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Randomized controlled clinical trials designed and conducted by Dr. Christine Sang and her group typically incorporate strategies to understand mechanisms of action and infer effects on relevant targets. Phenotypic screening and the development of clinical outcome assessments and potential biomarkers are approaches that are incorporated in their trials; these are particularly important in heterogeneous chronic painful conditions such as central neuropathic pain (CNP) following spinal cord injury (SCI). For example, Dr. Sang and her team reported the results of a First-in-Human Phase 1a clinical trial in CNP following lower thoracic SCI in which the neurotensin A analogue CGX-1160 was well tolerated when administered intrathecally at doses up to 1000 μg/h; phenotypic profiling allowed them to detect improvements from baseline across specific types of pain, and overall pain intensity was reduced by 63% at the highest dose administered without side effects. Moreover, the peak analgesic effect occurred after the peak intrathecal concentration, indicating the presence of an effect site compartment to the pharmacokinetic model to represent the concentration and effect profiles for this unique compound. The use of target validation, another design strategy commonly incorporated in their trial designs, is particularly useful in interpreting negative data. In a Phase 2a clinical trial in CNP following SCI, the inhibition of fatty acid amide hydrolase (FAAH), responsible for metabolizing endocannabinoids (including anandamide, an endogenous ligand for cannabinoid type 1/type 2 receptors), did not significantly reduce pain intensity or other associated functional endpoints, despite expected increases in endocannabinoid concentrations. The inability to show an analgesic effect despite achieving the FAAH inhibition plateau supports the hypothesis that reduced endocannabinoid levels at or near the epicenter of the SCI may contribute to the refractory nature of CNP, as demonstrated in rodent SCI models (Hama et al., 2014).

Christine Sang, MD, MPH

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