Biomarker Qualification for Neurofilament Light Chain in ALS: Theory and Practice

Biomarker Monitoring

• How are biomarkers used now, and what is still research?

  ✓Supports this

  “Markers measured in blood or spinal fluid that may reflect nerve-cell damage are being explored for tracking ALS/MND and are used in trials.”

  The marker is neurofilament light, released when nerve fibres are damaged. The paper says the evidence supports using it to predict how ALS will progress, to see whether a treatment is having a biological effect, and as a safety signal. It is measured in blood and in spinal fluid, which track each other closely, and is used in many current ALS trials.

  For ALS, the body of scientific evidence supports its use as a prognostic, response, and potential safety biomarker in the broad ALS population, as well as a risk/susceptibility biomarker at least among a subset of SOD1 pathogenic variant carriers.

  Introduction

• How are biomarkers used now, and what is still research?

  iAdds context

  “Biomarker tests offered privately, outside established medical or research settings, are worth treating with caution.”

  Does not discuss private test sellers, so it is not the basis for the warning. It does establish the two facts behind it: the best developed ALS biomarker can already be ordered as a commercial laboratory test, and the authors say plainly that it can be misused if what it can and cannot tell you is not understood.

  NfL is currently available commercially as an orderable laboratory test; and a nuanced understanding of the pros and cons of using NfL for different purposes, will help to minimize the potential for its misuse.

  How might this potentially impact on the practice of neurology?

• What are biomarkers, and how do they relate to ALS/MND?

  ✓Supports this

  “A biomarker gives researchers a measurable signal of whether a treatment is having an effect, which can let a trial show that in less time and in fewer people.”

  Says the clinical measures ALS trials rely on are insensitive early in drug development, and that the benefit of using a fall in neurofilament light as a response measure is showing a biological response over a shorter time and in a smaller number of patients.

• What are biomarkers, and how do they relate to ALS/MND?

  !Qualifies this

  “Most ALS/MND biomarkers are still being studied rather than used routinely in everyday care.”

  Agrees no ALS biomarker has been formally qualified by the US regulator, and notes only eight biomarkers of any kind ever have been, none of them for a neurological condition. But it also says one marker, neurofilament light, is already firm enough that a treatment approval was based partly on it, so for that one marker the answer's picture is more cautious than the field's.

  Though NfL has not yet been formally qualified for any of these contexts-of-use, the FDA has provided accelerated approval for an SOD1-lowering antisense oligonucleotide, based partially on the recognition that a reduction in NfL is reasonably likely to predict a clinical benefit.

  Results.