Background

PBFT02 is a gene-replacement therapy that uses adeno-associated virus serotype 1 (AAV1) to deliver a functional copy of the progranulin gene GRN to the brain. Progranulin mutations are a frequent cause of familial frontotemporal dementia. Mutations result in 30 to 50 percent reductions in cerebrospinal fluid progranulin levels compared to the normal range. Progranulin insufficiency interferes with proper lysosomal function. PBFT02 is intended to overcome progranulin deficiency in mutation carriers.

PBFT02 is delivered as a one-time injection into the cerebrospinal fluid in the cisterna magna at the base of the brain.

In preclinical work, intraventricular injection of AAV-GRN into progranulin-deficient mice led to elevated progranulin concentration in the brain and CSF, normalization of lysosome function, and reduction in microgliosis. In nonhuman primates, a single injection into the cisterna magna raised CSF progranulin to 40 times normal human levels, with no apparent toxic effects (Hinderer et al., 2020).

Findings

In January and March 2021, PBFT02 received Orphan Drug Designation and Fast Track status, respectively, from the U.S. FDA (company press release).

In September 2021, Passage Bio began UpliFT-D, a Phase 1/2 trial to assess safety, tolerability, and efficacy of PBFT02 in 15 people with symptomatic FTD and progranulin mutations. Participants must be between ages 35 and 75 and not live in a nursing home. The open-label study will test doses of 3.3 x 1010 and 1.1 x 1011 gene copies per gram brain weight in two sequentially enrolled cohorts, with an optional third cohort at a higher dose of 2.2 x 1011 copies per gram. Primary outcomes are adverse events, safety measures of peripheral nerve function, and antibodies to the vector and transgene in serum and CSF up to five years after administration. The 23 secondary outcomes span neurocognitive and other FTD assessments, plasma and CSF progranulin levels, biomarkers of disease progression, MRI, activities of daily living, and survival from baseline to two years. The study is running at centers in North America, Brazil, and Europe, with primary completion slated for August 2024.

In On December 20, 2023, the company announced six-month safety results from the first dose cohort (press release; May 2024 company slides). The first patient, who received low-dose steroid immunosuppressive treatment, experienced two serious adverse events of liver toxicity and blood clots in the brain. Both were asymptomatic. The patient left the study after 10 weeks. The next two patients were given higher steroid doses, and reported only mild to moderate adverse events. The investigators reported no evidence of immune response, liver toxicity, or imaging abnormalities in these two patients, who continue to be monitored. None of the three showed changes in peripheral nerve function that would indicate dorsal root ganglion toxicity. In all patients, CSF progranulin concentrations increased 3.6- to 6.6-fold over baseline after 30 days, and exceeded the levels in healthy adults. Plasma progranulin remained low.

For details on PBFT02 trials, see clinicaltrials.gov.