Autosomal-dominant mutations underlie about 40 percent of frontotemporal dementia cases. This strong genetic component comes with a silver lining—it gives scientists a clear therapeutic target. At the Alzheimer’s Association International Conference, held July 26-30 online and in Denver, Robert Paul of Alector, South San Francisco, reported promising findings from a small open-label study testing AL001 in people with symptoms of FTD-GRN, a familial form of the disease caused by a mutation in the progranulin gene.

  • In a small, open-label Phase 2 trial, AL001 restored progranulin.
  • AL001 also normalized fluid biomarkers of lysosomal function and neuroinflammation.
  • Compared to historical controls, symptoms worsened more slowly, and the brain shrank less.

Paul reported that the anti-sortilin antibody restored flagging progranulin levels in the plasma and cerebrospinal fluid. Changes in other biomarkers suggested that the antibody corrected lysosomal dysfunction and soothed neuroinflammation. Over 12 months of treatment, symptoms worsened in trial participants at roughly half the rate seen in untreated volunteers in a large international cohort study, hinting at a clinical effect.

The findings offer hope that correcting progranulin deficiency halts the disease cascade, Paul said. Alector is putting AL001 to the test in an ongoing Phase 3 trial, called INFRONT3.

AL001’s target, sortilin-1, is a trafficking receptor that whisks progranulin and other proteins to the lysosome for disposal. Blocking the receptor boosts the half-life of progranulin, a protein whose concentration is more than halved in people with FTD-GRN. In the Phase 1 INFRONT study, Alector scientists found that AL001 boosted progranulin levels in the CSF of healthy volunteers and in people with FTD-GRN.

At AAIC, Paul reported 12-month findings from INFRONT-2, the open-label Phase 2 study. It treats three different cohorts: five asymptomatic GRN mutation carriers, 12 symptomatic carriers, and up to 20 symptomatic carriers of hexanucleotide expansions in the C9ORF72 gene. The latter group is still enrolling. All participants are receiving monthly infusions of 60 mg/kg AL001 for 96 weeks. The trial is small because FTD-GRN is rare, Paul said. Greater numbers of participants will be required to run the ongoing, placebo-controlled, Phase 3 trial. Only an estimated 15,000 people are known to be living with symptomatic FTD-GRN in the U.S. and Europe, the current reach of this study.

Paul presented findings from the 12 symptomatic FTD-GRN patients. First and foremost, he announced, AL001 completely rescued progranulin deficiency. Within two weeks of the first infusion, levels tripled in plasma, and remained stable out to 12 months. CSF measurements taken at baseline, six, and 12 months told a similar story, with progranulin more than doubling in response to treatment.

Dysfunctional lysosomes are a hallmark of FTD-GRN. At baseline, participants had elevated levels of two markers of lysosomal damage—cathepsin D and LAMP1—in their CSF relative to age-matched healthy controls. Both markers had dropped to control levels by six months and remained low at 12 months, Paul reported. This suggested that boosting progranulin levels had restored lysosomal function. CSF levels of the complement protein C1Q took a similar trajectory, suggesting that restoring progranulin deficiency also may have soothed damaging neuroinflammation. No other neuroinflammation markers were presented.

Did these corrections protect neurons from dying? To address this, the researchers measured fluid neurofilament light (NfL), a marker of axonal damage known to rise as FTD worsens. Here, Paul found that on average, both plasma and CSF NfL held steady throughout the trial. However, he noted that the concentration of NfL was extremely variable, both between people and within the same person from time point to time point. While there is no biological explanation yet for this variability, Paul considers the findings promising in that NfL did not appear to rise throughout the trial.

Because INFRONT-2 is an open-label study, no solid conclusions about effects on disease progression can be drawn. To attempt to put the findings in context, the researchers took advantage of data from GENFI-2, an international cohort study that tracks fluid and imaging biomarkers and clinical disease progression in people with different genetic forms of FTD (Mar 2021 conference news). Paul “randomized” 10 controls from GENFI who were matched to trial participants for age, sex, plasma NfL, and baseline scores on the CDR plus NACC-FTLD, a composite measure tailored to track FTD symptoms.

In collaboration with Howard Rosen, University of California, San Francisco, Alector scientists compared brain atrophy in AL001 trial participants and GENFI controls. As gauged by whole-brain atrophy, frontotemporal-cortical atrophy, or enlargement of the ventricles, all 22 people examined lost brain tissue over a 12-month period. That said, the people receiving AL001 lost less than did the GENFI “controls,” and the effect was most pronounced in ventricles, which expanded by half as much in AL001-treated patients as in “controls.” By contrast, some anti-amyloid treatments tested for Alzheimer’s disease, including BACE inhibitors and immunotherapies, seem to accelerate brain shrinkage (Mintun et al., 2021; Dec 2019 news). 

Finally, Paul compared worsening of symptoms on the CDR plus NACC FTLD-SB. Those receiving AL001 declined 3 points, or 47 percent, less than GENFI controls over one year. Had this occurred in the context of a placebo-controlled RCT, this difference would have amounted to a clinically meaningful result, Paul claimed.

Putting the Brakes on FTD? Compared to historical controls from GENFI, trial participants receiving AL001 worsened 47 percent less on the CDR plus NACC FTLD-SB over one year. [Courtesy of Robert Paul, Alector.]

To that end, last July Alector started a Phase 3 study, called INFRONT-3. This global placebo-controlled, randomized study will test AL001 in 180 people with GRN mutations who either have symptoms or have elevated levels of plasma NfL, suggesting they are on the cusp of symptomatic disease. The trial will run for 24 months.—Jessica Shugart


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Therapeutics Citations

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News Citations

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  2. Picking Through the Rubble, Field Tries to Salvage BACE Inhibitors

Paper Citations

  1. . Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021 May 6;384(18):1691-1704. Epub 2021 Mar 13 PubMed.

External Citations

  1. INFRONT-3

Further Reading