A Phase 2b, Multicenter, Randomized, Open-label, Two-Arm Study to Evaluate the Clinical Efficacy and Safety of OHB-607 Compared to Standard Neonatal Care for the Prevention of Bronchopulmonary Dysplasia, the Most Common Cause of Chronic Lung Disease of Prematurity

Extremely premature infants are at very high risk for developing
morbidities such as BPD, intraventricular hemorrhage (IVH) and
retinopathy of prematurity (ROP), often resulting in preterm infants
with extremely low birth weight and has been shown to strongly
predict the risk of later death or neurocognitive impairment. In a
retrospective analysis of 12,050 extremely preterm infants in the US, the
frequent co-occurrence of these three morbidities is associated with
an incremental increase in mortality, readmissions, length
of hospital stay and costs. Although the survival rates have
greatly improved in recent years for infants of borderline viability, these
infants remain at risk of developing a wide array of neonatal and
long-term complications.

When preterm infants are deprived of their natural intrauterine environment,
they lose important factors normally found in utero, such as proteins,
growth factors and cytokines. It has been demonstrated that IGF-1 is
one such factor that is introduced through placental absorption or
ingestion from amniotic fluid. Thus, agents such as IGF-1 that promote organ
development and drive growth in extremely preterm infants have the potential to
address multiple complications of prematurity

OHB-607 (Mecasermin rinfabate; rhIGF-1/rhIGFBP-3 [formerly known as
SHP607]) is the recombinant human version of the naturally occurring
protein complex of insulin-like growth factor 1 (IGF-1) and its most
abundant binding protein, insulin-like growth factor binding protein 3
(IGFBP-3). An increase of serum IGF-1 levels provided by OHB-607 administration
may reduce the incidence of BPD and other complications of extreme prematurity.
This would be the only available preventive pharmacological therapy leading to
an absolute decrease in the incidence of moderate or severe BPD and an absolute
decrease in the incidence of IVH for extremely premature babies translating to
an improvement in long-term pulmonary and neurodevelopmental outcomes in these
patients.

This study has been transitioned to CTIS with ID 2024-515914-41-00 check the CTIS register for the current data.

The primary objective of this study is to assess the effect of OHB-607 on
reducing the burden of CLD, as indicated by a reduction in the incidence of
severe BPD (as defined by the modified NICHD severity grading) at 36 weeks (±3
days) PMA, or death at or before 36 weeks PMA, whichever comes first as
compared to the SNC group.

Secondary objectives are:
• To assess the effect of OHB-607 on reducing the burden of CLD, as indicated
by a reduction in time to final weaning off of RTS through 12 months CA, as
compared to the SNC group.
• To assess the effect of OHB-607 on reducing the burden of CLD, as indicated
by a reduction in the incidence of Grade 2 and Grade 3 (severe) BPD at 36 weeks
(±3 days) PMA, or death, whichever comes first as compared to the SNC group, as
classified according to Jensen et al., 2019.
•To assess the effect of OHB-607 on the occurrence of severe (Grade 3 and 4)
IVH before 40 weeks PMA, as assessed by CUS as compared to the SNC group.
•To assess the effect of OHB-607 on occurrence of severe ROP (Stage 3 and
above) up to 40 weeks PMA as compared to the SNC group.
•To assess the effect of OHB-607 on chronic respiratory outcomes as measured by
the CLDPSS as compared to the SNC group at 12 months CA.

The subjects will be randomized to receive either 400 µg/kg/24
hoursOHB-607, or Standard Neonatal Care in a 1:1 ratio on an open-label
basis. Standard Neonatal Care is determined based upon the individual
premature infant*s condition and clinical judgment of the treating physician
and may include interventions for thermoregulation, blood pressure
support, respiratory/ventilatory support, nutritional support, treatment
for infections, etc. Recognizing that medical care required for each premature
infant may vary, other than those specific parameters outlined in the protocol,
local standards of clinical practice and investigator judgement will guide care
decisions for study subjects.

Subjects randomly assigned to treatment with OHB-607 will receive
continuous IV infusion of OHB-607 commencing within 24 hours of
birth, once all baseline assessments have been completed. The infusion
of study treatment will continue until 29 weeks +6 days PMA, when the subjects*
endogenous production of IGF-1 is considered sufficient to maintain physiologic
serum IGF-1 levels for corresponding GA. Infusion of study treatment
may be discontinued before 29 weeks +6 days PMA if IV access is not
possible according to the clinical judgment of the investigator or when
the responsible physician, for other medical reasons, decides that infusion of
study treatment should be discontinued or that the central line should be
removed.

Under Protocol Amendment 2.1 dated 30Aug2022, all subjects randomized to
receive OHB-607 will now receive the 400 µg/kg/24 hours dose. The
rationale for selecting the higher dose is provided in Section 6.2.6.
Stratification will be employed to enroll lower GA and higher GA
subjects in approximately a 60:40 ratio.A 60:40 enrollment strategy
will take advantage of the higher incidence of severe BPD among the lower
GA subgroup hence favorably reducing the total number of subjects needed to
demonstrate a 20% reduction in severe BPD in subjects receiving OHB 607
relative to SNC. Sites who cannot perform FAST IGF-1 measurements may not
enroll subjects of lower GA until after the DSMB have reviewed IGF-1 levels
measured through FAST IGF-1 when the twentieth subject in the lower GA
group has been treated with OHB-607 for 14 days and 20 subjects have
been treated with Standard Neonatal Care.

The study will be conducted in two parts (Parts A and B). Part A will complete
when all subjects reach 40 weeks PMA, or are discharged from, or
transferred from, the newborn, neonatal or equivalent hospital medical or
intensive care unit or to a nonaffiliated medical care unit or facility,
withdraw from the study, or die, whichever comes first. Safety and
efficacy analyses will be conducted, and a clinical study report prepared
based on these data.

Following discharge, clinical site visits in Part B will take place
6, 12 and 24 months CA (all ±4 weeks). In addition, follow-up telephone
calls will be performed monthly for the first 3 months (each ±1 week) and at 9,
15, 18 and 21 months (all ±4 w eeks) CA (assessments can alternatively be
completed in person if coincident with a routine hospital appointment). Part B
will complete when all subjects have reached 24 months CA, withdraw
from the study, die, or are lost to follow-up, whichever comes first.

The independent DSMB will provide periodic, independent review and assessment
of safety data, to safeguard the interests and safety of the subjects
participating in the study.An ad hoc meeting will be called to review analysis
of IGF-1 levels measured through FAST IGF-1 when the twentiethsubject in the
lower GA group has been treated with OHB-607 for 14 days and
approximately 20 subjects have been enrolled in SNC. Only sites that can
perform FAST IGF-1 will be included in advance of this review. In addition,
an interim analysis will be conducted for futility by an Interim
Analysis Review Committee (IARC) after 50% randomized subjects have reached
36 weeks PMA.

OHB-607 doses will be administered at a dose of400 µg/kg/24 hours via
continuous intravenous (IV) infusion from birth up to 29 weeks +6 days
post-menstrual age (PMA).

Extremely premature infants are at high risk of complications from extreme
preterm birth, which can lead to lower life expectancy and long-term
disabilities. Despite recent increases in the survival rates of premature
infants with minimal viability, the need for prevention of these complications
due to extreme preterm birth is high. In this study, the subjects are subjected
to different study procedures to determine the effect of OHB-607. The study
activities are mainly non-invasive (eg questionnaires) or are an extension of
the invasive actions that are already performed for the standard care (eg
collecting blood more often). Results from previous studies with OHB-607 show a
positive risk-benefit profile. Therefore, the sponsor believes that the
available safety information from non-clinical and clinical studies with
OHB-607 support the continuation of research in extremely preterm infants.