF PGRN seen through 18 months1 PBFT02: Summary of Approach 21 April 2026 1. Interim data from upliFT-D as of January 26, 2026. A novel and potentially transformative therapy for FTD-GRN patients |
| Completed development of high-productivity, suspension-based manufacturing process Single production lot estimated to yield >1,000 doses1 with >70% full capsids Robust Manufacturing Process Aligned with the FDA on an analytical approach to establish comparability of suspension-based process Process Comparability Plan Developed assay and reached alignment with FDA on suitability of assay for PBFT02 release Functional Potency Assay Critical Manufacturing Milestones Achieved to Enable Late-Stage Development of PBFT02 22 April 2026 1. Estimated yield based on Dose 2. |
| Huntington’s Disease Preclinical Program |
| OVERVIEW • Fatal, monogenic, autosomal dominant neurodegenerative disease • Caused by trinucleotide (CAG) expansion in the huntingtin (HTT) gene resulting in mutant huntingtin (mHTT) protein expression • More than 200,000 people estimated to be at risk in the US1 CLINICAL SYMPTOMS • Symptom onset typically occurs between 30–50 years old • Characterized by progressive motor, cognitive, and behavioral deterioration, due to neuronal dysfunction then degeneration Huntington’s Disease: A Fatal Neurodegenerative Disease with No Disease-Modifying Therapy Average life expectancy after symptom onset is 15–20 years 24 April 2026 Motor deterioration Cognitive deterioration Behavioral deterioration 1. HDSA; Fisher and Hayden Mov Disord. 29:105-14, 2014. |
| Unaffected HD Is Caused By A Mutation In Huntingtin (HTT) Gene: A Stretch Of CAG Nucleotides Is Expanded CAG repeat expansion leads to production of mutant huntingtin protein (mHTT) 25 April 2026 Normal huntingtin gene, HTT, CAG </= 35 Mutant huntingtin gene, mHTT, CAG > 35 GLUTAMINES Exon 1 Exons 2–67 SHORT CAG HTT DNA LONG GLUTAMINE STRETCH HTT PROTEIN Exon 1 Exons 2–67 LONG CAG mHTT DNA mHTT PROTEIN Huntington’s Disease |
| DNA Repair (DR) Proteins Play a Key Role in CAG Repeat Expansion • CAG expansion above a certain threshold leads to neurodegeneration • Longer CAG repeats associated with worse disease pathology • CAG expansion occurs at different rates in different neurons, and is fastest in the caudate and putamen brain regions which degenerate first 26 April 2026 1. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, Nat Genet. 2025; 57:1426-36. 2. Dragileva E et. al, Neurobio Dis. 2009; 33:37-47. 3. Mouro Pinto et. al, Nat Genet. 2025; 57:314-322. In Huntington’s disease (HD), the CAG repeat in the HTT gene can elongate over time, termed somatic instability • In the presence of certain CAG motifs, MSH3 can erroneously incorporate CAGs into DNA, leading to CAG expansion • In HD: certain genetic variants altering MSH3 function are associated with delayed onset and slowed progression1 • In HD mice: MSH3 is essential for CAG expansion, and MSH3 knock-down reduced somatic instability and HTT pathology2,3 MSH3, a DR protein, is a key driver of somatic instability |
| Our Approach: Decrease MSH3 to Reduce Somatic Instability in the HTT Gene Program Status 27 April 2026 Developing a differentiated approach to decrease MSH3 expression via AAV delivery of a miRNA Proof-of-concept studies completed, with additional preclinical studies ongoing Plan to utilize an optimized intraparenchymal delivery approach • One-time delivery • Direct delivery to critical brain regions • Reduced total procedure time • Limited peripheral exposure to reduce safety risks |
| © 2026 Passage Bio. All rights reserved. passagebio.com Thank you! |
| Program Indication US/EU prevalence Discovery Preclinical Phase 1/2 Pivotal PBFT02 Frontotemporal dementia — GRN 18,0001-3 Frontotemporal dementia — C9orf72 21,0002-4 Unnamed Huntington’s disease 70,0005 Focused Pipeline Addressing Rare and Prevalent Neurodegenerative Indications 1. Greaves CV, et al. J Neurol 2019; 266:2075-2086. 2. Galvin JE, et al. Neurology 2017; 89:2049-2056. 3. Onyike CU, et al. Int Rev Psychiatry 2013; 25:130-137. 4. Moore KM, et al. Lancet Neurol 2020; 19: 145–156. 5. Crowell et al. Neuroepi. 2021; 55:361-368. 29 April 2026 ALS and Alzheimer’s disease represent additional pipeline expansion opportunities for PBFT02 |
| LEADERSHIP TEAM Demonstrated Leadership BOARD OF DIRECTORS Maxine Gowen, Ph.D. Chairwoman Athena Countouriotis, M.D. Avenzo Therapeutics Derrell Porter, M.D. cTRL Therapeutics Dolan Sondhi, Ph.D. Weill Cornell Medicine Sandip Kapadia Former CFO Harmony Biosciences Thomas Kassberg Former CBO Ultragenyx William Chou, M.D. President and Chief Executive Officer Deep experience in rare disease, CNS disorders and genetic medicines Eden Fucci SVP Technical Operations Stuart Henderson Chief Business Officer William Chou, M.D. President and Chief Executive Officer Kathleen Borthwick Chief Financial Officer Karl Whitney, Ph.D. SVP Global Regulatory Affairs Sue Browne, Ph.D. Chief Scientific Officer 30 April 2026 |
| Preclinical NHP: AAV1 Achieved the Highest Levels of CSF PGRN 31 April 2026 After ICM administration to NHPs: • AAV1 capsid resulted in CSF hPGRN levels 5x higher than AAVhu68 (an AAV9 variant) • Superior hPGRN response led to selection of AAV1 capsid for PBFT02 Rhesus macaques (n=2/gp) ICM-delivered AAV.hPGRN (3.3 x 1011 GC/g brain), day 0 *Size and duration of elevation muted by immune response to human PGRN. Shading: Healthy adult sample range for CSF PGRN, n = 61 (Passage Bio data) CSF, cerebrospinal fluid; GC, genome copies; ICM, intra-cisterna magna; NHP, non-human primate. Reference: Hinderer et al., Ann Clin Trans Neurol. 2020; 7:1843-1853. Human PGRN in NHP CSF Vector Comparison Healthy adult range Days BL 0 7 14 21 28 35 hPGRN *ng/mL) 80 70 60 50 40 30 20 10 0 AAV1.CB7.hGRN AAV5.CB7.hGRN AAVhu68.CB7.hGRN AAVhu68.UbC.hGRN |
| Preclinical NHP: ICM Administration of PBFT02 Led to Broad Distribution of Vector Throughout Brain/Spinal Cord • Robust, dose-dependent vector delivery to cortical and sub-cortical brain regions affected in FTD • NHP low dose, equivalent to clinical Dose 1 of PBFT02 in upliFT-D study, resulted in ~10⁴ GC/μg DNA in all sampled areas throughout the brain 32 April 2026 n=3/gp. Data are mean +/- SEM. CBL, cerebellum; Cerv, cervical; DRG, dorsal root ganglion; FCX, frontal cortex; GC, genome copies; Hipp, hippocampus; ICM, intra-cisterna magna; LLoQ, lower limit of quantitation; Lumb, lumbar; OCX, occipital cortex; PCX, parietal cortex; TCX, temporal cortex; Thor, thoracic; TRG, trigeminal root ganglion; Veh, vehicle Vector Biodistribution in NHPs 90 Days Post-ICM PBFT02 GC/µg DNA 107 106 105 104 103 102 101 FCX PCX TCX OCX Hipp Medulla CBL Cerv Lumb Thor Cerv Lumb Thor TRG LLoQ Veh Low Medium High dose Cortex DRG |
| Preclinical Grn–/– Mice: Expression of hPGRN Improved Lysosomal Dysfunction and Neuroinflammation in the Brain 33 April 2026 Greatest pathological benefit was associated with the highest PGRN levels in the CSF Lipofuscin deposition and microglial activation are hallmark pathologies seen in FTD; Improvements in both measures were seen in cerebral cortex, thalamus, and hippocampus after PBFT02 administration Grn–/– and WT mice (n=14-15/gp) ICV-administered PBFT02 or vehicle (V). Baseline controls were untreated mice on Day 1. Bars: mean +/- SEM. # ## p < 0.01, ### p < 0.005 vs WT control; *p < 0.05, ***p < 0.005 vs Grn-/-+ V , one-way ANOVA followed by Tukey’s multiple comparisons test. Grn, granulin gene; ICV, Intra-cerebroventricular; PGRN, progranulin; WT, wildtype Thalamus Lipofuscin Thalamus CD68 Immunohistochemistry PBFT02 Reduced Lipofuscin Deposition at All Doses, Suggesting Improved Lysosomal Dysfunction Dose-Dependent Elevations in CSF PGRN after PBFT02 Led to Progressive Reductions in Microglial Activation Lipofuscin Count 1000 800 600 400 200 0 Baseline Day 90 Baseline Day 90 CD68 Area (µm2 ) 5000 4000 3000 2000 1000 0 PBFT02 Dose 1 Dose 2 Dose 3 Dose 4 PBFT02 Dose 1 Dose 2 Dose 3 Dose 4 WT Grn-/- WT Grn-/- WT Grn-/- WT Grn-/- V V PBFT02 V V PBFT02 |
