When is a potential new neuroprotective treatment ready for translation?

Abstract

Now that therapeutic hypothermia for neonatal encephalopathy (NE) has successfully translated to routine care, the key challenge is to find adjunct therapies that can safely further improve outcomes. Selection is complicated by the curse of choice, as over 1000 different interventions are reported to show neuroprotection in various settings. In the present issue of Pediatric Research, Favié et al. report a two-phase trial to establish the pharmacokinetics and short-term safety of a potential adjuvant, an inhibitor of neuronal and inducible nitric oxide synthase (NOS), 2iminobiotin. The second phase was needed as the initial dose regime was an approximation derived from piglet studies undertaken during normothermia. Species differences, global hepatic and renal injury associated with NE, and of course therapeutic hypothermia itself, all can, and commonly do, substantially affect drug clearance. This is a nice example of one of the steps needed for clinical translation. The authors highlight that in the piglet study 2-iminobiotin was given for just 24 h, whereas in this dose finding study, they chose to give it for 48 h, based on limited animal data. There is no human evidence for the duration of upregulation of NOS in NE or for the optimal duration of therapy in animal studies. They conclude that human studies are now needed to establish the optimal duration of therapy. This is an important time to reflect on what strategy we should use to translate promising interventions and whether it is important to establish pharmacodynamics first. Some of the issues are highly specific for neonatal neuroprotection, while others are common across many areas of pediatric research.