PMID- 25487082 OWN - NLM STAT- MEDLINE DCOM- 20160401 LR - 20181202 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 37 IP - 5 DP - 2015 May 1 TI - Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial. PG - 1012-1021.e6 LID - S0149-2918(14)00741-3 [pii] LID - 10.1016/j.clinthera.2014.11.005 [doi] AB - PURPOSE: Morquio A syndrome (mucopolysaccharidosis IVA [MPS IVA]) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetylgalactosamine-6-sulfatase, which is required to degrade the glycosaminoglycan keratan sulfate. Morquio A is associated with extensive morbidity and early mortality. Elosulfase alfa is an enzyme replacement therapy that provides a treatment option for patients with Morquio A. We examined the immunogenicity profile of elosulfase alfa, assessing any correlations between antidrug antibodies and the efficacy and safety outcomes in 176 patients with Morquio A from a 24-week international Phase III trial. METHODS: Patients were randomized to placebo (n = 59) or elosulfase alfa 2.0 mg/kg administered weekly (n = 58) or every other week (n = 59) as an ~4-hour infusion. Blood samples were routinely tested to determine drug-specific total antibody titer and neutralizing antibody (NAb) positivity. Drug-specific immunoglobulin E positivity was tested routinely and in response to severe hypersensitivity adverse events (AEs). Antidrug antibody positivity and titer were compared with efficacy and safety metrics to assess possible correlations. FINDINGS: The 176 patients in the trial were 54% female, with a mean age of 11.9 years. In all patients treated with elosulfase alfa antidrug antibodies developed, and in the majority, antibodies capable of interfering with cation-independent mannose-6-phosphate receptor binding in vitro (NAb) developed. Less than 10% of patients tested positive for drug-specific IgE during the study. Despite the high incidence of anti-elosulfase alfa antibodies, no correlations were detected between higher total antibody titers or NAb positivity and worsened 6-minute walk test results, urine keratin sulfate levels, or hypersensitivity AEs. Drug-specific IgE positivity had no apparent association with the occurrence of anaphylaxis, other hypersensitivity AEs, and/or treatment withdrawal. IMPLICATIONS: Despite the universal development of antidrug antibodies, elosulfase alfa treatment was both safe and well tolerated and immunogenicity was not associated with reduced treatment effect. ClinicalTrials.gov identifier: NCT01275066. (Clin Ther. CI - Copyright (c) 2015 Elsevier HS Journals, Inc. All rights reserved. FAU - Schweighardt, Becky AU - Schweighardt B AD - BioMarin Pharmaceutical Inc, Novato, California. Electronic address: BSchweighardt@bmrn.com. FAU - Tompkins, Troy AU - Tompkins T AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Lau, Kelly AU - Lau K AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Jesaitis, Lynne AU - Jesaitis L AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Qi, Yulan AU - Qi Y AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Musson, Donald G AU - Musson DG AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Farmer, Pamela AU - Farmer P AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Haller, Christine AU - Haller C AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Shaywitz, Adam J AU - Shaywitz AJ AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - Yang, Ke AU - Yang K AD - BioMarin Pharmaceutical Inc, Novato, California. FAU - O'Neill, Charles A AU - O'Neill CA AD - BioMarin Pharmaceutical Inc, Novato, California. LA - eng SI - ClinicalTrials.gov/NCT01275066 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20141206 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Antibodies, Neutralizing) RN - 0 (Recombinant Proteins) RN - 37341-29-0 (Immunoglobulin E) RN - 9056-36-4 (Keratan Sulfate) RN - EC 3.1.6.- (Chondroitinsulfatases) RN - EC 3.1.6.4 (GALNS protein, human) SB - IM MH - Antibodies, Neutralizing/blood MH - Child MH - Child, Preschool MH - Chondroitinsulfatases/administration & dosage/adverse effects/*immunology/therapeutic use MH - Double-Blind Method MH - Drug Administration Schedule MH - Drug Hypersensitivity/etiology/immunology MH - Enzyme Replacement Therapy/adverse effects/*methods MH - Female MH - Humans MH - Immunoglobulin E/blood MH - Keratan Sulfate/urine MH - Male MH - Middle Aged MH - Mucopolysaccharidosis IV/*drug therapy/immunology MH - Recombinant Proteins/administration & dosage/adverse effects/immunology/therapeutic use OTO - NOTNLM OT - Morquio A OT - antibody OT - efficacy OT - enzyme replacement therapy OT - immunogenicity OT - mucopolysaccharidosis IVA EDAT- 2014/12/10 06:00 MHDA- 2016/04/02 06:00 CRDT- 2014/12/10 06:00 PHST- 2014/09/02 00:00 [received] PHST- 2014/10/29 00:00 [revised] PHST- 2014/11/07 00:00 [accepted] PHST- 2014/12/10 06:00 [entrez] PHST- 2014/12/10 06:00 [pubmed] PHST- 2016/04/02 06:00 [medline] AID - S0149-2918(14)00741-3 [pii] AID - 10.1016/j.clinthera.2014.11.005 [doi] PST - ppublish SO - Clin Ther. 2015 May 1;37(5):1012-1021.e6. doi: 10.1016/j.clinthera.2014.11.005. Epub 2014 Dec 6.