Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer.

To the Editor: PEGylation is commonly used to extend half-life and limit volume of distribution of an increasing number of nucleic acid, peptide, and small molecule therapeutics. Pegnivacogin is a modified 31-nucleotide RNA aptamer that binds to and inhibits factor IXa conjugated to an inert 40-kD branched methoxypolyethylene glycol polymer. Although early clinical testing did not identify any safety concerns, the phase IIb Randomized, Partially Blinded, Multicenter, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation System in Patients with Acute Coronary Syndromes (RADAR) trial was stopped after 3 allergic reactions. An extensive investigation demonstrated elevated levels of IgG anti-PEG antibodies in the 3 patients with allergic events, suggesting that the PEG moiety, and not the oligonucleotide, was the causative allergic agent. On the basis of previous safety record of PEGylated products, investigators and regulatory authorities agreed that pegnivacogin should undergo additional definitive testing incorporating a risk mitigation and action plan in a phase III trial (Randomized, Open-label, Multi-Center, Active-Controlled, Parallel Group Study to Determine the Efficacy and Safety of the REG1 Anticoagulation System Compared to Bivalirudin in Patients Undergoing Percutaneous Coronary Intervention [REGULATE-PCI]) in which subjects undergoing percutaneous coronary intervention were randomized to pegnivacogin or bivalirudin.Methodology of the trial, planned biochemical analyses, statistical analyses, and allergy definitions are available in the first and second sections in this article’s Online Repository at www.jacionline.org. REGULATE-PCI was ultimately terminated after enrollment of 3,232 of a planned 13,200 patients after an excess of allergic reactions in pegnivacogin-treated patients. The incidence and timing of allergic reactions are summarized in Table I. Descriptions of allergies meeting reporting criteria, as judged by the investigators, are provided in the third section in this article’s Online Repository at www.jacionline. org. Assignment to pegnivacogin was associated with a statistically significant increase in allergic reactions. Of the clinical variables assessed, female sex, allergic reactions in the past year, current smoking, and previous percutaneous coronary