Emerging neurology safety biomarkers for advanced modality therapeutic-associated neurotoxicity in nonhuman primates

There have been exciting advances in basic neuroscience research, yet the approval rate of novel therapeutics for neurodegenerative indications is low. In addition to poor efficacy, previously unidentified safety concerns in clinical trials are a major contributor to neurology drug attrition. Although there are regulatory-mandated safety assessments of the central nervous system in nonclinical studies, these are limited to neurofunctional tests, which are adequate for detecting overtly neurotoxic-mediated deficits, but more sensitive, specific, and quantitative methods are needed to advance the safety profiling of drug candidates early in nonclinical studies. Fluid-based biomarkers have emerged as a potential tool for improving neurotoxicity assessment, especially in life, across species. Here, we evaluated a subset of neurology biomarkers in a nonclinical toxicity study in nonhuman primates administered a single intrathecal dose of an advanced modality therapeutic molecule over an 8-week observation period. We show dose-dependent and time-dependent increases in total Tau, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1, and to a lesser extent neurofilament light (NfL) in the cerebrospinal fluid, but less compelling responses in plasma. Elevations in these biomarkers correlated with even minor microscopic evidence of neuronal necrosis, yet clinical observations were not identified on neurofunctional tests. These results demonstrate that Tau, UCH-L1, and NfL are sensitive, specific, and quantitative biomarkers of advanced modality therapeutic-associated neurotoxicity early in nonclinical studies. Furthermore, these biomarkers have the potential to improve drug candidate screening for neurologic indications and create a therapeutic index for forward translation into the clinic for these potentially life-altering drugs.