Therapeutics

AL001

Overview

Name: AL001
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 2)
Company: Alector

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 frontomporal 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 serves as a lysosomal trafficking receptor for progranulin, and sortilin-mediated progranulin endocytosis has been implicated in FTD pathophysiology (Hu et al., 2010). Heterozygous progranulin mutations reduce progranulin levels and are a leading cause of frontotemporal dementia by way of haplo-insuffiency.  

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 insuffuciency in preclincial models (Lee et al., 2013).

Findings

In September 2018, a first-in-man trial started enrolling 60 healthy adults and people with progranulin mutations causative for FTD at eight sites across North America and the U.K. Called INFRONT, the trial compares up to six single-ascending-doses of A001 infusion to placebo on outcomes safety, pharmacokinetics, and exposure, and is slated to run through 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.

In September 2019, recruitment began for a Phase 2 open-label multidose study in people with progranulin or C9ORF72 mutations causative of FTD. This trial will assess safety, tolerability, PK and pharmacodynamics in 32 participants receiving monthly infusions for up to one year. The study will take place at 11 sites in North America, Europe, and the U.K., and run until March, 2021 (see press release).

For all clinical trials of A001, see clinicaltrials.gov.

Last Updated: 28 Nov 2019

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References

Paper Citations

  1. . Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. 2010 Nov 18;68(4):654-67. PubMed.
  2. . The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
  3. . High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Apr 3; PubMed.
  4. . 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.
  5. . 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.
  6. . Sortilin and SorLA regulate neuronal sorting of trophic and dementia-linked proteins. Mol Neurobiol. 2012 Apr;45(2):379-87. PubMed.
  7. . 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.
  8. . 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. clinicaltrials.gov
  4. U.S. FDA

Further Reading