DESCRIPTION (provided by applicant): Recombinant human CC10 protein (rhCC10) is a novel therapeutic agent used to prevent the development of chronic respiratory morbidity (CRM; repeated respiratory infections, asthma, re-hospitalizations) in preterm infants. Native CC10 protein is a natural anti-inflammatory and immunomodulatory factor produced by Clara Cells in the lung and is the most abundant protein in respiratory mucosa. Animal data demonstrate that a single intratracheal dose of rhCC10 protein administered shortly after birth reduces lung inflammation, promotes normal lung development, preserves lung architecture, improves pulmonary function, suppresses the response to endotoxin and enhances resistance to pulmonary infections. In preterm infants who die or develop lung inflammation and subsequent bronchopulmonary dysplasia (BPD), both the concentration and activity of CC10 protein are significantly reduced indicating that CC10 protein is essential for preventing lung injury and promoting normal lung development. In a small Phase 1 study, recombinant human CC10 protein significantly decreased several indices of pulmonary inflammation in the lungs of premature infants who were at risk of developing BPD and associated chronic respiratory morbidity. The drug appeared to be safe, well-tolerated, and reduced risk of re-hospitalization due to respiratory illness for 9-10 months after a single intratracheal dose at the time of birth (0 of 11 recombinant human CC10 protein-treated infants versus 3 of 6 placebo treated). This supports the protective role of recombinant human CC10 protein against damage from hyperoxia, mechanical ventilation, inflammation, and infection in the immature lung. A more normal airway epithelium will produce significantly more endogenous CC10 protein, with both factors contributing to enhanced resistance to infections, less asthma, and improved long-term respiratory outcome. The applicant proposes to conduct a Phase 2 clinical trial to evaluate rhCC10 protein in extremely premature infants (<29 weeks gestation) for the prevention of BPD and chronic respiratory morbidity (CRM). This will be a randomized, double-blind, placebo-controlled dose escalation study in 88 premature infants. A single intratracheal dose of study drug (rhCC10 protein or placebo) will be administered to preterm infants receiving surfactant and mechanical ventilation for treatment of respiratory distress syndrome. Infants will be followed to evaluate safety, pharmacokinetics, and short and long term efficacy of this approach. Safety will be evaluated through serious adverse event (SAE) and adverse event monitoring and by Bayley neurodevelopmental assessments at 18 months corrected gestational age (CGA). Efficacy measurements will include the primary combined endpoint of alive without evidence of CRM at 12 months CGA comparing recombinant human CC10 protein treated to placebo controls. This will be defined by parental diaries and pulmonary questionnaires.

Project Narrative Premature birth now represents almost 13% of all live births in the US (over 500,000 infants). Infants born very prematurely (<29 weeks gestation) are at highest risk for developing respiratory distress syndrome (RDS) and subsequent bronchopulmonary dysplasia (BPD). Approximately 15-20% of premature infants will require assisted ventilation (~80,000) and 15,000 - 20,000 will ultimately develop BPD. BPD is characterized by lung inflammation followed by airway injury and obstruction, alveolar hypoplasia, impaired lung function, and long- term respiratory morbidity. Anti-inflammatory agents such as dexamethasone or hydrocortisone can prevent or ameliorate BPD, but unacceptable side-effects (death, cerebral palsy, intestinal perforation) have precluded the routine use of these agents. Compared to term infants, preterm infants are more susceptible to chronic respiratory morbidities (CRM) including asthma and infections throughout infancy and childhood. It is difficult to accurately predict which preterm infant will develop CRM, since short-term endpoints correlate with long-term pulmonary outcome only 50% of the time. This suggests that novel approaches are necessary to evaluate potential new therapies. Despite multiple federal laws being implemented, only two drugs have been FDA approved for use in preterm infants over the last 20 years that have made a significant impact in outcome (surfactant, caffeine). In addition, over 75% of medications used in these patients are off-label and relatively few high impact drugs are currently in development due to the high risk nature of these patients and poor market demographics. Thus, premature birth is an "epidemic" in the US and there is an urgent, unmet medical need for therapeutic interventions to improve clinical outcomes in this population. In newborn infants, CC10 concentration and activity progressively increase during gestation, similar to antioxidant enzymes and pulmonary surfactant. Most importantly, premature infants who die or develop severe lung injury have been shown to be deficient in both the concentration and activity of native CC10 (less expression as well as more oxidative inactivation). Animal data (including premature models) demonstrate that a single intratracheal dose of rhCC10 administered shortly after birth reduces lung inflammation, promotes normal lung development, preserves lung architecture, improves pulmonary function, suppresses the response to endotoxin and enhances resistance to viral infections. A preliminary Phase 1/2 clinical study in preterm infants demonstrated that a single dose of rhCC10 administered by intratracheal (IT) instillation significantly reduced some inflammatory markers in the lung while improving longer-term respiratory outcome (no infants receiving rhCC10 developed significant respiratory illness by 6 months corrected gestational age). In order to more definitely evaluate longer-term pulmonary outcome in preterm infants, validated caregiver diaries, pulmonary questionnaires, and medical records need to be more carefully assessed over longer periods of time. These data support the protective role of rhCC10 against damage from hyperoxia, mechanical ventilation, inflammation, and infection in the immature lung. A more normal airway epithelium will produce significantly more endogenous CC10, with both factors contributing to enhanced resistance to viral infections, less asthma, and improved long-term respiratory outcome. The primary goal of this proposal is to examine safety and efficacy of rhCC10 in high risk preterm infants (<29 weeks gestation). In an "intent-to-treat", randomized, double-blinded, placebo-controlled dose escalation study in 88 premature infants, a single IT dose of rhCC10 will be administered to preterm infants receiving exogenous surfactant and mechanical ventilation for treatment of RDS. Infants will then be followed to evaluate safety, pharmacokinetics, and short and long term efficacy of this dosing regimen. Safety will be established by examining serious adverse events (SAE), adverse events, and Bayley neurodevelopmental examinations at 12 and 18 months corrected gestational age (CGA). Efficacy measurements will include the combined primary endpoint of alive without evidence of CRM at 12 months CGA defined by parental diaries, pulmonary questionnaires, and medical records. The incidence and severity of BPD at 36 weeks CGA (by physiologic O 2 challenge test) will also be assessed as an important secondary outcome measure. Tracheal aspirate fluids (TAF), serum, and urine will be analyzed for pharmacokinetics of CC10 and TAF will be studied for any biomarkers of inflammation (e.g. cell counts, total protein, TH2 cytokines, IL-6, TNF-¿, etc). Finally, ancillary studies will establish: 1) normal CC10 levels in healthy full term infants (intubated for non- pulmonary reasons), 2) pharmacogenomic profiles of disease related CC10 gene alleles in enrolled infants, and 3) a new ELISA of oxidized/damaged CC10 as an early biomarker of abnormal outcome. At the conclusion of the studies, the investigators expect to have sufficient information to select appropriate outcome measures, dosing regimens, and study design criteria (including sample size estimates) for more definitive Phase 2 and Phase 3 clinical trials using single or multiple dosing strategies.