Design considerations for C9orf72 disease prevention trials

Abstract

The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10%-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.

Keywords: amyotrophic lateral sclerosis (ALS); biomarker; frontotemporal dementia (FTD); phenoconversion; pre-symptomatic; regulatory considerations.

Figure 1

Design considerations for C9orf72 disease prevention trials. The principles discussed at the C9orf72 FTD/ALS prevention trial workshop held in Washington D.C., June 2024, although centred around C9orf72, are more broadly applicable and summarized schematically. The orange-shaded banner (right, bottom) conceptualizes the natural history of disease as evolving through a continuum from clinically silent to clinically manifest disease (e.g. ALS and/or FTD). This paper focuses on preventing the onset of clinical manifestations of disease (rather than the onset of biologically defined disease). Outcome measures may be time to an event (e.g. phenoconversion) or rate of disease progression, which might be quantified by disease progression models that incorporate biomarkers or clinical markers of disease burden. Filled circles in the blue shaded area (right, middle) indicate the time of enrollment in a prevention trial. Dotted, dashed and solid curves in the green shaded area (right, top) depict different timings and rates of change in potential measures (or composite measures) of disease burden. Biomarkers (e.g. thalamic volume on brain MRI, neurofilament light chain concentration in blood, characteristics of the C9orf72 repeat expansion, digital health technology-based measures) may also be used to inform eligibility criteria and thereby enrich for a trial population in whom a signal on the selected outcome measure(s) is most likely to be measurable. Importantly, broad engagement of stakeholders, including the pre-symptomatic carrier community, is essential to advancing the goals of C9orf72 disease prevention. ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia.