Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions
ECTRIMS Online Library. Derfuss T. Sep 11, 2019; 279399; 65
Prof. Tobias Derfuss
Prof. Tobias Derfuss

Abstract: 65

Type: Scientific Session

Abstract Category: Therapy - Immunomodulation/Immunosuppression

T. Derfuss1, M.S. Weber2,3, R. Hughes4, Q. Wang4, A. Sauter4, H. Koendgen4, S.L. Hauser5, A. Bar-Or6, H.-P. Hartung7

1University Hospital Basel, University of Basel, Basel, Switzerland, 2Institute of Neuropathology, Universitätsmedizin Göttingen, 3Department of Neurology, Universitätsmedizin Göttingen, Göttingen, Germany, 4F. Hoffmann-La Roche Ltd, Basel, Switzerland, 5University of California, San Francisco, CA, 6Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, United States, 7Department of Neurology, UKD, Center of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

Background: Exposure-dependent decreased serum levels of immunoglobulin (Ig)G, IgM and/or IgA can occur in patients treated with B-cell-depleting therapies. An increased risk of serious infections (SIs) has been observed, mainly with reduced serum IgG levels.
Objectives: To assess serum Ig levels over 5.5 years and evaluate a potential association between a decrease in IgG, IgM or IgA levels and SIs, in the Phase III OPERA I/OPERA II (NCT01247324; NCT01412333) and ORATORIO (NCT01194570) trials/open-label extensions of ocrelizumab (OCR) in multiple sclerosis (MS).
Methods: Serum IgG, IgM and IgA levels were measured at least every 24 weeks. Lower limit of normal (LLN) for IgG, IgA and IgM was defined as 5.65g/L, 0.70g/L and 0.40g/L, respectively. SI rates during episodes of < LLN were compared with SI rates during episodes of ≥ LLN. Episodes of < LLN were defined as from the day the laboratory value reached < LLN, until normalisation. Analyses are presented using a July 2018 data-cut.
Results: Over 5.5 years of OCR treatment, the reduction in serum levels (relative reduction [%]; mean decrease from baseline to 264 weeks [g/L]) in relapsing MS were: IgG, 17.0% (from 10.53 to 8.79); IgA, 21.3% (from 2.13 to 1.74); IgM, 58.1% (from 1.35 to 0.60) and in primary progressive MS were: IgG, 16.9% (from 10.68 to 8.96); IgA, 20.5% (from 2.17 to 1.76); IgM, 56.3% (1.37 to 0.64). At Week 264, the proportions of patients reaching IgG, IgA and IgM levels < LLN were 5.7%, 5.4% and 29.2%, respectively. Overall, 14 SIs occurred during a drop in IgG levels < LLN (14 adverse events [AEs] per 215.5 patient years [PY], equating to a rate of 6.50 AEs/100PY), compared with IgG levels ≥ LLN, (191 AEs/9049.1PY; 2.11/100PY). Five SIs occurred during a drop in IgA levels < LLN (5 AEs/215.8PY; 2.3/100PY) vs IgA levels ≥ LLN (200 AEs/9038.7PY; 2.21/100PY). A total of 64 SIs occurred during a drop in IgM < LLN (64 AEs/1749.1PY; 3.66/100PY) vs IgM levels ≥ LLN (141 AEs/7515.6PY; 1.88/100PY). No pattern of SIs was identified in terms of organ affected, pathogen, duration, latency or severity comparing < LLN/≥ LLN for each Ig subclass. All SIs resolved with standard care, whilst patients continued OCR therapy. Updated analyses (January 2019 data-cut) will be presented.
Conclusions: Over 5.5 years of OCR treatment, a reduction in serum Ig levels was observed, with an apparent association with increased rates of SIs. The association was strongest for IgG and less so for IgM or IgA.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK.
T. Derfuss has served on scientific advisory boards, steering committees and data safety monitoring boards for Actelion, Biogen, Celgene, Genzyme, GeNeuro, Merck, Mitsubishi Pharma, Novartis, Roche, Octapharma and MedDay; has received travel and/or speaker honoraria from Biogen, Genzyme, Merck, Novartis, Roche and Merck Serono; has received research support from Biogen, Novartis, the Swiss MS Society and the Swiss National Foundation.
M. S. Weber receives research support from the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen; serves as an Editor for PLoS One; has received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme.
R. Hughes is an employee and shareholder of F. Hoffmann-La Roche Ltd.
Q. Wang is an employee of F. Hoffmann-La Roche Ltd.
A. Sauter is an employee and shareholder of F. Hoffmann-La Roche Ltd.
H. Koendgen is an employee and shareholder of F. Hoffmann-La Roche Ltd.
S. L. Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Alector, Annexon, Bionure, Molecular Stethoscope, and Symbiotix; has received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations.
A. Bar-Or has received consulting fees from Actelion, Atara Biotherapeutics, Biogen Idec, Brainstorm Celgene/Receptos, Genentech, Inc., GlaxoSmithKline, F. Hoffmann-La Roche Ltd, MAPI, Medimmune, Merck/EMD Serono, Novartis, and Sanofi-Genzyme; has carried out contracted research for Genentech, Inc., and Biogen; and receives a salary from The University of Pennsylvania, Perelman School of Medicine.
H.-P. Hartung has received honoraria for consulting, serving on steering committees and speaking at scientific symposia with approval from the Rector of Heinrich Heine University Düsseldorf from Bayer, Biogen, Celgene, F. Hoffmann-La Roche Ltd, GeNeuro SA, Genzyme, MedImmune, Merck, Novartis, Octapharma, Receptos, Teva and Sanofi.

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