Objective: We investigated plasma NfL levels, as well as clinical measures, in Huntingtin (Htt)-mutation carriers 48 years of age and under, with a CAP score <500, compared to those with a CAP score ≥500, with the aim of identifying differences between these cohorts that may be relevant for clinical trial inclusion.

Background: The field of Huntington’s Disease (HD) research recently faced a setback with the halting of Roche’s GENERATION HD1 clinical trial. However, while the drug candidate tominersen was not deemed clinically effective overall, it was suggested that it might be more useful for a subset of trial participants ≤48 years of age with a CAG repeat-Age Product (CAP) score <500. In addition, we have recently shown that plasma neurofilament light (NfL) levels are associated with predicted years to manifest symptom onset in premanifest HD participants (PM) and proposed that participants with plasma levels <45.0 pg/ml would not be suitable for clinical trials [1, 2].

Method: This study included 116 (29 HD, 87 PM) Htt-mutation carriers recruited through the UCSD Huntington’s Disease Society of America CoE. Plasma NfL levels were measured in duplicate using a Meso Scale Discovery R-PLEX Assay.

Results: Ninety-eight participants had a CAP score <500 (88% PM), and 18 had a CAP score ≥500 (6% PM). Participants with CAP scores <500 had significantly lower median plasma NfL values, as well as Total Motor, Chorea (p<0.0001 for all) and Timed Up and Go scores (p<0.05), and significantly higher Symbol Digit Modalities test, Total Functional Capacity, Independence Scale, MoCA, MMSE, Stroop Word Reading and composite Unified Huntington’s Disease Rating Scale scores (p<0.0001 for all). The median plasma NfL value in participants with CAP scores <500 was 38.8 pg/ml (IQR: 20.4-57.2).

Conclusion: Our data suggests significant differences between participants ≤48 years of age with CAP scores below and above 500. While we have previously proposed that a plasma NfL cut-off value of <45.0 pg/ml may be useful in excluding participants who are too far from manifest onset to progress during the time frame of a clinical trial, thereby providing a lower limit for exclusion, these new findings provide an upper limit, by potentially excluding participants who may have progressed too far to benefit from therapeutic treatment.

References: 1. Parkin GM, Corey-Bloom J, Long JD, Snell C, Smith H, Thomas EA. Associations between prognostic index scores and plasma neurofilament light in Huntington’s disease. Parkinsonism Relat Disord. 2022.
2. Parkin GM, Corey-Bloom J, Snell C, Castleton J, Thomas EA. Plasma neurofilament light in Huntington’s disease: a marker for disease onset, but not symptom progression. Parkinsonism Relat Disord. 2021;87:32-8.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-biomarker-characteristics-of-huntingtons-disease-patients-recently-proposed-for-huntingtin-lowering-clinical-trial-inclusion/