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: Xiao Hu, Larisa Miller, Sandra Richman, Stacy Hitchman, Gabrielle Glick, Shifang Liu, Ying Zhu, Mary Crossman, Ivan Nestorov, Robert S Gronke, Darren P Baker, Mark Rogge, Meena Subramanyam, Gudarz Davar
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 52 Issue 6 Pg. 798-808 (Jun 2012) ISSN: 1552-4604 [Electronic] England
• PMID: 21680782 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• RNA, Messenger
• Polyethylene Glycols
• Neopterin
• Interferon-beta
• Interferons
• 2',5'-Oligoadenylate Synthetase
• peginterferon beta-1a

Topics

• 2',5'-Oligoadenylate Synthetase (blood, genetics, metabolism)
• Adolescent
• Adult
• Biotransformation
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Gene Expression Regulation (drug effects)
• Half-Life
• Humans
• Immunosuppressive Agents (administration & dosage, adverse effects, blood, pharmacology)
• Injections, Intramuscular
• Injections, Subcutaneous
• Interferon-beta (administration & dosage, adverse effects, chemistry, pharmacology)
• Interferons (administration & dosage, adverse effects, blood, pharmacology)
• Male
• Middle Aged
• Multiple Sclerosis, Relapsing-Remitting (drug therapy)
• Neopterin (blood)
• Polyethylene Glycols (administration & dosage, adverse effects, pharmacology)
• RNA, Messenger (blood, metabolism)
• T-Lymphocytes, Helper-Inducer (drug effects, metabolism)
• Young Adult