Emerging fluid-based safety biomarkers for advanced modality therapeutic-related neurotoxicity in nonhuman primates

Abstract

There have been exciting advances in neurologic therapeutics, but their progression to clinical trials has been disappointing. Despite impressive efficacy demonstrated in preclinical studies, delayed onset of drug-related neurotoxicity has become a major obstacle for many of these novel therapeutic modalities. Neurotoxicity can be challenging to identify and neurobehavioral tests are only minimally sensitive and insufficient at detecting early neurodegeneration. Therefore, long (≥ 8-week) in vivo preclinical studies with histopathology evaluation are required, which are resource and time intensive. More efficient, sensitive and quantitative methods are needed to better identify the neurotoxic potential, both in dose level and time of onset, of drug candidates early in preclinical safety assessment. Fluid-based biomarkers have emerged as a potential tool for improving neurotoxicity detection across species. Here, we evaluated a subset of safety biomarkers for nervous system injury in preclinical toxicity studies in nonhuman primates administered a single intrathecal dose of an advanced modality therapeutic molecule with a 60 or 113 day observation period. We show dose-dependent and time-dependent increases in neurofilament light (NfL), total microtubule associated protein (tTau), and to a lesser extent ubiquitin carboxy-terminal hydrolase L1 (UCHL1) in the cerebrospinal fluid, but less compelling responses in plasma. Elevations in these biomarkers in the CSF above the receiver operator curve (ROC)-defined threshold of concern correlated with microscopic evidence of neuronal necrosis/loss, and preceded any clinical observations or abnormalities reported on neurofunctional tests. These results demonstrate that NfL and tTau are sensitive and specific safety biomarkers for advanced modality therapeutic-associated neurotoxicity in preclinical studies. Furthermore, these biomarkers have the potential to accelerate screening for drugs with neurologic indications and help create a therapeutic index for forward translation into the clinic.