Inhaled ciclesonide - a phase I study in preterm infants

Preterm infants born before 30 weeks gestation are at risk of developing bronchopulmonary dysplasia (BPD), a leading cause of death and long-term pulmonary insufficiency. Both hydrocortisone and synthetic glucocorticoid (sGC) are commonly used to prevent BPD in premature infants. Clinical trials have shown that hydrocortisone

targeted to infants with emerging lung disease does not prevent BPD, while inhaled sGC therapy has shown mixed efficacy with potentially increased mortality. Dexamethasone (DEX) has been shown in clinical trials to reduce BPD rates in premature infants but is associated with short term and long-term adverse effects including

cerebral palsy. There is an unmet need for efficacious GC therapy in premature infants to prevent BPD without encumbering serious adverse events. To address this challenge, our group has been investigating ciclesonide (CIC), a sGC pro-drug that in the inhaled form is FDA approved for use in asthma and allergic rhinitis

in older children. We recently showed that DEX and CIC regulate GR transcriptional targets and several genes implicated in lung protective effects in neonatal rats. Remarkably, CIC does not suppress somatic growth, IGF- 1 levels, induce hyperglycemia or cause neuroanatomical changes in the cerebral cortex of neonatal rats, which

are known pathologies caused by DEX in premature infants. Furthermore, ongoing studies reveal that CIC is as efficacious as DEX in preventing lung injury in a hyperoxia-model of experimental BPD. We hypothesize that CIC will have minimal systemic absorption and a favorable safety profile in premature infants at risk of

developing BPD. In Aim 1, we will determine the maximum tolerable dose (MTD) of inhaled CIC in preterm infants that does not trigger adverse systemic side effects characteristic of GCs. An open label dose escalation study will be done in preterm infants born at