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.

Keywords: disease‐modifying therapy; frontotemporal dementia; latozinemab; loss‐of‐function GRN mutation; phase 1 clinical trial; progranulin; sortilin.

FIGURE 1

Participant disposition (enrolled population). ^* The safety population included all enrolled participants who received at least one dose of latozinemab. ^† The PK population included all participants in the safety population who had adequate assessments for determination of PK parameters. ^‡ The PD population included all participants in the safety population who had both a baseline and at least one postdose PD assessment. CSF, cerebrospinal fluid; PD, pharmacodynamics; PK, pharmacokinetics

FIGURE 2

Pharmacokinetics of multiple‐dose administration of latozinemab in participants with FTD‐GRN. Mean ± SD serum concentration of latozinemab versus time. Arrows indicate the timing of latozinemab infusions. n = 7–8 for all time points except Day 141 for which n = 3. Note that serum latozinemab concentrations were zero on Days 80 and 140. FTD‐GRN, frontotemporal dementia caused by loss‐of‐function GRN mutation; SD, standard deviation

FIGURE 3

Latozinemab decreases median sortilin expression in WBCs and increases PGRN levels in the plasma and CSF of participants with FTD‐GRN (PD population). A–B, Median percentage change from baseline in WBC sortilin (A) and plasma PGRN (B) plotted as a function of time. Arrows indicate the timing of latozinemab infusions. For WBC sortilin, n = 8 at all time points, except for the end of infusion and 4, 12, and 24 hours after the first dose (n = 1) and 7 days (n = 7), 56 days (n = 5), and 140 days (n = 3) after the third dose. For plasma PGRN, n = 8 at all time points, except for 4 hours after the second dose (n = 7) and 56 days (n = 4) and 140 days (n = 3) after the third dose. C, Mean ± SD CSF PGRN concentrations at baseline for HVs and FTD‐GRN participants and for FTD‐GRN participants on Day 57, which is 28 days after administration of three doses of 30 mg/kg latozinemab. For HVs, n = 33, and for FTD‐GRN participants, n = 7 at baseline and n = 8 post‐treatment. CSF, cerebrospinal fluid; FTD‐GRN, frontotemporal dementia caused by loss‐of‐function GRN mutation; HV, healthy volunteer; PD, pharmacodynamic; PGRN, progranulin; SD, standard deviation; WBC, white blood cell