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

Findings

In September 2018, a first-in-man 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 trial compares up to six single-ascending-doses of A001 infusion to placebo on outcomes including 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.

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.

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 will assess safety, tolerability, PK, and pharmacodynamics in 40 participants receiving 60 mg/kg monthly infusions for nearly two years. The study runs at 10 sites in North America, Europe, and the U.K., until November 2021. According to the 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 have 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. The trial will run through November 2021.

In July 2020, Alector started a Phase 3, placebo-controlled trial. Called INFRONT-3, it will enroll 180 people between 18 and 85 who are at risk of or have frontotemporal dementia due to heterozygous mutations in the progranulin gene. Participants will receive a monthly IV infusion of AL001 60 mg/kg or placebo for up to 18 months. 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 47 sites in North America, Australia, and Europe, and will run through 2023.

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

Last Updated: 01 Sep 2020

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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

Further Reading