Evaluation of Mecasermin Rinfabate for the Prevention of Bronchopulmonary Dysplasia in Extremely Premature Neonates: A Randomized, Open-label, Phase 2b Study

The primary objective of this study is to evaluate the effect of **OHB-607** on reducing the burden of **Chronic Lung Disease (CLD)** in extremely premature infants. This is measured by a reduction in the incidence of severe **Bronchopulmonary Dysplasia (BPD)**, as defined by the modified NICHD severity grading, at 36 weeks postmenstrual age (PMA) or death at or before 36 weeks PMA, whichever occurs first, compared to the standard neonatal care (SNC) group. This objective is clinically relevant as it addresses the prevention of BPD, a significant cause of morbidity and mortality in premature infants.

Secondary objectives include: - Assessing the effect of OHB-607 on reducing the burden of CLD by evaluating the time to final weaning off respiratory support through 12 months corrected age (CA) and the incidence of Grade 2 and Grade 3 BPD at 36 weeks PMA or death. - Evaluating the occurrence of severe intraventricular hemorrhage (IVH) before 40 weeks PMA and severe retinopathy of prematurity (ROP) up to 40 weeks PMA. - Assessing chronic respiratory outcomes using the CLDPSS at 12 months CA and neurodevelopmental outcomes using the BSID III at 24 months CA. - Evaluating chronic respiratory morbidity outcomes at 24 months CA, incidence and severity of BPD, Jensen BPD grade at 36 weeks PMA, incidence and severity of IVH and ROP, and other neurodevelopmental outcomes. - Assessing mortality from randomization through 24 months CA, exposure-response pharmacokinetic/pharmacodynamic (PK/PD) relationships, and the safety profile of OHB-607 compared to the SNC group.

The clinical trial involves a total of **221 participants** diagnosed with **Chronic Lung Disease**. The study population includes both male and female subjects, specifically focusing on a vulnerable population. Participants are selected based on gestational age, ranging from 23 weeks +0 days to 27 weeks +6 days. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that informed consents and assents are obtained from the parents or guardians of the subjects, adhering to ethical standards approved by the Institutional Review Board or Independent Ethics Committee. The trial aims to evaluate the impact of OHB-607 on reducing the burden of chronic lung disease, with a focus on severe bronchopulmonary dysplasia and mortality outcomes at 36 weeks postmenstrual age.

The clinical trial is a **Phase 2b**, multicenter, randomized, open-label, two-arm study designed to evaluate the clinical efficacy and safety of **Mecasermin rinfabate** (OHB-607) compared to standard neonatal care for the prevention of **bronchopulmonary dysplasia** (BPD), a common cause of chronic lung disease in premature infants. The trial aims to assess the effect of OHB-607 on reducing the incidence of severe BPD or death at or before 36 weeks postmenstrual age (PMA). The study is expected to run from June 2020 to December 2027, with participant involvement lasting up to 24 months corrected age (CA).

Participants will be randomly assigned to one of two groups: the experimental group receiving OHB-607 or the control group receiving standard neonatal care. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to collect final data. The inclusion criteria require participants to be between 23 weeks +0 days and 27 weeks +6 days gestational age. Written informed consent must be obtained from the parents or legal guardians before any study-related procedures.

The primary endpoint is the incidence of severe BPD or death at or before 36 weeks PMA. Secondary endpoints include time to final weaning off respiratory support, incidence of severe intraventricular hemorrhage, and neurodevelopmental outcomes at 24 months CA. Participants may be withdrawn from the study if they experience adverse events that compromise their safety or if they do not adhere to the study protocol. The study will utilize **intravenous** administration of the investigational product, with a maximum treatment period of 29 days. The trial is not considered low intervention and is categorized as a Category 2 trial under regulatory guidelines.

The clinical trial involves the administration of **Mecasermin rinfabate**, a recombinant protein complex, as the experimental medication. This investigational product is provided in the form of a **solution for infusion** and is administered **intravenously**. The active substance, Mecasermin rinfabate, is a complex of recombinant human insulin-like growth factor I (IGF-I) and recombinant human insulin-like growth factor-binding protein 3 (IGFBP-3). The pharmaceutical form is specifically designed for infusion, ensuring precise delivery of the active components. The dosing regimen is determined based on the participant's body weight, with the dose expressed in micrograms per kilogram (µg/Kg). The maximum treatment period for this study is set at 29 days. The investigational product is identified by the sponsor product code OHB-607 and is designated as an orphan drug under the designation number EU/3/06/399.

In addition to the experimental treatment, the study includes a comparator group receiving **standard neonatal care** (SNC) for the prevention of bronchopulmonary dysplasia (BPD), a common cause of chronic lung disease in premature infants. The standard care group serves as a control to evaluate the efficacy and safety of Mecasermin rinfabate in reducing the incidence of severe BPD or death at or before 36 weeks postmenstrual age (PMA). The trial is designed as a Phase 2b, multicenter, randomized, open-label, two-arm study, ensuring a robust comparison between the investigational product and standard care. Participant compliance with the dosing schedule and administration protocol is monitored throughout the study to ensure data integrity and reliability.

The clinical trial aims to evaluate the efficacy of **Mecasermin rinfabate** (OHB-607) in preventing **Bronchopulmonary Dysplasia (BPD)**, a common cause of chronic lung disease in premature infants. The primary efficacy endpoint is the incidence of severe BPD, as defined by the modified NICHD severity grading, or death at or before 36 weeks postmenstrual age (PMA). The severity of BPD is categorized as follows: no BPD (oxygen for less than 28 days or none), mild BPD (oxygen for 28 days but on room air at 36 weeks PMA), moderate BPD (oxygen for 28 days plus treatment with less than 30% oxygen at 36 weeks PMA), and severe BPD (oxygen for 28 days plus oxygen 30% and/or any positive pressure ventilation at 36 weeks PMA).

Secondary endpoints include the time to final weaning off respiratory support from Day 1 of randomization through 12 months corrected age (CA), incidence of Grade 2 and Grade 3 BPD as defined by the modified Jensen severity grading, incidence of severe intraventricular hemorrhage (IVH) before 40 weeks PMA, incidence of severe retinopathy of prematurity (ROP) up to 40 weeks PMA, and neurodevelopmental impairment as determined by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID III) at 24 months CA. Additional assessments include respiratory severity scoring, physical and cognitive development using the Ages and Stages Questionnaire, Third Edition (ASQ-3), and mortality rates from randomization to initial hospital discharge and from initial discharge through 24 months CA.

Efficacy parameters will be measured and collected at specified intervals, including follow-up telephone calls and clinical site visits, until 12 months CA. The trial will utilize validated scales and classifications, such as the modified NICHD and Jensen severity gradings, the International Classification for ROP, and the Volpe criteria for IVH. The relationships between IGF-1 exposure and various endpoints, including respiratory, neurologic, BPD, IVH, necrotizing enterocolitis (NEC), and ROP, will also be explored. Data analysis will focus on the incidence and severity of these conditions, as well as the development of anti-IGF-1/IGFBP-3 antibodies and organ hypertrophy.