Therapeutics

Latozinemab

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Overview

Name: Latozinemab
Synonyms: AL001, GSK4527223
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Frontotemporal Dementia (Phase 3), Amyotrophic Lateral Sclerosis (Inactive)
Company: Alector, GlaxoSmithKline (GSK)

Background

AL001 is a recombinant human anti-human sortilin (SORT1) monoclonal IgG1 developed by Alector in partnership with Abbvie. In June 2018, this antibody received orphan drug designation from the U.S. FDA for the treatment of frontotemporal dementia.

Sortilin is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family. Sortilin is abundantly expressed in the central nervous system. As a sorting receptor in the trans-Golgi network, sortilin is involved in neurotrophin signaling, lysosomal degradation, and APP metabolism. Sortilin regulates the endocytosis and degradation of progranulin, and this process has been implicated in FTD pathophysiology (Hu et al., 2010). Progranulin mutations are a leading cause of frontotemporal dementia, and are associated with 50 to 70 percent reduction in progranulin protein levels. Blocking sortilin with AL001 is a strategy to increase progranulin levels. 

The SORL1 gene is one of the strongest genetic risk factors for Alzheimer's disease, and is associated with frontotemporal dementia, as well (Rogaeva et al., 2007Pottier et al., 2012Holstege et al., 2017Raghavan et al., 2018Pallesen and Vægter et al., 2012Philtjens et al., 2018).

Targeting the sortilin-progranulin axis was reported to improve outcomes associated with progranulin insufficiency in preclinical models (Lee et al., 2013).

In cell assays, latozinemab blocked the interaction of sortilin with progranulin, reduced sortilin protein levels, and increased progranulin. In a mouse model of FTD-PGN, a rodent cross-reactive form of AL001 decreased sortilin levels in white blood cells, restored plasma proganulin to normal levels, and rescued a social behavior deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in blood cells, and increased plasma and CSF progranulin by two to three times (Kurnellas et al., 2023).

Findings

In September 2018, a first-in-human trial started enrolling 64 healthy adults and people with progranulin mutations causative for FTD at eight sites across North America and the U.K. Called INFRONT, the plan was to compare up to six single-ascending doses of AL001 intravenous infusion to placebo on outcomes including safety, pharmacokinetics, and exposure. The trial was completed in December 2019. At AAIC in July 2019, Alector reported results from 50 healthy volunteers and four FTD-GRN patients. According to the abstract and press release, AL001 infusion was “generally safe and well tolerated,” and resulted in a dose-dependent increase in progranulin levels in plasma and CSF in healthy adults and FTD patients. The press release notes a doubling of progranulin concentration in CSF of asymptomatic and symptomatic patients, restoring progranulin levels to the normal range. The results were published after peer review (Kurnellas et al., 2023).

Details of the complete cohort of 14 FTD-GRN mutation carriers were presented at AAIC July 2020. In six asymptomatic FTD-GRN mutation carriers, CSF progranulin levels were restored to normal 12 days after a single dose of 60 mg/kg. Among eight symptomatic patients, three doses of 30 mg/kg over four weeks raised progranulin into the normal range for at least eight weeks after the last dose. CSF markers of lysosomal function, inflammation, and gliosis were partially normalized. A non-significant 14 percent reduction in plasma neurofilament light chain (NfL) was observed eight weeks after dosing. Data on safety and progranulin elevation in symptomatic patients were subsequently published (Ward et al., 2024). Adverse events were mild to moderate. Some participants had elevated cholesterol or triglyceride levels. No patients dropped out due to side effects, and there were no deaths in the study.

In September 2019, recruitment began for INFRONT-2, an open-label, multi-dose Phase 2 study in people with progranulin or C9ORF72 mutations causative of FTD. This trial is assessing safety, tolerability, PK, and pharmacodynamics in 40 participants receiving 60 mg/kg monthly infusions for nearly two years. The study is running at 12 sites in North America, Europe, and the U.K. It was slated to end in 2021, but the date has been pushed back to early 2026. According to an AAIC 2020 presentation, by May 2020 the trial had enrolled 15 patients, including some rollovers from the Phase 1 study. The longest-treated patient had received six months of drug, which remained safe and well-tolerated. CSF progranulin reached normal levels within 10 days after the first dose in all participants, and stayed elevated with continued treatment. Due to the COVID-19 pandemic, two patients missed a dose, and some missed biomarker evaluations. A preliminary analysis based on this incomplete data indicated that plasma NfL declined in six of eight participants who received all scheduled infusions. In one patient, plasma NfL decreased during the Phase 1 trial, rebounded off drug, and decreased again when treatment recommenced in Phase 2.

At the July 2021 AAIC, Alector presented 12-month data from 12 symptomatic FTD-GRN patients in INFRONT-2. Participants maintained normal plasma and CSF progranulin levels, with no new safety issues. The company also reported normalization of lysosomal and inflammatory biomarkers, and stabilization of NfL in this group. A comparison with historical controls showed potential for slowing decline on exploratory clinical endpoints of brain atrophy and dementia (Aug 2021 conference news). A cohort of 10 symptomatic FTD-CORF72 patients posted similar results, according to a company presentation at the March 2022 AD/PD conference (press release).

In July 2020, Alector started a Phase 3, placebo-controlled trial. Called INFRONT-3, it with the aim of enrolling 180 people between 25 and 85 who are at risk of or have frontotemporal dementia due to heterozygous mutations in the progranulin gene. Participants are receiving a monthly intravenous infusion of AL001 60 mg/kg or placebo in a blinded fashion, or open-label AL001, for up to two years. The primary outcome is change in a combination of the Clinical Dementia Rating plus the NACC FTLD-Sum of Boxes, a measure adapted for frontotemporal dementia patients. Secondary clinical outcomes include standard measures of disease severity or improvement. The study will evaluate volumetric MRI, as well as CSF and blood pharmacodynamic biomarkers. It is taking place at 65 sites in North America, Australia, and Europe, and will run through 2025. In October 2023, the trial was declared fully enrolled at 101 symptomatic patients; an open-label continuation study of once-monthly 60 mg/kg latonizemab is recruiting (press release).

In July 2021, the company announced an agreement with GlaxoSmithKline to co-develop AL001 for FTD and ALS (press release). In September 2021, the first patient was enrolled in Phase 2 for ALS due to C9ORF72 mutations. The study planned to randomize 45 participants to six monthly infusions of AL001 or placebo, added to their current treatment. The primary endpoints were to be safety, tolerability, pharmacokinetics and pharmacodynamics, including plasma and CSF progranulin levels, with blood and CSF neurofilament light chain concentration as a secondary outcome. The study was terminated in October 2022, after enrolling 5 patients. The reason given was that Alector is considering a different study in ALS. The ALS program no longer appears in the company pipeline.

In February 2024, the FDA granted latozinemab breakthrough therapy designation, based on Phase 2 results (press release).

Alector has a related sortilin antibody, AL101, in Phase 2 for Alzheimer’s disease.

For all clinical trials of AL001, see clinicaltrials.gov.

Last Updated: 10 Jul 2024

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References

News Citations

  1. AL001 Boosts Progranulin. Does it Slow Frontotemporal Dementia?

Therapeutics Citations

  1. AL101

Paper Citations

  1. . Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia. J Transl Med. 2023 Jun 15;21(1):387. PubMed.
  2. . Phase 1 study of latozinemab in progranulin-associated frontotemporal dementia. Alzheimers Dement (N Y). 2024;10(1):e12452. Epub 2024 Jan 31 PubMed.
  3. . Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. 2010 Nov 18;68(4):654-67. PubMed.
  4. . The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
  5. . High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Apr 3; PubMed.
  6. . Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.
  7. . Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol. 2018 Jul;5(7):832-842. Epub 2018 May 24 PubMed.
  8. . Sortilin and SorLA regulate neuronal sorting of trophic and dementia-linked proteins. Mol Neurobiol. 2012 Apr;45(2):379-87. PubMed.
  9. . Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia. Neurobiol Aging. 2018 Jun;66:181.e3-181.e10. Epub 2018 Feb 17 PubMed.
  10. . Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. Hum Mol Genet. 2013 Nov 7; PubMed.

External Citations

  1. abstract
  2. press release
  3. press release
  4. press release
  5. press release
  6. company pipeline
  7. press release
  8. clinicaltrials.gov

Further Reading

Papers

  1. . Sortilin regulates blood-brain barrier integrity. FEBS J. 2022 Feb;289(4):1062-1079. Epub 2021 Oct 20 PubMed.
  2. . Involvement of progranulin (PGRN) in the pathogenesis and prognosis of breast cancer. Cytokine. 2022 Mar;151:155803. Epub 2022 Jan 20 PubMed.
  3. . Analysis of the SORT1 gene in familial amyotrophic lateral sclerosis. Neurobiol Aging. 2012 Aug;33(8):1845.e7-9. Epub 2012 Feb 22 PubMed.
  4. . Progranulin and TDP-43: mechanistic links and future directions. J Mol Neurosci. 2011 Nov;45(3):561-73. PubMed.
  5. . Sortilin-related receptor CNS expressed 2 (SorCS2) is localized to Bunina bodies in amyotrophic lateral sclerosis. Neurosci Lett. 2015 Nov 3;608:6-11. Epub 2015 Sep 28 PubMed.
  6. . TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor. Hum Mol Genet. 2016 Feb 1;25(3):534-45. Epub 2015 Nov 27 PubMed.
  7. . Progranulin as a therapeutic target in neurodegenerative diseases. Trends Pharmacol Sci. 2022 Aug;43(8):641-652. Epub 2022 Jan 15 PubMed.