8-K: Passage Bio Reports Promising Interim Data for FTD Gene Therapy PBFT02, Outlines Strategic Protocol Amendments

Passage Bio, Inc. announced updated interim data from its Phase 1/2 upliFT-D clinical trial for PBFT02 in FTD-GRN, showing robust biomarker improvements and outlining plans for a protocol amendment to enhance safety and broaden patient enrollment.

Summary

• PBFT02 treatment resulted in robust and durable increases in cerebrospinal fluid (CSF) progranulin (PGRN) expression through 18 months post-treatment.
• Dose 1 PBFT02 increased CSF PGRN expression in all patients from below 3 ng/mL at baseline to a mean of 12.4 ng/mL at one month (n=7), 19.4 ng/mL at six months (n=6), 25.9 ng/mL at 12 months (n=4), and 23.8 ng/mL at 18 months (n=2).
• The first patient treated with Dose 2 PBFT02 (50% of Dose 1) saw CSF PGRN levels increase substantially from 1.5 ng/mL at baseline to 7.6 ng/mL at one month, approaching the upper limit of a healthy adult reference range.
• Patients who received Dose 1 PBFT02 experienced a reduced annual rate of change of plasma neurofilament (NfL) (4% increase on average at 12 months, n=4) compared to expected increases of 28% and 29% per year in untreated symptomatic FTD-GRN patients based on natural history studies.
• Safety data (as of June 15, 2025) indicated that in five of eight patients, all treatment-emergent adverse events were mild to moderate in severity.
• Three of eight patients experienced a total of four serious adverse events (SAEs), including venous sinus thrombosis (n=2), hepatotoxicity, and pulmonary embolism (n=1, assessed as possibly related to treatment).
• The company plans to amend the upliFT-D clinical trial protocol to introduce a short course of low-dose prophylactic anticoagulation and modify inclusion criteria to allow for enrollment of patients earlier in disease progression.
• Patient 9 will proceed with dosing in Cohort 2 with additional safety monitoring, and enrollment in Cohort 3 (FTD-GRN) and Cohort 4 (FTD-C9orf72) is planned to begin upon review and acceptance of the amended protocol.
• Passage Bio expects its cash runway to extend to the end of Q1 2027, based on cash, cash equivalents, and marketable securities as of March 31, 2025.

Sentiment

Score: 8

Explanation: The document presents strong positive clinical data for PBFT02, particularly regarding biomarker improvements and comparison to natural history. While there are serious adverse events, the company has a clear plan to mitigate them through protocol amendments. The established manufacturing process and extended cash runway also contribute to a positive outlook, despite the inherent risks of clinical development.

Positives

• PBFT02 demonstrated robust and durable increases in CSF progranulin (PGRN) expression, a key biomarker, through 18 months post-treatment, with Dose 1 increasing levels to a mean of 23.8 ng/mL at 18 months (n=2).
• The lower Dose 2 (50% of Dose 1) also substantially increased CSF PGRN levels, approaching the upper limit of a healthy adult reference range (7.6 ng/mL at one month from 1.5 ng/mL baseline), indicating potential efficacy at a reduced dose.
• Patients treated with Dose 1 PBFT02 showed a significantly reduced annual rate of change in plasma neurofilament (NfL) (4% increase) compared to untreated patients in natural history studies (28-29% increase), suggesting a positive impact on disease progression.
• Most treatment-emergent adverse events (5 of 8 patients) were mild to moderate in severity, and no evidence of dorsal root ganglion (DRG) toxicity or complications during intra cisterna magna (ICM) administration was observed.
• The company has established a high-productivity, suspension-based manufacturing process for PBFT02, estimated to yield over 1,000 doses per single production lot with over 70% full capsids, supporting late-stage development.
• Cash runway is expected to extend to the end of Q1 2027, providing financial stability for ongoing operations and clinical development.

Negatives

• Three of eight patients experienced a total of four serious adverse events (SAEs), including two cases of asymptomatic venous sinus thrombosis, one case of hepatotoxicity, and one case of pulmonary embolism (possibly related to treatment).
• The occurrence of SAEs necessitates a protocol amendment to introduce prophylactic anticoagulation and additional safety monitoring for future patients, which could add complexity to the trial.
• The need to amend the protocol and gain regulatory acceptance could potentially introduce delays in the overall trial timeline for Cohort 3 and 4 enrollment, despite Patient 9 proceeding with dosing.

Risks

• Ability to develop and obtain regulatory approval for product candidates.
• Timing and results of preclinical studies and clinical trials.
• Risks associated with clinical trials, including the ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, and regulatory authorities requiring additional information or further studies, or failing to approve or delaying approval of drug candidates.
• Occurrence of adverse safety events.
• 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 intellectual property and other proprietary rights.
• Dependence on collaborators and other third parties for the development and manufacture of product candidates and other aspects of the business, which are outside of full control.
• Risks associated with current and potential delays, work stoppages, or supply chain disruptions.

Future Outlook

Passage Bio plans to submit an upliFT-D protocol amendment to health authorities in July 2025, seek regulatory feedback on suspension-based manufacturing process comparability in the second half of 2025, report updated interim safety and biomarker data from Dose 2 in the first half of 2026, and seek regulatory feedback on registrational trial design in FTD-GRN in the first half of 2026. The company expects its cash runway to extend to the end of Q1 2027.

Management Comments

• "We are pleased to share updated data highlighting the promise of PBFT02 for the frontotemporal dementia community. These data continue to demonstrate the ability of our investigational, one-time gene therapy to elevate progranulin, the deficient protein in FTD-GRN, in a robust and durable manner while also reducing the rate of increase of plasma neurofilament levels compared to rates observed in natural history studies." Will Chou, M.D., President and Chief Executive Officer of Passage Bio.
• "In addition, we continue to refine our understanding of the safety profile of PBFT02 and believe that our planned changes to the study protocol will further optimize the benefit-risk profile of the program." Will Chou, M.D., President and Chief Executive Officer of Passage Bio.
• "We remain on track to engage with regulatory authorities on a future registrational trial design in the first half of 2026." Will Chou, M.D., President and Chief Executive Officer of Passage Bio.

Industry Context

The announcement positions PBFT02 as a potential best-in-class, one-time gene therapy for FTD-GRN, a devastating neurodegenerative disease with no approved disease-modifying therapies. The company highlights the urgent patient need and the significant market opportunity across multiple neurodegenerative diseases where progranulin deficiency or TDP-43 pathology plays a role, including FTD-C9orf72, ALS, and Alzheimer's disease. This development could significantly advance treatment options in the genetic medicines space for neurodegenerative conditions.

Comparison to Industry Standards

• PBFT02 (AAV1 gene therapy, ICM administration) achieved mean CSF PGRN levels of 26 ng/mL at 12 months (n=4), with durability observed at 18 months (n=2).
• In comparison, an anti-sortilin antibody (Phase 3, IV administration) achieved approximately 4-5 ng/mL CSF PGRN (n=9) with monthly administration.
• Another AAV9 gene therapy (Phase 1/2, ICM administration) achieved approximately 4-8 ng/mL CSF PGRN (n=7 higher dose) but showed declining levels from 2 to 12 months.
• Passage Bio asserts that PBFT02 is "uniquely positioned to offer a one-time therapy capable of achieving highest progranulin levels" compared to these other clinical candidates.
• Plasma NfL levels in PBFT02-treated patients increased by 4% on average at 12 months, which is significantly lower than the 28% and 29% annual increases observed in untreated symptomatic FTD-GRN patients from ALLFTD natural history data (n=11) and published natural history data (n=15), respectively.

Stakeholder Impact

• Shareholders: Positive impact due to promising clinical data, potential for a best-in-class therapy, extended cash runway, and clear development pathway. Negative impact from safety concerns and potential for delays.
• Patients (FTD-GRN): Potential for a new, effective, one-time gene therapy to treat a devastating disease with no approved therapies. Improved safety protocols (prophylactic anticoagulation) could benefit future patients.
• Employees: Continued progress in clinical development and a stable financial outlook provide job security and motivation.
• Regulatory Authorities: Engagement with FDA and IDMC on protocol amendments and safety monitoring indicates ongoing collaboration and adherence to regulatory processes.

Next Steps

• Submit upliFT-D protocol amendment to health authorities in July 2025.
• Seek regulatory feedback on suspension-based manufacturing process comparability in the second half of 2025.
• Report updated interim safety and biomarker data from Dose 2 in the first half of 2026.
• Seek regulatory feedback on registrational trial design in FTD-GRN in the first half of 2026.
• Begin enrollment in Cohort 3 (FTD-GRN) and Cohort 4 (FTD-C9orf72) upon review and acceptance of the amended protocol.
• Patient 9 to complete Cohort 2 with additional safety monitoring.
• Continue exploring benefits of elevated progranulin in multiple adult neurodegenerative diseases.
• Advance Huntington's disease preclinical program.

Key Dates

Recommendation

Keywords

Frontotemporal Dementia, FTD-GRN, Gene Therapy, PBFT02, Neurodegenerative Diseases, Clinical Trial, Phase 1/2, upliFT-D, Progranulin, PGRN, Neurofilament, NfL, Biomarkers, AAV1, Passage Bio, Genetic Medicines, Rare Disease, Orphan Drug