Therapeutic intervention strategies in frontotemporal dementia: drug development pipeline.

Abstract

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer's disease, characterized by substantial genetic, clinical, and pathological heterogeneity. Despite progress in understanding its pathophysiology, no disease-targeted therapies (DTTs) have been approved to date. This study provides an updated overview of ongoing and completed clinical trials in FTD, analyzing therapeutic strategies, trial phases, and molecular targets. All registered trials were systematically searched on the online registers ClinicalTrials.gov, the EU Clinical Trials Register, and the International Clinical Trials Registry Platform, using the search terms "Frontotemporal Dementia," "FTD," and "svPPA" (semantic variant primary progressive aphasia). Included studies investigated pharmacological or cell-based interventions in Phases 1 through 4 or in trials with no reported phase. Non-pharmacological and biomarker-only trials were excluded. The Common Alzheimer's Disease Research Ontology (CADRO) was used to classify mechanisms of action. Data were collected as of February 3, 2026. A total of 49 trials were identified, investigating 35 pharmacological and three cell interventions. Among them, 16 trials (32.7%) were still active and had an expected sample size of 1036 participants. More than half of the pharmacological interventions investigated were classified as DTTs (67.3%), targeting specifically <i>GRN</i>- and <i>C9orf72</i>-associated genetic forms of FTD, while 26.5% targeted symptomatic treatments, addressing behavioral and neuropsychiatric symptoms. Seventeen molecules (32.7%) were repurposed drugs. The pipeline for the development of new potential treatments for FTD is still limited, with a predominant focus on rare genetic forms and a limited number of trials addressing sporadic FTD. Many trials remain inactive or unpublished, hindering translational progress. The scarcity of reliable biomarkers and the exclusion of patients without access to genetic testing further limits trial inclusivity. Improving biomarker research, trial transparency, and global accessibility are critical steps toward developing effective, scalable therapies for FTD.