Passage Bio (PASG) investor relations material

Clinical program updates

• Focused on a clinical-stage AAV gene therapy for FTD-GRN, targeting patients with granulin mutations and shifting inclusion to earlier-stage, mild cognitive impairment cases.

• Therapy aims to restore progranulin levels, addressing neurodegeneration by replacing the deficient protein via a one-time AAV1 vector administered intracisternally.

• Early data show robust increases in CSF progranulin, especially at higher doses, with lower doses now prioritized for safety.

• Lower dose cohort introduced after observing three serious adverse events at higher doses; no SAEs reported since dose reduction and prophylactic anticoagulation added.

• Enrollment in the latest cohort is brisk, aided by discontinuation of competing studies, and new data are expected in the first half of the year.

Competitive landscape and mechanistic differentiation

• Previous anti-sortilin antibody approaches failed to meet endpoints, likely due to insufficient progranulin elevation and mechanistic limitations.

• AAV1 vector shows higher efficacy in progranulin production compared to AAV9, possibly due to cell tropism, and offers a shorter, less invasive administration.

• Other therapies require chronic dosing or lengthy surgical procedures, while this approach is a single, brief intervention.

• Patient selection is critical; focusing on earlier-stage patients may improve outcomes compared to prior studies that included more advanced cases.

Biomarker and efficacy insights

• CSF progranulin is the primary target engagement biomarker, with plasma neurofilaments and volumetric MRI as secondary endpoints.

• Early results show a marked slowing in neurodegeneration, with plasma neurofilament increases much lower than natural history rates.

• Durability of effect observed up to 18 months at higher doses, with ongoing evaluation of lower dose efficacy.