A recent article in Nature Biotechnology highlighted six clinical trials currently underway to test experimental treatments for progranulin-related FTD (GRN-FTD). Different companies are trying different approaches to treat it, but all approaches aim to raise progranulin levels. That’s because disease-causing changes in the progranulin gene result in reduced levels of progranulin, so restoring progranulin levels is expected to be therapeutic. Some companies (like Alector and Vesper) are working on stopping the breakdown of progranulin by targeting a protein called sortillin. Another company, Denali, is injecting a man-made version of progranulin. Three companies—Lilly/Prevail, Passage Bio, and AviadoBio—are using gene therapy to introduce a new, healthy copy of the progranulin gene.

Alector’s trial is the furthest along, with results of their pivotal Phase 3 study eagerly expected later this year. Laura Mitic, the acting president and chief scientific officer at Bluefield, is hopeful. She says, “It’s fantastic that there’s such interest in the field because it will translate into knowledge faster, to the benefit of patients.”

Passage Bio shared early results from its ongoing clinical trial of PBFT02, upliFT-D, which is testing progranulin gene replacement as a treatment for frontotemporal dementia (FTD) caused by GRN mutations. The first dose level tested showed a significant and lasting increase in progranulin levels in participants’ cerebrospinal fluid (CSF). It is anticipated, though not proven, that increasing progranulin levels in CSF may slow disease progression. In addition, participants’ aggregate plasma neurofilament light chain (NfL) levels changed less after 12 months than in historical controls. This is notable since published data suggest that plasma NfL levels typically increase in symptomatic individuals.  Passage Bio is now testing a lower dose (50% of the original) to explore its effects and gather more data. Safety monitoring showed that most side effects to date were mild to moderate, with two patients experiencing serious but manageable conditions. The company is also expanding its trial to include patients with FTD caused by C9orf72 mutations, aiming to begin dosing in the first half of 2025. Passage Bio plans to report more data in late 2025 and will seek regulatory guidance on the next steps in 2026.

After their Phase Ia trial to evaluate the investigational drug VES001 in healthy volunteers that showed that VES001 was safe, well-tolerated, and successfully increased progranulin levels, Vesper Bio announced the launch of a Phase Ib/IIa clinical trial, called SORT-IN-2, to test VES001 in patients with genetic variants in progranulin (GRN) that cause frontotemporal dementia (FTD-GRN).

VES001 is an oral treatment designed to increase progranulin levels, a key protein for brain health that is deficient in FTD-GRN patients. This phase will enroll patients with GRN mutations who are currently asymptomatic and will test whether VES001 can aise progranulin levels in individuals with GRN variants.

The study will take place at two medical centers in Europe (University College London and Erasmus University) and aims to complete dosing by mid-2025.