Efficacy and Safety of Zelpultide Alfa in Preterm Neonates at High Risk of Developing Bronchopulmonary Dysplasia (BPD)

Randomized, Double-Blind Parallel-Group, Adaptive, Three-Arm, Phase 2b/3 Multicenter Study to Evaluate the Efficacy and Safety of Zelpultide Alfa in Preventing Bronchopulmonary Dysplasia (BPD) in High-Risk Preterm Neonates Compared to Standard of Care (SOC)

This is a randomized, parallel-group, double-blind, placebo-controlled multicenter phase 2b/3 study with an adaptive seamless design.

The goal fo this study is to determine if an investigational drug, Zelpultide Alfa, can reduce the occurrence of Bronchopulmonary Dysplasia (BPD) in extremely premature babies.

The study comprises 2 parts:

• Part 1: Phase 2b, dose selection and exploratory efficacy and safety.
• Part 2: Phase 3, confirmatory efficacy and safety.

In Part 1, the study subjects will be randomized with a 1:1:1 allocation ratio to either :

1. Standard of care + zelpultide alfa 4 mg/kg or,
2. Standard of care + zelpultide alfa 6 mg/kg or,
3. Standard of care + placebo (air-sham).

In Part 1, all three arms will be evaluated descriptively to support dose selection based on safety, tolerability, and exploratory efficacy signals. Upon completion of Part 1, the DSMC will recommend which Phase 2b dose ("selected dose") to progress into Part 2 to the Study Steering Committee, which will decide the dose for Part 2 (Phase 3). A sample size reassessment will be performed after Part 1 completion.

In Part 2, the selected dose of zelpultide alfa will be compared against placebo (air-sham) in a confirmatory analysis on the primary and key secondary endpoints. The study subjects will be randomized with a 1:1 allocation ratio to either:

1. Standard of care + zelpultide alfa (selected dose from Part 1), or
2. Standard of care + placebo (air-sham). The main objective in part 2 is to compare the efficacy of zelpultide alfa added to standard of care versus standard of care plus placebo (air-sham) in terms of incidence of grade 2 and grade 3 bronchopulmonary dysplasia (BPD) and death in neonates at high risk for developing BPD.

In both parts, treatment will be administered intratracheally. Participants will receive up to 7 administrations of zelpultide alfa at (4mg/kg or 6 mg/kg) or air-sham in 24 h intervals while the subjects are still intubated per standard of care.

Inclusion Criteria:

1. Born between gestational age (GA) 22 0/7 to 27 6/7 weeks, inclusive.
2. Received at least 1 dose of SOC-indicated animal-derived pulmonary surfactant treatment after birth.
3. Intubated and on invasive mechanical ventilation per SOC.
4. Able to receive the first dose of zelpultide alfa or air-sham at least 15 min after the surfactant administration but within 96 h of birth and within 48 h from the start of invasive mechanical ventilation. Subjects extubated and re-intubated after their pulmonary surfactant dose(s) are eligible as long as the inclusion criteria are met.
5. Informed consent and personal information authorization form signed by the subject's parent(s) or legal guardian(s).

Exclusion Criteria:

1. Birth weight < 400 g or > 1,500 g.

2. Major apparent congenital abnormalities impacting cardio and pulmonary function identified before randomization, such as, but not limited to:

   • Clinically relevant Potter-like syndrome and any pulmonary congenital anomalies,
   • Clinically relevant congenital diaphragmatic hernia,
   • Omphalocele or gastroschisis, esophageal atresia,
   • Known or suspected cyanotic congenital heart disease (ie, tetralogy of fallot, transposition of the great arteries, etc).

3. Active do no resuscitate (DNR) order in place.

4. History of allergy or sensitivity to any surfactant or any component of zelpultide alfa.

5. Concurrent enrollment in any clinical study that utilizes treatments (investigational medical products or devices) outside of SOC or participation in studies within the last 30 days (or 5 half-lives of an IMP) prior to birth (for the mother) or up to week 36 PMA.

6. Any condition or situation that, in the Investigator's judgement, puts the neonate at significant risk, could confound the study results, or may interfere significantly with the neonate's participation in the study.