Session Information
Date: Tuesday, November 10, 2015
Title: Rheumatoid Arthritis-Small Molecules, Biologics and Gene Therapy V: Immunogenecity
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Intravenous
(IV) and subcutaneous (SC) formulations of tocilizumab (TCZ) are available for
treatment of adult RA based upon the efficacy and safety outcomes of the Phase III
and IV trials and their open-label, long-term extensions. The objective of this
study was to provide an
overview of the immunogenicity profile of TCZ-SC
and TCZ-IV as monotherapy or in combination with DMARDs, including the
incidence of anti-TCZ antibodies and their impact on safety and efficacy in
patients with RA.
Methods: In the
TCZ-IV (4 or 8 mg/kg every 4 weeks) studies, patients were monitored for up to
5 years, and for TCZ-SC (162 mg weekly or every other week), up to 2 years. Blood
samples were taken at baseline and regularly prior to TCZ dosing throughout the
studies for anti-drug antibody (ADA) assessment. All samples were screened
using a bridging enzyme-linked immunosorbent assay method for ADAs, and samples
that tested positive were analyzed by a confirmation assay for specificity. Those
samples that were confirmation assay positive were further characterized for
neutralizing potential and the immunoglobulin E (IgE) isotype (SC studies only).
Safety and efficacy measures were evaluated in association with ADA development.
Results: For
patients who received TCZ-SC, the proportion that developed ADAs postbaseline
was low and comparable to that for TCZ-IV (2.0% vs 1.2%; Table). Overall, the
incidence of ADA development was ≤2.0%
and similar between patients who received TCZ monotherapy (1.3%) or TCZ+DMARDs
(1.4%), regardless of formulation. No anaphylaxis or serious hypersensitivity
reactions were observed in patients who received TCZ-SC monotherapy, TCZ-SC+DMARDs
or TCZ-IV monotherapy and developed ADAs. Of the patients who had anaphylaxis,
serious hypersensitivity or clinically significant hypersensitivity (n=131), 7.6%
developed ADAs. Of the 63 patients who received TCZ-IV+DMARDs and developed
ADAs, 5 had anaphylaxis; 1 additional patient had a serious hypersensitivity
reaction and 4 additional had clinically significant hypersensitivity
reactions. One patient who received TCZ-IV monotherapy and developed ADAs had a
clinically significant hypersensitivity reaction. Three patients who received
TCZ-SC+DMARDs and developed ADAs had injection site reactions (ISRs), and no
ISRs occurred in patients who received TCZ-SC monotherapy and developed ADAs. Among
patients who developed ADAs with neutralizing potential, none experienced loss
of efficacy, regardless of formulation or concomitant DMARDs.
Conclusion:
TCZ-SC and TCZ-IV have a low risk of immunogenicity potential, with no impact
on safety or efficacy. For patients who received TCZ-SC, the proportion that
developed anti-TCZ antibodies was comparable to that for TCZ-IV. TCZ had low
and comparable immunogenicity to that of monotherapy or in combination with
DMARDs.
|
TCZ-SC vs TCZ-IV
|
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|
|
TCZ-SC all exposure (N = 1638)
|
TCZ-IV all exposure (N = 5875)
|
|
|
|
Total pts screened, n (%)a
|
1636 |
5806 |
||
|
Anaphylaxisb
|
0 |
9 (0.2) |
||
|
Clinically significant hypersensitivityc
|
13 (0.8) |
89 (1.5) |
||
|
Serious hypersensitivityd
|
6 (0.4) |
48 (0.8) |
||
|
Injection site reactionse
|
171 (10.4) |
N/A |
||
|
|
||||
|
Total pts who developed ADAs, n (%)a
|
33 (2.0)
|
69 (1.2)
|
||
|
Neutralization assay +f
|
25 (1.7) |
54 (0.9) |
||
|
IgE assay +g
|
11 (0.7) |
N/A |
||
|
Anaphylaxisb
|
0 |
5 (0.1) |
||
|
Clinically significant hypersensitivityc
|
0 |
10 (0.2) |
||
|
Serious hypersensitivityd
|
0 |
6 (0.1) |
||
|
Injection site reactionse
|
3 (0.2) |
N/A |
||
|
TCZ monotherapy vs TCZ + DMARDs
|
||||
|
|
TCZ-SC mono (N = 173)
|
TCZ-SC + DMARDs (N = 1465)
|
TCZ-IV mono (N = 753)
|
TCZ-IV + DMARDs (N = 5122)
|
|
Total pts screened, n (%)a
|
173 |
1463 |
745 |
5061 |
|
Anaphylaxisb
|
0 |
0 |
1 (0.1) |
8 (0.2) |
|
Clinically significant hypersensitivityc
|
1 (0.6) |
12 (0.8) |
12 (1.6) |
77 (1.5) |
|
Serious hypersensitivityd
|
0 |
6 (0.4) |
7 (0.9) |
41 (0.8) |
|
Injection site reactionse
|
30 (17.3) |
141 (9.6) |
N/A |
N/A |
|
|
||||
|
Total pts who developed ADAs, n (%)a
|
6 (3.5) |
27 (1.8) |
6 (0.8) |
63 (1.2) |
|
Neutralization assay +f
|
N/A |
25 (1.7) |
4 (0.5) |
50 (1.0) |
|
IgE assay +g
|
5 (2.9) |
6 (0.4) |
N/A |
N/A |
|
Anaphylaxisb
|
0 |
0 |
0 |
5 (0.1) |
|
Clinically significant hypersensitivityc
|
0 |
0 |
1 (0.1) |
9 (0.2) |
|
Serious hypersensitivityd
|
0 |
0 |
0 |
6 (0.1) |
|
Injection site reactionse
|
0 |
3 (0.2) |
N/A |
N/A |
|
ADA, anti-drug antibody; DMARD, disease-modifying antirheumatic drugs; IV, intravenous; mono, monotherapy; SC, subcutaneous; TCZ, tocilizumab. TCZ-SC was dosed at 162 mg weekly or every other week. TCZ-IV was dosed at 4 or 8 mg/kg every 4 weeks. a Denominator is total patients screened. b Anaphylactic reactions were defined using Sampson criteria (Sampson HA, J Allergy Clin Immunol, 2006). c In the MUSASHI study, hypersensitivity events were defined as adverse events (AEs), excluding ISRs, that occurred during or within 24 hours of an infusion or injection and were judged as a hypersensitivity event by the clinical expert. In all other studies, hypersensitivity events were defined as all AEs, excluding injection site reactions, that occurred during or within 24 hours of an infusion or injection and were not judged “unrelated”’ to treatment by the investigator; those events may or may not be consistent with hypersensitivity clinically. Clinically significant hypersensitivity events were hypersensitivity events that also led to withdrawal from treatment. d Serious hypersensitivity events were defined as hypersensitivity events that were reported as serious AEs. e Injection site reactions were AEs occurring at the local injection site. f The neutralization assay was not performed in MUSASHI. The denominator used for this does not include the MUSASHI population. g IgE assay was not performed in the TCZ-IV studies. |
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To cite this abstract in AMA style:
Genovese MC, Ogata A, Nomura A, Bao M, Hitraya E, Lacey S, Burmester G. Immunogenicity of Subcutaneous and Intravenous Tocilizumab As Monotherapy or in Combination with Dmards [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/immunogenicity-of-subcutaneous-and-intravenous-tocilizumab-as-monotherapy-or-in-combination-with-dmards/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/immunogenicity-of-subcutaneous-and-intravenous-tocilizumab-as-monotherapy-or-in-combination-with-dmards/