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Background <p>The GM2 gangliosidoses (GM2) are ultra-rare neurodegenerative disorders caused by deficient hexosaminidase A and/or B activity, leading to lysosomal GM2 ganglioside accumulation. Disease onset ranges from infancy to adulthood, with earlier onset associated with more rapid progression. Neurofilament light chain (NfL), a sensitive marker of axonal injury, has been extensively investigated as a biomarker for neurodegenerative disorders, including GM2.</p> Methods <p>To evaluate its clinical utility as a biomarker for GM2, NfL was measured in patients with GM2 enrolled in a Phase 2b, multinational, rater-blinded study of levacetylleucine [NCT03759665], and in its open-label Extension Phase (EP).</p> Results <p>Nineteen participants had viable samples for NfL analysis at baseline, after six weeks of treatment, and after a six-week washout; 10 had samples in the long-term EP. After the initial 6-week treatment phase, NfL concentration declined a mean − 8.9% (SD 13%; <i>p</i> &lt; 0.008), followed by a rebound of + 9.2% (SD 16.1%; <i>p</i> = 0.022) during the post-treatment 6-week washout. Changes in NfL correlated with the statistically significant and clinically meaningful changes captured on the primary Clinical Impression of Change in Severity (CI-CS), and secondary Scale for the Assessment and Rating of Ataxia (SARA) and Modified Disability Rating Scale (mDRS). In the EP, patients showed a mean NfL reduction of − 16.9% after 1&#xa0;year (SD 15.0; <i>p</i> = 0.010) and − 33.5% after 2&#xa0;years (SD 12.8; <i>p</i> &lt; 0.001) of levacetylleucine treatment.</p> Conclusions <p>These findings support NfL as a promising surrogate outcome candidate for GM2 and link biochemical improvement with functional benefit, which is reasonably likely to predict both disease activity and treatment response/clinical benefit.</p>

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Neurofilament light chain (NfL) as a surrogate outcome measure for GM2 gangliosidoses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月17日

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  • Kyriakos Martakis,
  • Nicolas J. Abreu,
  • Joshua J. Baker,
  • Peter R. Baker II,
  • Ian Billington,
  • T. Andrew Burrow,
  • Mallory Factor,
  • Taylor Fields,
  • Cassandra Fields,
  • Jennifer L. Gannon,
  • Megan Grosso,
  • Jorgji Kerthi,
  • Marc C. Patterson,
  • Brian J. Shayota,
  • Michael Strupp,
  • Lennard Strupp,
  • Tatiana Bremova-Ert

摘要

Background

The GM2 gangliosidoses (GM2) are ultra-rare neurodegenerative disorders caused by deficient hexosaminidase A and/or B activity, leading to lysosomal GM2 ganglioside accumulation. Disease onset ranges from infancy to adulthood, with earlier onset associated with more rapid progression. Neurofilament light chain (NfL), a sensitive marker of axonal injury, has been extensively investigated as a biomarker for neurodegenerative disorders, including GM2.

Methods

To evaluate its clinical utility as a biomarker for GM2, NfL was measured in patients with GM2 enrolled in a Phase 2b, multinational, rater-blinded study of levacetylleucine [NCT03759665], and in its open-label Extension Phase (EP).

Results

Nineteen participants had viable samples for NfL analysis at baseline, after six weeks of treatment, and after a six-week washout; 10 had samples in the long-term EP. After the initial 6-week treatment phase, NfL concentration declined a mean − 8.9% (SD 13%; p < 0.008), followed by a rebound of + 9.2% (SD 16.1%; p = 0.022) during the post-treatment 6-week washout. Changes in NfL correlated with the statistically significant and clinically meaningful changes captured on the primary Clinical Impression of Change in Severity (CI-CS), and secondary Scale for the Assessment and Rating of Ataxia (SARA) and Modified Disability Rating Scale (mDRS). In the EP, patients showed a mean NfL reduction of − 16.9% after 1 year (SD 15.0; p = 0.010) and − 33.5% after 2 years (SD 12.8; p < 0.001) of levacetylleucine treatment.

Conclusions

These findings support NfL as a promising surrogate outcome candidate for GM2 and link biochemical improvement with functional benefit, which is reasonably likely to predict both disease activity and treatment response/clinical benefit.