Jocelyn H Leu1, Omoniyi J Adedokun1, Cynthia Gargano2, Elizabeth C Hsia3, Zhenhua Xu1, Gopi Shankar4. 1. Global Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, PA, USA. 2. Clinical Biostatistics, Janssen Research & Development, LLC, Spring House, PA, USA. 3. Immunology, Janssen Research & Development, LLC, Spring House, PA, USA. 4. Biologics Development Sciences, Janssen Research & Development, LLC, Spring House, PA, USA.
Abstract
OBJECTIVE: Golimumab immunogenicity was extensively studied during clinical development. As anti-drug antibody (ADA) detection with the standard bridging EIA (original-EIA) can yield false-negative results or underestimate ADA incidence and titres due to drug interference, a more sensitive assay was needed to determine clinical impact. METHODS: A highly sensitive drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original-EIA. Samples from phase-3 subcutaneous golimumab rheumatological trials (GO-FORWARD-rheumatoid arthritis, GO-REVEAL-psoriatic arthritis, GO-RAISE-ankylosing spondylitis) were then retested. Associations between ADAs and golimumab pharmacokinetics, efficacy and safety were assessed. RESULTS: The DT-EIA was more sensitive than the original-EIA and capable of detecting ADAs amid golimumab concentrations far exceeding those in immunogenicity test samples. Consequently, an 8-fold increase in the incidence of ADAs was observed with the DT-EIA (31.7%) vs original-EIA (4.1%) in the studies. Most ADA-positive patients identified by the DT-EIA had lower antibody titres, while most with higher titres were previously identified as ADA-positive by the original-EIA. With the DT-EIA, ADA-positive patients generally had lower trough serum golimumab concentrations than ADA-negative patients; however, ADA impact on serum golimumab concentrations was more notable at higher ADA titres (⩾100). No impact of ADAs on clinical efficacy or injection-site reactions was evident. CONCLUSION: ADA incidence was expectedly higher using the DT-EIA vs original-EIA; newly detected ADAs were characterized mostly by low titres, with no impact on clinical efficacy or injection-site reactions, consistent with previously observed original-EIA results. Golimumab immunogenicity with the DT-EIA is consistent with existing knowledge regarding the clinical relevance of ADAs detected with the original-EIA in patients with rheumatological disorders. TRIAL REGISTRATION: NCT00264550, NCT00265096, NCT00265083.
OBJECTIVE:Golimumab immunogenicity was extensively studied during clinical development. As anti-drug antibody (ADA) detection with the standard bridging EIA (original-EIA) can yield false-negative results or underestimate ADA incidence and titres due to drug interference, a more sensitive assay was needed to determine clinical impact. METHODS: A highly sensitive drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original-EIA. Samples from phase-3 subcutaneous golimumab rheumatological trials (GO-FORWARD-rheumatoid arthritis, GO-REVEAL-psoriatic arthritis, GO-RAISE-ankylosing spondylitis) were then retested. Associations between ADAs and golimumab pharmacokinetics, efficacy and safety were assessed. RESULTS: The DT-EIA was more sensitive than the original-EIA and capable of detecting ADAs amid golimumab concentrations far exceeding those in immunogenicity test samples. Consequently, an 8-fold increase in the incidence of ADAs was observed with the DT-EIA (31.7%) vs original-EIA (4.1%) in the studies. Most ADA-positive patients identified by the DT-EIA had lower antibody titres, while most with higher titres were previously identified as ADA-positive by the original-EIA. With the DT-EIA, ADA-positive patients generally had lower trough serum golimumab concentrations than ADA-negative patients; however, ADA impact on serum golimumab concentrations was more notable at higher ADA titres (⩾100). No impact of ADAs on clinical efficacy or injection-site reactions was evident. CONCLUSION:ADA incidence was expectedly higher using the DT-EIA vs original-EIA; newly detected ADAs were characterized mostly by low titres, with no impact on clinical efficacy or injection-site reactions, consistent with previously observed original-EIA results. Golimumab immunogenicity with the DT-EIA is consistent with existing knowledge regarding the clinical relevance of ADAs detected with the original-EIA in patients with rheumatological disorders. TRIAL REGISTRATION: NCT00264550, NCT00265096, NCT00265083.
Authors: M Elaine Husni; Atul Deodhar; Sergio Schwartzman; Soumya D Chakravarty; Elizabeth C Hsia; Jocelyn H Leu; Yiying Zhou; Kim H Lo; Arthur Kavanaugh Journal: Arthritis Res Ther Date: 2022-03-21 Impact factor: 5.156
Authors: Nicolino Ruperto; Hermine I Brunner; César Pacheco-Tena; Ingrid Louw; Gabriel Vega-Cornejo; Alberto J Spindler; Daniel J Kingsbury; Heinrike Schmeling; Arturo Borzutzky; Rubén Cuttica; C J Inman; Victor Malievskiy; Christiaan Scott; Vladimir Keltsev; Maria Teresa Terreri; Diego Oscar Viola; Ricardo M Xavier; Taciana A Pedrosa Fernandes; María Del Rocío Maldonado Velázquez; Michael Henrickson; Michael B Clark; Karen A Bensley; Xiaoming Li; Kim Hung Lo; Jocelyn H Leu; Chyi-Hung Hsu; Elizabeth C Hsia; Zhenhua Xu; Alberto Martini; Daniel J Lovell Journal: Rheumatology (Oxford) Date: 2021-10-02 Impact factor: 7.580