latozinemab · program
Latozinemab for Frontotemporal dementia
- FDA Orphan Drug (Frontotemporal Dementia; June 2018)
- FDA Breakthrough Therapy (FTD-GRN; February 2024)
Indications for latozinemab: Frontotemporal dementia · Discontinued Amyotrophic lateral sclerosis · Discontinued
Alector's latozinemab (AL001/GSK4527223), a first-in-class anti-sortilin monoclonal antibody, for frontotemporal dementia due to progranulin (GRN) mutations — discontinued October 2025 after the pivotal Phase 3 failed. The program ran the full INFRONT series: INFRONT-1 (Phase 1, 2018–2019, 64 healthy volunteers and GRN carriers; dose-dependent progranulin elevation including doubling of CSF progranulin), INFRONT-2 (Phase 2 open-label, 2019–2024, 33 GRN/C9orf72 carriers on 60 mg/kg monthly; normalized progranulin and stabilized neurofilament light chain), and INFRONT-3 (Phase 3, 2020–2025, 119 enrolled including 101 symptomatic FTD-GRN patients, 96-week double-blind vs placebo). On 2025-10-21 Alector announced INFRONT-3 met its biomarker co-primary endpoint (plasma progranulin) but did not meet the clinical co-primary endpoint of slowing FTD-GRN progression on CDR plus NACC FTLD-SB, with limited benefit on fluid biomarkers and vMRI; the open-label extension and the planned continuation study were discontinued. Developed in collaboration with GSK (July 2021 deal, $700M upfront, covering latozinemab and AL101). FDA Orphan Drug (June 2018) and Breakthrough Therapy (February 2024) designations had been granted.
Development timeline
- missedPhase 3 INFRONT-3 failed: latozinemab significantly raised plasma progranulin (biomarker co-primary met) but did not slow FTD-GRN clinical progression on CDR plus NACC FTLD-SB (clinical co-primary missed); open-label extension and continuation study discontinued.↗
- INFRONT-3 (NCT04374136) pivotal Phase 3 started: randomized, double-blind, placebo-controlled, 96-week study of latozinemab 60 mg/kg IV every 4 weeks in FTD-GRN; 119 enrolled (101 symptomatic patients in the primary analysis population). Co-primary endpoints: plasma progranulin concentration and CDR plus NACC FTLD-SB.
- INFRONT-2 (NCT03987295) open-label Phase 2 started: 33 participants with GRN or C9orf72 mutations, latozinemab 60 mg/kg IV every 4 weeks. Twelve-month data (July 2021) showed maintained normal progranulin levels, normalization of disease-associated fluid biomarkers, and stabilized neurofilament light chain with potential clinical benefit — the basis for the 2024 Breakthrough Therapy designation.
- INFRONT-1 (NCT03636204) first-in-human study started: single and multiple ascending IV doses in 64 healthy volunteers and asymptomatic/symptomatic GRN mutation carriers. July 2019 results: generally safe and well tolerated, dose-dependent progranulin increases in plasma and CSF including a doubling of CSF progranulin concentration.
Readouts
- 2025-10-21ReportedTopline datamissedNCT04374136
Phase 3 INFRONT-3 failed: latozinemab significantly raised plasma progranulin (biomarker co-primary met) but did not slow FTD-GRN clinical progression on CDR plus NACC FTLD-SB (clinical co-primary missed); open-label extension and continuation study discontinued. ↗
Clinical trials in Frontotemporal dementia
NCT04374136AL001-3Phase 3Discontinuedn=119
A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3)
mixedprimaryCo-primary: change in CDR plus NACC FTLD-SB (clinical) and plasma progranulin concentration (biomarker) over 96 weeks vs placebo
The biomarker co-primary endpoint was met — latozinemab produced a statistically significant increase in plasma progranulin — but the clinical co-primary endpoint of slowing FTD-GRN progression on CDR plus NACC FTLD-SB was not met, and secondary/exploratory endpoints (fluid biomarkers, volumetric MRI) showed limited benefit. Numeric effect sizes and p-values were not disclosed in the topline announcement. Recorded 'mixed' for endpoint fidelity (one co-primary met, one missed); the program consequence was an outright failure and discontinuation.
NCT03987295AL001-2Phase 2Completedn=33
A Phase 2 Study to Evaluate Safety of Long-term AL001 Dosing in Frontotemporal Dementia (FTD) Patients (INFRONT-2)
NCT03636204AL001-1Phase 1Completedn=64
A First in Human Study in Healthy Volunteers and in Participants With Frontotemporal Dementia (INFRONT)
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Latozinemab IV infusion (60 mg/kg every 4 weeks) 60 mg/kg by intravenous infusion every four weeks in INFRONT-2 (open-label Phase 2, dosed for nearly two years) and INFRONT-3 (Phase 3, 96 weeks). Phase 1 (INFRONT-1) used single and multiple ascending IV doses in healthy volunteers and GRN mutation carriers. | Intravenous | Once monthly | — |
Mechanism of action
Human monoclonal antibody against sortilin (SORT1), a Vps10p-domain receptor that binds progranulin and mediates its endocytosis and lysosomal degradation. Latozinemab binds sortilin with high affinity, blocks the progranulin–sortilin interaction and reduces cell-surface sortilin levels, thereby increasing extracellular progranulin concentrations. The ALS rationale rested on progranulin's neurotrophic and TDP-43-pathology-modifying role in C9orf72-associated disease; the program ended before generating efficacy data.
| Target | Action | Affinity |
|---|---|---|
| SortilinprimarySORT1 | Antagonist | —ⓘ |
← Full latozinemab compound page (identity, identifiers, all indications)
Sources
- Alector topline announcement (2025-10-21) — end of latozinemab development, foreclosing ALS revival — Alector Inc. via GlobeNewswire
- Latozinemab — Alzforum Therapeutics database profile (mechanism, GSK collaboration, ALS trial history, program discontinuation) — Alzforum (FBRI LLC)
- NCT03636204 (AL001-1, INFRONT) — Phase 1 first-in-human, healthy volunteers and FTD participants; completed 2019-12-31 — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT03987295 (AL001-2, INFRONT-2) — Phase 2 open-label long-term dosing in FTD; completed 2024-06-05 — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT04374136 (AL001-3, INFRONT-3) — Phase 3 in FTD-GRN; TERMINATED, whyStopped: did not meet the clinical co-primary endpoint (CDR plus NACC FTLD-SB) — ClinicalTrials.gov (U.S. National Library of Medicine)