Phase 1 study of latozinemab in progranulin‐associated frontotemporal dementia

Abstract

INTRODUCTION

Heterozygous mutations in the
GRN
gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss‐of‐function
GRN
mutations.



METHODS

A first‐in‐human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple‐dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss‐of‐function
GRN
mutation (FTD‐
GRN
).



RESULTS

Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple‐dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD‐
GRN
to levels that approximated those seen in healthy volunteers.



DISCUSSION

Data from the first‐in‐human phase 1 study support further development of latozinemab for the treatment of FTD‐
GRN
.



Highlights




GRN
mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD).



Latozinemab is being developed as a PGRN‐elevating therapy.


Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial.



Latozinemab increased PGRN levels in the CNS of symptomatic FTD‐
GRN
participants.