# Update on Disease-Modifying Pharmacological Treatments for Frontotemporal Dementia (FTD): A Scoping Review of Registered Trials

## TL;DR

This review summarizes ongoing clinical trials for disease-modifying treatments in frontotemporal dementia, focusing on genetic and inflammatory pathways.

## Contribution

The paper provides a scoping review of registered trials for disease-modifying FTD therapies, highlighting recent advances and gaps in research.

## Key findings

- Six trials targeting GRN mutations show safety and progranulin restoration.
- Two phase 2 trials for sporadic FTD show disease-modifying potential.
- More large-scale RCTs are needed to confirm long-term efficacy.

## Abstract

Frontotemporal dementia (FTD) represents a cluster of adult-onset neurodegenerative diseases resulting from a combination of genetic and epigenetic factors. Currently, treatment is symptomatic and there are no licensed disease-modifying therapies available. The aim of this review was to provide an overview of ongoing or recently completed clinical studies targeting disease modification in FTD. A structured search of interventional trials of pharmacological compounds was conducted on three clinical trial registries (National Library of Medicine Clinical Trials, European Union Clinical Trials, and the Australian New Zealand Clinical Trials registries) up to September 2025. Twelve interventional trials were found. Half targeted autosomal-dominant progranulin (GRN) mutations (n = 6) and half examined therapies targeting neuroinflammatory-induced sporadic FTD (n = 6). The interim results of the early-phase (1/2) randomized controlled trials (RCTs), comprising three ongoing gene replacement studies (PROCLAIM, ASPIRE-FTD, upliFT-D) and one immune-modulating monoclonal antibody (INFRONT, now in phase 3)—all targeting the FTD-GRN mutation—show safety, tolerability, and effectiveness in restoring progranulin levels. Two recently completed phase 2 RCTs for sporadic FTD targeting neuroinflammation, the PEA-FTD and C9orf72 ALS/FTD trials, show disease-modifying potential. While interim results from six trials suggest clear mechanistic efficacy, prospective high-quality later-phase RCTs are required to ascertain long-term clinical efficacy. Since familial FTD encompasses less than half of the people with this disease, it is important to continue exploring the underlying pathophysiology, neuroimmunology, and treatment of epigenetic-induced sporadic FTD.