title: First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.
abstract: This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I.
  
  
  
  The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50μg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated.
  
  
  
  PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV.
  
  
  
  PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases.
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Kletzl
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Guenther
authors.affiliation: Department of Signal Transduction, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Höflich
authors.affiliation: Ligandis GbR, Dorfstr. 14, 18276 Gülzow-Prüzen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Höflich
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Department of Endocrinology & Internal Medicine, University Hospital, 8000 Aarhus C, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Frystyk
authors.affiliation: Roche Pharma Research and Early Development (pRED), Pharmaceutical Sciences, Global DMPK and Bioanalytical R&D, Roche Innovation Center Munich, Germany.
authors.forename: R F
authors.initials: RF
authors.lastname: Staack
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Schick
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Wandel
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Bleich
authors.affiliation: Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: friedrich.metzger@versameb.com.
authors.forename: F
authors.initials: F
authors.lastname: Metzger
mesh_terms: D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006133:Growth Substances / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020714:Maximum Tolerated Dose; D011092:Polyethylene Glycols / Q000737:chemistry*; D011379:Prognosis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D006133:Growth Substances; C583557:IGF1 protein, human; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D007334:Insulin-Like Growth Factor I
keywords: Elongated half life; GH feedback loop; Hypoglycemia; IGF-1; PEG-IGF-1