Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening neonatal condition wherein an elevation in pulmonary vascular resistance after birth diverts pulmonary blood flow via a right-to-left shunt, at the levels of the ductus arteriosus and foramen ovale, into the systemic circulation. Current therapy includes mechanical ventilation, oxygen, and inhalational nitric oxide (iNO), a gas that selectively dilates the pulmonary vasculature but is only effective in 30-50% of patients. Non-responders to iNO therapy are supported via extracorporeal membrane oxygenation (ECMO). Although PPHN has multiple biological triggers, our current understanding is consistent with a convergence to a final common effector mechanism of injury produced by an excess of superoxide and a deficiency of NO in the newborn pulmonary vasculature. The imbalance of these two free radicals directly impairs the ability of the pulmonary arteriole to dilate appropriately after birth. To address this unmet need, and overcome the limitations in response to iNO therapy, Radikal Therapeutics is developing R-100, a small molecule agent formed from the covalent linkage of: 1) an organic nitrovasodilator domain that releases NO, and 2) a pyrrolidine nitroxide domain that acts as a superoxide dismutase mimetic, catalase mimetic, and peroxynitrite decomposition catalyst. R-100 has been shown to be dramatically effective in selectively relieving pulmonary arterial hypertension in monocrotaline-challenged rats and in pilot studies of newborn lamb models of severe PPHN refractory to iNO. Phase I Specific Aim: Contrast the efficacy and selectivity of iNO and R-100 in a newborn lamb model of severe PPHN refractory to iNO. We will carry out a dose-escalation study in anesthetized and mechanically-ventilated newborn lambs in which PPHN has been induced by in utero ligation of the ductus arteriosus. R-100 is expected to be superior to iNO in selectively reducing mean pulmonary arterial blood pressure. Criteria for progression to the Phase 2 NIH SBIR: Treatment with R-100 must satisfy, relative to baseline hemodynamics, all of the following hemodynamic endpoints: 1) >50% reduction in the elevation relative to baseline in mean pulmonary arterial blood pressure (MPAP), 2) >50% increase relative to baseline in pulmonary blood flow, 3) <10% reduction in peripheral mean arterial blood pressure, 4) <10% increase in baseline MPAP after cessation of treatment, and 5) equivalence or superiority to iNO on all of the above parameters. Phase II Specific Aim: Establish the subacute safety and tolerance of IV R-100 in GLP toxicology and safety pharmacology studies. Genetic toxicology studies will include the Ames, chromosomal aberration assay, and rat micronucleus assay. Safety pharmacology studies will include juvenile rat neurobehavioral and respiratory studies and juvenile canine cardiovascular studies. Toxicology investigations will be carried out over 4 weeks in newborn rats and dog pups. These studies will identify the No Observed Adverse Event Level (NOAEL) in each species, and provide the regulatory basis for a dose range to be explored for safety, tolerance, and pharmacokinetics in human neonates.
Persistent pulmonary hypertension of the newborn (PPHN) is a rare but life-threatening condition of the term infant in which the blood pressure in the lungs fails to decrease to a normal level after birth. Existing therapy for this condition involves the inhalation of nitric oxide gas, but this proves ineffective in more than a third of infants. We are developing a novel drug that targets the basic mechanisms of PPHN and has been shown to be effective in pilot studies in a large animal PPHN model wherein inhaled nitric oxide exhibits only a weak response. We now propose to define the value of our technology in a definitive clinically-relevant animal model of PPHN.