Does exenatide in conjunction with therapeutic hypothermia reduce cerebral palsy in neonatal hypoxic-ischemic encephalopathy?

Hypoxic-ischemic encephalopathy (HIE) occurs when a baby experiences reduced blood flow and oxygen delivery to the brain near the time of birth. When the amount of blood and oxygen supplied to the brain is reduced, the baby may sometimes sustain injury to the brain. Not all newborn babies exposed to this condition suffer brain injury. However, if brain injury occurs, there is high risk for death or neurologic disabilities including cerebral palsy, learning difficulties, epilepsy, and visual impairment. HIE is a global problem resulting in 400,000 babies with devastating neurodevelopmental impairment every year accounting for 2.4% of the total Global Burden of Disease.
This Group have previously successfully developed therapeutic hypothermia (cooling) as treatment for HIE. Cooling the baby's body temperature for 3 days reduces the risk of brain injury after HIE. However, cooling therapy only helps about 1 in 7 infants with HIE. Therefore, additional treatments are needed to further improve brain function and brain recovery after HIE. Furthermore, it has been shown in clinical trials that cooling is not effective in low- and middle-income countries.
We now propose that exenatide will reduce the incidence of cerebral palsy in babies born with HIE when combined with cooling treatment. Exenatide is a licensed anti-diabetic medicine which is now available as a generic drug. It is known to act on receptors present in the brain to protect it from further injury. In Parkinson's disease, results from animal studies and early human studies were encouraging leading to a large phase III clinical trial that is currently ongoing.
We have investigated the potential brain protective effects of exenatide using rodent models of neonatal HIE. We know that if exenatide is administered as four injections 12-hours apart, in rodents who have experienced reduced blood flow and oxygen delivery to the brain, there is a significant reduction in brain injury. We also know that we can wait up to 6-hours after injury before starting treatment which is helpful for babies who need to travel to another hospital to receive treatment. In this proposal, we want to repeat the experiments in a higher animal model (piglets). We will first confirm the optimum dose of exenatide needed for brain protection in piglets. We will then randomise piglets who have been exposed to lack of blood and oxygen supply to either receive or not receive exenatide and find out if there are differences between the groups in their brains.
Exenatide is currently commercially available as pens which allow for subcutaneous injections in adults. When medicines are given subcutaneously in babies their absorption can be slow and erratic. Since we want to reliably achieve high concentrations of exenatide rapidly in the body, we want to administer exenatide as an intravenous infusion. To do this and to make sure the medicine is safe for newborn babies, we aim to develop a new intravenous formulation of exenatide.
Exenatide has proven safe in high dose animal studies and in human over-dose case reports. However, since we are administering exenatide to babies for the first time, we want to make sure it doesn't cause any developmental problems in newborn animals. To do this, we will conduct toxicology studies using the new intravenous formulation of exenatide in newborn minipigs. We will always care for the research animals, minimise the pain, suffering, distress or lasting harm that may be experienced. Completing the proposed research will bring us to readiness for clinical trials.
In summary, this is an exciting opportunity to provide some real benefit to babies affected by this devastating condition throughout the world. The potential benefits are likely to outweigh any anticipated safety concerns. Exenatide has the potential to enhance the brain protective effects of cooling treatment and be a first line treatment in low-income countries where cooling treatment is not an option.

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a global problem resulting in 400,000 babies with devastating neurodevelopmental impairment every year accounting for 2.4% of the total Global Burden of Disease. In a sustained translational research programme, we found that glucagon-like peptide-1 (GLP-1) receptor activation is neuroprotective in HIE. We propose that exenatide, a licensed antidiabetic and GLP-1 agonist, will reduce the incidence of cerebral palsy in neonatal HIE in conjunction with standard care: therapeutic hypothermia (TH).

We have investigated the potential neuroprotective effect of exenatide using rodent models of neonatal HIE. An optimal treatment dosing regimen was found, where four high doses in 12-hourly intervals starting <6 hours after hypoxic-ischaemic insult augmented TH resulting in 80% reduction in infarct volume. Exenatide penetrates the blood brain barrier and acts on GLP-1 receptors known to be present in the neonatal human brain. In vitro and in vivo studies have suggested that exenatide has anti-inflammatory, anti-apoptotic and mitoprotective properties. These data have led to a phase III human trial in Parkinson's disease.

In this proposal, we want to confirm the efficacy and assess the pharmacokinetics and pharmacodynamics of exenatide in the piglet model of neonatal HIE. We then aim to develop a new intravenous formulation of exenatide and extend the toxicology data to juvenile animals using the new formulation.

Exenatide has the potential to enhance the neuroprotective effects of TH and be a first line treatment in low- and middle-income countries where TH is not an option. The intended exit strategy consists of granting an early license option to a pharmaceutical company following orphan designation. Exenatide has proven safe in high dose animal studies and in human over-dose case reports; the potential benefits are likely to outweigh any anticipated safety concerns, making this an exciting opportunity.