INFRONT-3 is a randomized, double-blind, placebo-controlled phase 3 clinical trial evaluating latozinemab in frontotemporal dementia caused by heterozygous GRN mutations (FTD-GRN).
Latozinemab is a human recombinant monoclonal IgG1 antibody that binds to human sortilin receptors on the cell surface, thereby blocking the binding of progranulin (PGRN) to sortilin and reducing sortilin receptors on the cell surface via internalization. As a consequence, these actions result in reducing the degradation of PGRN and increasing PGRN levels. Latozinemab, therefore, counteracts the PGRN deficiency due to mutations in the progranulin gene (GRN), which are causal for development of FTD.
Eligible symptomatic participants aged 25–85 were known carriers of a heterozygous loss-of-function GRN mutation, with a global CDR® plus NACC FTLD (CDR-FTLD) score of 0.5 to 2 and a CDR-FTLD sum of boxes (SB) score >0.5, with a diagnosis of possible or probable bvFTD or PPA. Intravenous latozinemab 60 mg/kg or placebo was administered once monthly. Efficacy, safety, and biomarkers were assessed. Co-primary endpoints were change from baseline in CDR-FTLD-SB and change in plasma PGRN concentration over 96 weeks.
The primary 96-week analysis included 102 symptomatic participants. Latozinemab treatment increased plasma PGRN by 165% compared to placebo at week 96 (p-value <0.0001), confirming target engagement. Latozinemab did not show evidence of slowing disease progression versus placebo on the CDR-FTLD–SB. Secondary and exploratory endpoints—including fluid biomarkers (neurofilament light chain and glial fibrillary acidic protein) and volumetric MRI—showed no treatment-related effects on slowing disease progression. No adverse safety signals were identified.
INFRONT-3 provides the first phase 3 efficacy and safety results for an investigational therapy in FTD-GRN. Sustained increase in plasma progranulin levels confirmed target engagement of latozinemab. However, no improvements were observed in clinical efficacy endpoints versus placebo, while no evidence of disease modification was found in the biomarker and imaging data.