RARE Daily

Passage Bio Narrows Pipeline Focus, Looks to Partner Pediatric Lysosomal Storage Disease Programs

December 20, 2023

Rare Daily Staff

Passage Bio said it was further “optimizing” its portfolio for the treatment of neurodegenerative conditions and that it as seeking to partner its clinical-stage pediatric programs in GM1 gangliosidosis, Krabbe disease and metachromatic leukodystrophy.

It made the announcement as it reported initial safety and biomarker data from the ongoing global phase 1/2 upliFT-D clinical trial evaluating its gene therapy PBFT02 for the treatment of patients with frontotemporal dementia with granulin (GRN) mutations.

“Driven by promising initial data for PBFT02 in FTD-GRN and evidence supporting progranulin’s role in neurodegeneration, we are refining our strategic priorities to explore the therapeutic potential of PBFT02 in multiple diseases, including FTD-C9orf72, amyotrophic lateral sclerosis, and Alzheimer’s disease,” said William Chou, president, and CEO at Passage Bio. “As we pursue this strategy, we are actively exploring potential partnerships to advance our GM1 gangliosidosis program as well as our other clinical-stage pediatric programs. This shift in strategy aims to optimize focus and resources and provides each of our gene therapy candidates the best chance to get to patients in need.”

Frontotemporal dementia (FTD) is one of the more common causes of early-onset dementia with no approved disease-modifying therapies. In approximately 5 to 10 percent of individuals with FTD–approximately 18,000 individuals in the United States and Europe—the disease occurs because of mutations in the GRN gene, causing a deficiency of progranulin (PGRN). PGRN is a complex and highly conserved protein thought to have multiple roles in cell biology, development, and inflammation. Emerging evidence suggests that PGRN deficiency may contribute to lysosomal dysfunction.

The upliFT-D clinical trial evaluates PBFT02 as a single dose delivered via intra-cisterna magna (ICM) injection. PBFT02 uses an AAV1 viral vector to deliver a functional copy of the GRN gene encoding PGRN to a patient’s cells. Topline interim results from first three patients in the uplift-D clinical trial showed dose 1 of PBFT02 achieved supraphysiologic CSF progranulin levels in each of the first three treated patients at 30 days after treatment that were sustained at up to six months post-treatment. Dose 1 of PBFT02 was generally well-tolerated in patients 2 and 3 who received an enhanced steroid regimen for immunosuppression. There were no serious adverse events and all treatment emergent adverse events (AEs) were mild to moderate in severity with no evidence of clinically significant immune response, hepatotoxicity, or safety related imaging abnormalities. Patient 1 received a low level of immunosuppression and experienced two SAEs that were both asymptomatic and consistent with an immune response.

Dose 1 of PBFT02 treatment resulted in a 3.6 to 6.6-fold increase in CSF PGRN at day 30 relative to baseline. CSF PGRN increased to supraphysiologic levels of 10.7 to 17.3 ng/mL at day 30, exceeding the range found in healthy adult controls of 3.3 to 8.2 ng/mL.

CSF PGRN remained at supraphysiologic levels at six months with a concentration of 27.3 ng/mL. Plasma PGRN levels remained below levels found in healthy adult controls through the available follow-up period across all patients.

Photo: William Chou, president, and CEO at Passage Bio

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