Title:IGF-1 as a Drug for Preterm Infants: A Step-Wise Clinical Development
VOLUME: 23 ISSUE: 38
Author(s):Ann Hellstrom*, David Ley, Boubou Hallberg, Chatarina Lofqvist, Ingrid Hansen-Pupp, Luca A. Ramenghi, Jan Borg, Lois E. H. Smith and Anna-Lena Hard
Affiliation:Department of Ophthalmology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skane University Hospital, Lund, Department of Neonatology, Karolinska Institute and University Hospital, Stockholm, Department of Ophthalmology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skane University Hospital, Lund, Genova Neonatal Intensive Care Unit, Instituto Pediatrico Giannina Gaslini, Genova, Former Premacure AB, Uppsala, Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, Department of Ophthalmology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg
Keywords:Preterm infant, IGF-1, pharmacokinetic, drug development, preterm morbidity.
Abstract:Background: Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes
such as growth, metabolism, angiogenesis and differentiation. After very preterm birth, energy demands increase
while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral
nutrition for weeks. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain,
retinopathy of prematurity (ROP) and other morbidities. We will describe the process by which we aim to develop
supplementation with recombinant human (rh) IGF-1 and its binding protein rhIGFBP-3 as a possible therapy
to promote growth and maturation and reduce morbidities in extremely preterm infants.
Methods: In order to calculate a dose of IGF-1 tolerated by neonates, a pharmacokinetic study of transfusion with
fresh frozen plasma was performed, which provided a relatively low dose of IGF-1, (on average 1.4 µg/kg), that
increased serum IGF-1 to levels close to those observed in fetuses and preterm infants of similar GAs. Thereafter,
a Phase I 3 hours IV infusion of rhIGF-1/rhIGFBP-3 was conducted in 5 infants, followed by a Phase II study
with four sections (A-D). In the Phase II, sections A-D studies, time on infusion increased and younger gestational
ages were included.
Results: IV infusion increased IGF-1 but with short half-life (0.5h) implying a need for continuous infusion. In
order to obtain in utero levels of IGF-I, the dose was increased from 100 to 250 µg/kg/24 h and the infusion was
prolonged from 3 weeks postnatal age until a postmenstrual age of 29 weeks and 6 days.
Conclusion: The purpose has been to ensure high-quality research into the development of a new drug for preterm
infants. We hope that our work will help to establish a new standard for the testing of medications for preterm
infants.
