Journal of neurology · 2026
Neurofilament light chain (NfL) as a surrogate outcome measure for GM2 gangliosidoses.
Клиническое исследование II фазыСтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Martakis Kyriakos, Abreu Nicolas J, Baker Joshua J, Baker Ii Peter R, Billington Ian, Burrow T Andrew, Factor Mallory, Fields Taylor, Fields Cassandra, Gannon Jennifer L, Grosso Megan, Kerthi Jorgji, Patterson Marc C, Shayota Brian J, Strupp Michael, Strupp Lennard, Bremova-Ert Tatiana
Аннотация
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.
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.