28 May 2024

Even before the first flicker of symptoms surface in a person who carries a pathogenic frontotemporal dementia mutation, signs of the disease can be found in their blood, in the form of neurofilament light (NfL). Shed from eroding axons, NfL rises in many neurodegenerative diseases, FTD among them. On May 16, the FDA encouraged scientists and stakeholders to seek qualification of the biomarker for use in FTD trials. Specifically, the agency accepted a letter of intent, submitted by the Foundation for the National Institutes of Health (FNIH) Biomarker Consortium, to apply for approval of the biomarker through the FDA’s Biomarker Qualification Program. While this qualification is not required to use the biomarker in clinical trials, it would standardize and speed up such use, particularly for the purpose of selecting mutation carriers who are on the cusp of having symptoms.

FTD mutation carriers and their families have long wished to participate in prevention trials, said Debra Niehoff of the Association for Frontotemporal Dementia. Trials of several treatments aimed at specific mutations, such as in progranulin, are underway, and Niehoff said that regulatory approval of plasma NfL to select participants who are close to disease onset would advance the process.  

The FNIH is a nonprofit organization that leads partnerships between the NIH, academic institutes, patient organizations, and private companies. Its Biomarker Consortium focuses on accelerating the development of disease biomarkers. In 2022, the group started a two-year project to investigate if plasma NfL assays reliably reflect the impending onset of clinical FTD symptoms among carriers of pathogenic mutations, and to persuade regulators to qualify the most sensitive tests. The $2.1 million project convened 19 organizations from government, academia, industry, nonprofits, and patient groups.

The letter of intent documents data of NfL’s rise in the blood in presymptomatic stages of familial FTD. The most powerful evidence came from international consortia that, for more than a decade, have been tracking how fluid and neuroimaging markers change relative to cognitive, behavioral, and other clinical manifestations of this constellation of disorders.

One is ALLFTD, the multicenter, U.S.-based study led by Adam Boxer and Howard Rosen at the University of California, San Francisco, and Bradley Boeve at the Mayo Clinic in Rochester, Minnesota.

Tracking participants with familial and sporadic forms of the disease (Mar 2021 conference news), ALLFTD recently found that NfL ticks up in the plasma of carriers of pathogenic mutations in GRN, C9ORF72, or MAPT before symptoms start (Gendron et al., 2022).

Another is GENFI, the Genetic Frontotemporal Dementia Initiative, which tracks hundreds of participants with familial FTD in Europe and Canada. GENFI has likewise reported a robust and consistent jump in plasma NfL among asymptomatic carriers (van der Ende et al., 2021; Wilke et al., 2022; Linnemann et al., 2024). Combining forces, ALLFTD and GENFI have reported plasma NfL’s rise in asymptomatic mutation carriers in both cohorts (Rojas et al., 2021).

The group cited Biogen’s ongoing ATLAS trial of tofersen, aka Qalsody, as an example of how plasma NfL could be used for selection in FTD prevention trials. Biogen recently received conditional approval for this SOD1-ALS treatment based largely on its knocking down plasma NfL (Apr 2023 news). Full approval hinges on outcomes in the ATLAS trial, which enrolls presymptomatic SOD1 mutation carriers with elevated plasma NfL. In ATLAS, potential enrollees get a blood test every month and as soon as NfL starts to rise, they are randomized into a treatment arm (Benatar et al., 2022).

For FTD trials, what's the next step? FNIH consortium representatives will meet with the FDA to hammer out what data regulators want to see to qualify plasma NfL for this use, Laura Mitic of the University of California, San Francisco, and the Bluefield Project to Cure FTD, told Alzforum. Then, scientists will complete ongoing analytical studies comparing commercially available assays. They include plasma NfL tests from Quanterix, ProteinSimple, Roche Diagnostics, and Siemens Healthineers, though the list can still change. Assays are being run on ALS and FTD patient samples at third-party facilities, Mitic said. The top one or two tests will be submitted to the FDA as part of the qualification plan, although any assay that is sufficiently precise can qualify. The FDA could request further prospective studies for clinical validation, Mitic said.

If the agency qualifies assays, it will only be for early detection of impending symptomatic FTD among GRN mutation carriers for enrollment in clinical trials. That is the context of use at hand here.

That said, scientists already have their sights set on qualifying NfL as an endpoint in Phase 3 clinical trials, as well, a lá tofersen. To understand how NfL fluctuates on the timescale of a clinical trial, the Bluefield Neurofilament Surveillance Program is measuring plasma NfL every three months for three years among more 335 familial FTD mutation carriers and noncarriers enrolled in ALLFTD. The program is fully enrolled and slated to finish in 2027. It should inform efforts to use NfL as an early detector of disease, as well as an endpoint in trials, Mitic said. “We can monitor this marker regularly, and the minute you see a consistent change, that’s the time to intervene,” she said.—Jessica Shugart

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References

News Citations

1. Merged Consortia Forge Path to Trials in Frontotemporal Dementia 13 Mar 2021
2. FDA Grants Accelerated Approval for Tofersen 26 Apr 2023

Therapeutics Citations

1. QALSODY™

Paper Citations

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4. Linnemann C, Wilke C, Mengel D, Zetterberg H, Heller C, Kuhle J, Bouzigues A, Russell LL, Foster PH, Ferry-Bolder E, Van Swieten JC, Jiskoot LC, Seelaar H, Moreno F, Borroni B, Sánchez-Valle R, Galimberti D, Laforce R Jr, Graff C, Masellis M, Tartaglia MC, Rowe JB, Finger E, Vandenberghe R, de Mendonca A, Butler CR, Gerhard A, Ducharme S, Ber IL, Tiraboschi P, Santana I, Pasquier F, Levin J, Otto M, Sorbi S, Rohrer JD, Synofzik M, GENFI. NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study. J Neurol Neurosurg Psychiatry. 2024 Feb 1; PubMed.
5. Rojas JC, Wang P, Staffaroni AM, Heller C, Cobigo Y, Wolf A, Goh SM, Ljubenkov PA, Heuer HW, Fong JC, Taylor JB, Veras E, Song L, Jeromin A, Hanlon D, Yu L, Khinikar A, Sivasankaran R, Kieloch A, Valentin MA, Karydas AM, Mitic LL, Pearlman R, Kornak J, Kramer JH, Miller BL, Kantarci K, Knopman DS, Graff-Radford N, Petrucelli L, Rademakers R, Irwin DJ, Grossman M, Ramos EM, Coppola G, Mendez MF, Bordelon Y, Dickerson BC, Ghoshal N, Huey ED, Mackenzie IR, Appleby BS, Domoto-Reilly K, Hsiung GR, Toga AW, Weintraub S, Kaufer DI, Kerwin D, Litvan I, Onyike CU, Pantelyat A, Roberson ED, Tartaglia MC, Foroud T, Chen W, Czerkowicz J, Graham DL, van Swieten JC, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Sorbi S, Cash DM, Convery RS, Bocchetta M, Foiani M, Greaves CV, Peakman G, Russell L, Swift I, Todd E, Rohrer JD, Boeve BF, Rosen HJ, Boxer AL, ALLFTD and GENFI consortia. Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration. Neurology. 2021 May 4;96(18):e2296-e2312. Epub 2021 Apr 7 PubMed.
6. Benatar M, Wuu J, Andersen PM, Bucelli RC, Andrews JA, Otto M, Farahany NA, Harrington EA, Chen W, Mitchell AA, Ferguson T, Chew S, Gedney L, Oakley S, Heo J, Chary S, Fanning L, Graham D, Sun P, Liu Y, Wong J, Fradette S. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. Epub 2022 May 18 PubMed.

External Citations

1. project

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