Passage Bio (NASDAQ:PASG) outlined progress on its lead gene therapy program for frontotemporal dementia (FTD) tied to a granulin (GRN) mutation during a presentation at Oppenheimer’s 36th Annual Life Science Conference. President and CEO William Chou said the company’s near-term focus is generating additional clinical readouts in 2026 while maintaining a cash runway into the first quarter of 2027.
Lead program targets progranulin deficiency in FTD-GRN
Chou focused primarily on PBFT02, an AAV1-based one-time gene therapy being developed to treat FTD patients with a GRN mutation. He said there are currently no approved disease-modifying therapies for frontotemporal dementia, and described FTD-GRN as a genetic disease where replacing the missing protein could address a known proximal driver of neurodegeneration: low progranulin levels.
Chou characterized PBFT02 as differentiated based on its delivery and biomarker profile. The therapy is administered via an intra-cisterna magna (ICM) injection directly into cerebrospinal fluid (CSF) in a CT-guided procedure that takes about an hour and is often performed by interventional radiologists. He said this approach enables broad CNS biodistribution, lower doses than systemic IV delivery, and reduced impact from neutralizing antibodies.
Study status, dosing strategy, and patient selection
Passage Bio is running an ongoing Phase I/II study primarily in symptomatic FTD-GRN patients, and has also opened enrollment to FTD patients with the C9orf72 mutation (FTD-C9) in separate cohorts. Chou said efficacy evaluation needs to be handled separately because the time course of FTD-GRN is more accelerated than FTD-C9.
In FTD-GRN, the company has treated nine patients across two dose levels:
- Dose 1 (higher dose): 7 patients treated as of the update discussed
- Dose 2 (lower dose, half of Dose 1): 2 patients treated so far
Chou said Passage Bio moved to the lower dose due to strong progranulin responsiveness and to maximize risk-benefit. The company is currently enrolling Cohort 3, which is planned to include 10 patients all treated with Dose 2.
He also highlighted a shift toward earlier-stage patients. Early enrolled participants included individuals with Global Clinical Dementia Rating (CDR) scores of 1 or 2. Moving forward, the study is excluding CDR 2 patients and is including earlier symptomatic patients with scores of 0.5 and 1. Chou said the rationale is that the therapy is intended to preserve neurons rather than replace lost neurons, making earlier intervention more likely to show clinical benefit.
Biomarker updates: CSF progranulin and plasma neurofilaments
Chou said baseline CSF progranulin in treated patients ranged from 1.5 to 2.9, below a stated normal range of 3 to 8. He presented target engagement data showing Dose 1 produced a robust increase in CSF progranulin, with levels in the mid-20s and a peak occurring between six and 12 months, with durability shown out to 18 months.
For Dose 2, Chou said the company’s first data point showed a “robust increase” to the high end of the normal range. He said a key question for upcoming updates is whether Dose 2 continues rising and “settles” above the normal range, which would help inform dose selection and enable bridging to longer follow-up data from Dose 1.
He also discussed plasma neurofilaments as a disease progression biomarker with longitudinal natural history data. Chou cited external literature and the company’s own analysis indicating untreated symptomatic FTD-GRN patients show annual plasma neurofilament increases of about 28% to 29%. In Passage Bio’s dataset, he said four patients with one year of follow-up showed an average increase of about 4%, which he described as a sign of slowing neurodegeneration versus natural history comparisons.
Chou noted the company has not yet shared volumetric MRI data and said CDR outcomes typically require a larger dataset and longer follow-up. He said investors should not expect CDR data at this stage.
Safety update and protocol changes
Chou said PBFT02 has been generally well-tolerated, while noting serious adverse events occurred at the higher Dose 1. He reported two patients experienced three serious adverse events that were asymptomatic and responded to treatment: two episodes of venous sinus thrombus and one episode of elevated liver function tests (LFTs).
To address LFT elevations, he said the company adjusted immunosuppression from oral steroids alone to three days of IV steroids followed by a 60-day oral steroid course, and has not seen additional LFT-related serious adverse events since that change.
For venous sinus thrombus, which he compared to a DVT occurring in brain veins, Chou said the company attributed the events as likely product-related and possibly driven by a local inflammatory response. He said there was no evidence of thrombotic microangiopathy or other coagulation abnormalities. In Cohort 3, Passage Bio plans to implement five to six weeks of prophylactic anticoagulation using half-dose apixaban (Eliquis).
Upcoming catalysts and additional pipeline programs
Chou said Passage Bio expects to report updated interim safety and biomarker data in the first half of the year, including a six-month readout for Dose 2 and additional longitudinal updates for Dose 1 patients.
He also said Passage Bio is seeking regulatory feedback on registrational trial design in FTD-GRN, emphasizing the company wants clarity on FDA requirements before finalizing a pivotal development plan.
Beyond FTD-GRN, Chou said PBFT02 is also being evaluated in FTD-C9 based on a rationale tied to TDP-43 pathology as a “final common pathway” across multiple neurodegenerative diseases. He cited preclinical evidence, as described in the company’s corporate deck, suggesting elevated progranulin may ameliorate TDP-43 pathology, supporting exploration in FTD-C9 cohorts (Cohorts 4 and 5), with Cohort 4 already started.
In Huntington’s disease, Chou provided an update on a preclinical program targeting the DNA repair protein MSH3 to address somatic instability of CAG repeats. He said Passage Bio plans to deliver an AAV-based miRNA to knock down MSH3 using an optimized intraparenchymal approach and expects to declare a clinical candidate in the second half of the year. However, he said the company has not provided guidance on the timeline for entering the clinic.
On financials, Chou said Passage Bio ended the year with $46 million in cash and a current burn rate of $30 million to $35 million, supporting runway into the first quarter of 2027.
About Passage Bio (NASDAQ:PASG)
Passage Bio is a clinical-stage biotechnology company focused on the development of gene therapies to treat rare, monogenic central nervous system and neuromuscular disorders. The company applies its in-house gene therapy platform to design and engineer adeno-associated virus (AAV)–based vectors that restore or replace defective genes, aiming to deliver durable treatments with a single administration.
The company’s lead programs include PBGM01, an AAV9-based therapy for GM2 gangliosidoses (Tay–Sachs and Sandhoff diseases), which is conducting a first-in-human study to assess safety and potential therapeutic benefit.
