Passage Bio (PASG) Goldman Sachs 45th Annual Global Healthcare Conference summary

Program focus and scientific rationale

• PBFT02, an AAV1-based gene therapy, targets neurodegenerative diseases by elevating progranulin, initially focusing on FTD-GRN but with plans to expand to other indications like ALS and Alzheimer's.

• FTD-GRN is a rare but not ultra-rare disease with about 18,000 patients in the US and Europe, and currently lacks any disease-modifying therapies.

• Progranulin deficiency leads to neuronal dysfunction and pathogenic inflammation, with TDP-43 pathology as a key intersection in multiple neurodegenerative diseases.

• The AAV1 capsid used in PBFT02 has a unique tropism for ependymal cells, enabling efficient and durable delivery of progranulin into the CSF.

• The therapy leverages natural CNS pathways, using ependymal cells as factories for progranulin production, which is then distributed via CSF.

Clinical trial design and results

• Ongoing phase I/II trial spans 7 sites in 4 countries, using a dose escalation design with two mandatory cohorts and one optional.

• All five patients in cohort one have been treated at the same dose, with strong target engagement and no need for dose escalation.

• Administration is via intracisterna magna, a minimally invasive, 45-minute procedure under CT guidance, avoiding brain parenchyma penetration.

• Direct CNS delivery allows broad vector distribution at much lower doses than systemic therapy, reducing concerns about neutralizing antibodies.

• Safety profile improved after increasing immunosuppression; no SAEs or immune responses in subsequent patients, with further safety data expected in September.

Efficacy and biomarker data

• CSF progranulin levels in treated patients rose from below normal to 11–17 by day 30 and 22–27 at 6 months, surpassing other clinical programs.

• Elevated progranulin in CSF is expected to increase the probability of clinical responders, with no effect observed in plasma levels.

• Early data show best-in-class and durable CSF progranulin levels, with consistent results across patients.

• Preclinical evidence suggests that high progranulin levels (2–3x normal) are needed to reverse TDP-43 pathology, a hallmark of FTD-GRN, FTD-C9, and ALS.

• Plans to share 6-month safety and biomarker data in the second half of the year, and 12-month data in the first half of 2025.