Using a simulation study Benatar et al. [86] found that the sample size for an ALS trial would be reduced by 8.2% if adding baseline serum NfL measurements as covariates, whereas using serum NfL as a pharmacodynamic biomarker may allow significant sample size reduction compared to more traditional phase 2 studies in which changes in the ALSFRS-R are used as the primary endpoint. The gene discussed is NEFL; the disease is amyotrophic lateral sclerosis.