title: A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology.
abstract: This study clinically evaluated a novel PEGylated form of interferon beta-1a (PEG-IFN beta-1a), a potential first-line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single-dose study (n = 60) comparing subcutaneous or intramuscular PEG-IFN beta-1a (63, 125, or 188 µg) with intramuscular unmodified IFN beta-1a 30 µg and a multiple-dose study (n = 69) comparing subcutaneous PEG-IFN beta-1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2',5'-OAS) measures, exploratory immune assessments, safety, and tolerability. A dose-proportional increase in PEG-IFN beta-1a exposure was observed, with a 4-fold greater exposure at 63 µg (6 million international units [MIU]) of PEG-IFN beta-1a than with 30 µg (6 MIU) intramuscular unmodified IFN beta-1a. Increases in neopterin and 2',5'-OAS levels and changes in T helper cell pathway gene expression and lymphocyte subsets were greater and more sustained with PEG-IFN beta-1a than with unmodified IFN beta-1a. PEG-IFN beta-1a was well tolerated, with only transient reductions in absolute neutrophils and some lymphocytes. Flu-like symptoms were a commonly reported adverse event. These data support the continued clinical development of PEG-IFN beta-1a as a potentially effective treatment for patients with relapsing multiple sclerosis.
authors.affiliation: Biogen Idec, Inc, Weston, Massachusetts, USA. xiao.hu@biogenidec.com
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.forename: Larisa
authors.initials: L
authors.lastname: Miller
authors.forename: Sandra
authors.initials: S
authors.lastname: Richman
authors.forename: Stacy
authors.initials: S
authors.lastname: Hitchman
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Glick
authors.forename: Shifang
authors.initials: S
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Mary
authors.initials: M
authors.lastname: Crossman
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
authors.forename: Robert S
authors.initials: RS
authors.lastname: Gronke
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Mark
authors.initials: M
authors.lastname: Rogge
authors.forename: Meena
authors.initials: M
authors.lastname: Subramanyam
authors.forename: Gudarz
authors.initials: G
authors.lastname: Davar
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D016899:Interferon-beta / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D007372:Interferons / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy; D019798:Neopterin / Q000097:blood; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D012333:RNA, Messenger / Q000097:blood / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011092:Polyethylene Glycols; D019798:Neopterin; D016899:Interferon-beta; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase; C428112:peginterferon beta-1a