IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity

When preterm infants are deprived of their natural intrauterine environment they lose access
to important factors, normally found in utero, such as proteins, growth factors, and
cytokines. It has been demonstrated that insulin-like growth factor-1 (IGF-1) is one such
factor. In utero these biological factors are introduced to the fetus via placental
absorption or ingestion from amniotic fluid. Deprivation of such factors is likely to cause
inhibition or improper stimulation of important pathways, which in the case of the eye may
cause abnormal retinal vascular growth, the hallmark of retinopathy of prematurity (ROP).

Retinopathy of prematurity is the major cause of blindness in children in the developed and
developing world, despite the availability of current treatment of late-stage ROP. As
developing countries provide more neonatal and maternal intensive care, which increases the
survival of preterm born infants, the incidence of ROP is increasing.

This phase 2 study was originally designed in 3 sections, Sections A, B, and C which are now
complete. The protocol was amended and patients enrolled from this point forward will be
enrolled into Section D.

In Study Section D, a total of 120 subjects (GA of 23 weeks + 0 days to 27 weeks + 6 days)
will be randomly assigned with 1:1 allocation ratio to either treatment with
rhIGF-1/rhIGFBP-3 or to receive standard neonatal care (Control Group) to obtain at least 80
evaluable subjects. Duration of infusion will last at longest from Study Day 0 (day of
birth) up to and including PMA 29 weeks + 6 days, when the subject's endogenous production
of IGF-1 is considered sufficient to maintain physiologic serum IGF-1 levels. After
discontinuation of study drug infusion, each subject will be followed to PMA 40 weeks ± 4
days.

Inclusion Criteria:

- Signed informed consent from parents/guardians;

- Subject must be between GA of 26 weeks + 0 days and 27 weeks + 6 days (Study Section
A) or between GA of 23 weeks + 0 days and 27 weeks + 6 days (Study Sections B, C, and
D), inclusive

Exclusion Criteria:

- Subjects born small for gestational age (SGA), ie, body weight at birth <-2 standard
deviation score (SDS) (Study Section A only)

- Detectable gross malformation

- Known or suspected chromosomal abnormality, genetic disorder, or syndrome, according
to the Investigator's opinion

- Persistent blood glucose level <2.5 mmol/L or >10 mmol/L at Study Day 0 (day of
birth) to exclude severe congenital abnormalities of glucose metabolism

- Anticipated need of administration of erythropoietin (rhEPO) during treatment with
study drug.

- Any maternal diabetes requiring insulin during the pregnancy

- Clinically significant neurological disease according to the Investigator's
opinion(Stage 1 IVH allowed)

- Any other condition or therapy that, in the Investigator's opinion, may pose a risk
to the subject or interfere with the subject's ability to be compliant with this
protocol or interfere with interpretation of results

- Monozygotic twins

- Subject participating or plans to participate in a clinical study of another
investigational study drug