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.
Subject(s)
Immunosuppressive Agents/adverse effects , Interferon-beta/chemistry , Interferons/adverse effects , Polyethylene Glycols/adverse effects , 2',5'-Oligoadenylate Synthetase/blood , 2',5'-Oligoadenylate Synthetase/genetics , 2',5'-Oligoadenylate Synthetase/metabolism , Adolescent , Adult , Biotransformation , Dose-Response Relationship, Drug , Double-Blind Method , Female , Gene Expression Regulation/drug effects , Half-Life , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Immunosuppressive Agents/pharmacology , Injections, Intramuscular , Injections, Subcutaneous , Interferon-beta/administration & dosage , Interferon-beta/adverse effects , Interferon-beta/pharmacology , Interferons/administration & dosage , Interferons/blood , Interferons/pharmacology , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Neopterin/blood , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacology , RNA, Messenger/blood , RNA, Messenger/metabolism , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/metabolism , Young AdultABSTRACT
Multiple sclerosis is a chronic autoimmune disease of the central nervous system for which a number of disease-modifying therapies are available, including interferon beta (Avonex®, Rebif®, and Betaseron/Betaferon®), glatiramer acetate (Copaxone®), and an anti-VLA4 monoclonal antibody (Tysabri®). Despite the availability and efficacy of these protein and peptide drugs, there remains a significant number of patients who are untreated, including those with relatively mild disease who choose not to initiate therapy, those wary of injections or potential adverse events associated with therapy, and those who have stopped therapy due to perceived lack of efficacy. Since these drugs have side effects that may affect a patient's decision to initiate and to remain on treatment, there is a need to provide a therapy that is safe and efficacious but that requires a reduced dosing frequency and hence a concomitant reduction in the frequency of side effects. Here we describe the development of a PEGylated form of interferon beta-1a that is currently being tested in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study in relapsing multiple sclerosis patients, with the aim of determining the safety and efficacy of 125 microg administered via the subcutaneous route every 2 or 4 weeks.
