C2 The biomarker challenge: what is it, and are we there yet?

27-11-2019

MNDA SYMPOSIUM PERTH DEC19 PRESENTATIONS

Session 1 Joint opening session

Martin Turner - Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Background: ALS is not one disease, but a clinical syndrome reflecting a pattern of neuronal network changes arising from a range of upstream molecular and cellular disturbances. The multi-step process in at least 10% of cases appears to be strongly influenced by one of several different single gene variants. For the majority however, there is a more complex mixture of genetic and environmental contributors.

Despite the uniquely catastrophic physical effects of ALS, quantifying the significant variation in disease activity among those affected has proved difficult. A lack of biomarkers has prevented ALS therapy development from emulating the model of trials that has been so successful in cancer. ALS studies rely instead on blunt outcome measures such as survival or the rate of decrease of a subjective disability score, which require 12–18-month studies to reliably determine the success or failure of a candidate drug.

A biochemical test or a scan sensitive to motor system activity or the downstream loss of neuromuscular integrity, might permit faster decisions on whether to continue with a particular drug or switch to a new candidate. Biomarkers reflecting an individual’s particular pattern of ALS development would allow more efficient trial group and analysis design. A specific biomarker might also enable earlier diagnosis in those with more slowly-progressive forms of ALS to increase their inclusion in trials.

A decade of global research focused on ALS biomarkers has yielded multiple candidates in blood, spinal fluid and urine; and from the application of advanced neuroimaging and neurophysiological tools. For the 10% of ALS cases linked to single gene variants a revolution in precision therapy strategies is already underway. This has broadened the scope of biomarker development to consider the pre-symptomatic period. Such focus might reveal novel ‘compensatory’ pathways to help understand the wider at-risk population for sporadic ALS, with the hope of delayed symptom onset and ultimately prevention.

There are likely to be more drug trials that do not deliver success for those living with ALS. However, the international research community’s recent commitment to the routine inclusion of emerging biomarkers in all trials will help to ensure the reasons for failure are better understood, so that the lessons learned ensure future success.

 

Source: Abstract Book symposium Perth

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