IGF-1 as a Drug for Preterm Infants: A Step-Wise Clinical Development.

Ann Hellström,Boubou Hallberg,Lois E H Smith,Anna-Lena Hard,David Ley,Jan Borg,Ingrid Hansen-Pupp,Chatarina Löfqvist,Luca A Ramenghi

doi:10.2174/1381612823666171002114545

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 trans-fusion 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 stud-ies, 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 infu-sion. 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 medi-cations for preterm infants.

Highlights

Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation
In the plasma study we found decreasing half-life of IGF-1 with decreasing birth weight (BW) and GA at birth [24] which might be attributed to lack of acid labile subunit (ALS)
The developed pharmacokinetic model predicted that a dose of the rhIGF-1/rhIGFBP-3 complex of between 75 and 100 μg/d would be required to establish serum IGF-1 concentrations within the intrauterine range in a 1000g infant

Summary

Introduction

Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation. Energy demands increase while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral nutrition for weeks. Impaired transition to extrauterine life with under-nutrition, infections and insufficient lung maturation results in a catabolic state with very low serum IGF-1 concentrations compared to in utero (Fig. 1). Most other organs including the vasculature depend on IGF-1 for proper growth and differentiation [3]. IGF-1 has insulin-like effects and is involved in glucose and lipid metabolism [4]. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain, retinopathy of prematurity (ROP) and other morbidities [5]. In animals on hypocaloric nutrition, experimental studies on IGF-1 supplementation have shown decreased weight loss and

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