Biologic · latozinemab

Latozinemab

DiscontinuedAlector Inc. (ALEC)
  • FDA Orphan Drug (Frontotemporal Dementia; June 2018)
  • FDA Breakthrough Therapy (FTD-GRN; February 2024)

Recombinant human anti-sortilin (SORT1) monoclonal antibody developed by Alector, in collaboration with GSK from July 2021, for frontotemporal dementia caused by progranulin (GRN) gene mutations. By blocking sortilin-mediated endocytosis and degradation of progranulin, latozinemab elevates circulating and CSF progranulin concentrations — the therapeutic hypothesis being that restoring progranulin to normal levels slows FTD-GRN progression. Phase 1 showed dose-dependent progranulin increases including a doubling of CSF progranulin; Phase 2 (INFRONT-2) showed maintained normal progranulin levels and stabilized neurofilament light chain. The pivotal Phase 3 INFRONT-3 trial (96 weeks, monthly 60 mg/kg IV infusions) met its biomarker co-primary endpoint (plasma progranulin elevation) but failed the clinical co-primary endpoint (CDR plus NACC FTLD-SB) with limited effects on fluid biomarkers and volumetric MRI; Alector announced topline results on 2025-10-21 and discontinued the open-label extension and planned continuation study, ending latozinemab development. A Phase 2 in C9orf72-associated ALS was terminated in 2022 after enrolling 5 of 45 planned participants (this record).

Also known as: latozinemab, AL001, AL-001, GSK4527223, 2376132-27-1

Data current as of

Key facts

Modality
Biologic
Chemical class
monoclonal antibody
Mechanism
Sortilin antagonist
Highest phase
Discontinued
Lead indication
Frontotemporal dementia
Developer
Alector Inc. (ALEC)
Designations
FDA Orphan Drug (Frontotemporal Dementia; June 2018), FDA Breakthrough Therapy (FTD-GRN; February 2024)
Trials
4 tracked · 67 sites

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.

TargetActionAffinity
SortilinprimarySORT1Antagonist—ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
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.
IntravenousOnce monthly—

Development timeline#

2020202220242026TodayDiscontinued21 Oct 2025 — readout (missed) — 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.28 Oct 2022 — phase change — The Phase 2 ALS study was terminated after enrolling 5 participants. Registry whyStopped: 'The Sponsor is considering a subsequent study in ALS, potentially with different inclusion/exclusion criteria.' No subsequent ALS study was ever registered, and all latozinemab development ended 2025-10-21 after the FTD Phase 3 failure — so this termination date stands as the program's end.28 Oct 2022 — Trial terminated — Alector terminates the latozinemab Phase 2 in C9orf72-associated ALS after enrolling 5 of 45 planned participants1 Jun 2018 — Orphan Drug — FDA grants Orphan Drug designation to latozinemab for frontotemporal dementiaPhase 114 Sept 2018 — phase change — 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.Phase 22 Sept 2021 — phase change — Phase 2 study of latozinemab in C9orf72-associated ALS (AL001-ALS-201, NCT05053035) started, targeting 45 participants — the first expansion of the progranulin-elevation hypothesis beyond FTD, two months after the GSK collaboration was announced.27 Sept 2019 — phase change — 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.Phase 31 Feb 2024 — Breakthrough Therapy — FDA grants Breakthrough Therapy designation to latozinemab for FTD-GRN1 Jul 2021 — Licensing deal — GSK partners with Alector on latozinemab and AL101 ($700M upfront)23 Jul 2020 — phase change — 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.
Phase change Readout Event UpcomingHover a marker for details.
DiscontinuedJun 2018 – Oct 2025
  1. 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.Frontotemporal dementia↗
  2. The Phase 2 ALS study was terminated after enrolling 5 participants. Registry whyStopped: 'The Sponsor is considering a subsequent study in ALS, potentially with different inclusion/exclusion criteria.' No subsequent ALS study was ever registered, and all latozinemab development ended 2025-10-21 after the FTD Phase 3 failure — so this termination date stands as the program's end.Amyotrophic lateral sclerosis
  3. Trial terminatedAlector terminates the latozinemab Phase 2 in C9orf72-associated ALS after enrolling 5 of 45 planned participantsAmyotrophic lateral sclerosis
  4. Orphan DrugFDA grants Orphan Drug designation to latozinemab for frontotemporal dementiaFrontotemporal dementia↗
Phase 3Jul 2020 – Feb 2024
  1. Breakthrough TherapyFDA grants Breakthrough Therapy designation to latozinemab for FTD-GRNFrontotemporal dementia↗
  2. Licensing dealGSK partners with Alector on latozinemab and AL101 ($700M upfront)↗
  3. 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.Frontotemporal dementia
Phase 2Sept 2019 – Sept 2021
  1. Phase 2 study of latozinemab in C9orf72-associated ALS (AL001-ALS-201, NCT05053035) started, targeting 45 participants — the first expansion of the progranulin-elevation hypothesis beyond FTD, two months after the GSK collaboration was announced.Amyotrophic lateral sclerosis
  2. 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.Frontotemporal dementia
Phase 1Sept 2018
  1. 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.Frontotemporal dementia

Latozinemab for Frontotemporal dementia#

DiscontinuedDiscontinuedFrontotemporal dementia indication →

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.

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. ↗

Latozinemab for Amyotrophic lateral sclerosis#

DiscontinuedDiscontinuedAmyotrophic lateral sclerosis indication →

Alector's Phase 2 program of latozinemab (AL001), an anti-sortilin progranulin-elevating monoclonal antibody, in C9orf72-associated amyotrophic lateral sclerosis — terminated October 2022 after enrolling only 5 of 45 planned participants. The registry whyStopped states the sponsor was considering a subsequent ALS study with potentially different inclusion/exclusion criteria, but no follow-up ALS study was ever registered. ALS was part of the July 2021 GSK collaboration scope; after the FTD Phase 3 INFRONT-3 failure (announced 2025-10-21), Alector ended latozinemab development entirely, foreclosing any ALS revival. No ALS efficacy data was reported.

Clinical trials#

NCT05053035AL001-ALS-201Phase 2Discontinuedn=5

A Phase 2 Study to Evaluate AL001 in C9orf72-Associated ALS

Started Sept 2021· Primary completion Oct 2022· 3 sites across 1 country

United States

NCT04374136AL001-3Phase 3Discontinuedn=119

A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3)

Started Jul 2020· Primary completion Sept 2025· 44 sites across 16 countries

United StatesItalyPortugalFrance

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)

Started Sept 2019· Primary completion Jun 2024· 12 sites across 6 countries

United StatesCanadaGermanyNetherlands

NCT03636204AL001-1Phase 1Completedn=64

A First in Human Study in Healthy Volunteers and in Participants With Frontotemporal Dementia (INFRONT)

Started Sept 2018· Primary completion Dec 2019· 8 sites across 3 countries

United StatesCanadaUnited Kingdom

Sources#

  1. Alector topline announcement (2025-10-21) — end of latozinemab development, foreclosing ALS revival — Alector Inc. via GlobeNewswire
  2. Latozinemab — Alzforum Therapeutics database profile (mechanism, GSK collaboration, ALS trial history, program discontinuation) — Alzforum (FBRI LLC)
  3. 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)
  4. 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)
  5. 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)
  6. NCT05053035 (AL001-ALS-201) — Phase 2 of AL001 in C9orf72-associated ALS; TERMINATED 2022-10-28 with 5 enrolled, whyStopped: sponsor considering a subsequent study with different inclusion/exclusion criteria — ClinicalTrials.gov (U.S. National Library of Medicine)