Safety Information

TOFIDENCE: demonstrated a comparable safety profile to Actemra1-4*

Safety information from the TOFIDENCE Prescribing Information1

WARNING: RISK OF SERIOUS INFECTIONS

See full Prescribing Information for complete Boxed Warning.

  • Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving tocilizumab products.
  • If a serious infection develops, interrupt TOFIDENCE until the infection is controlled. 
  • Perform test for latent TB (except patients with COVID-19); if positive, start treatment for TB prior to starting TOFIDENCE.
  • Monitor all patients for active TB during treatment, even if initial latent TB test is negative.

*Actemra is represented by EU-approved tocilizumab in the study.

Ongoing monitoring and possible dose modifications is recommended for management of certain dose-related laboratory changes. Please see full Prescribing Information for more information.

Safety Data From the TOFIDENCE Clinical Trial Program

Phase I Clinical Study in Healthy Volunteers

The PK parameters were comparable between groups. AUC0–, Cmax, and AUC0-t were within the predefined PK bioequivalence margin for TOFIDENCE, EU-rTCZ, and US-rTCZ.2*

Parameter TOFIDENCE
(N=45)
EU-rTCZ (N=42) US-rTCZ
(N=42)
P value TOFIDENCE/EU-rTCZ
GMR (90% CI)
TOFIDENCE/US-rTCZ
GMR (90% CI)
US-rTCZ/EU-rTCZ
GMR (90% CI)
AUC0-∞ (μg*h/mL) 10,840 (16.6) 11,080 (19.5) 10,690 (15.4) 0.73 98.06
(92.10–104.41)
100.82
(95.76–106.15)
97.26
(91.75–103.10)
AUC0-t (μg*h/mL) 10,260 (17.8) 10,580 (21.5) 10,390 (16.4) 0.78 97.39
(91.01–104.20)
98.18
(92.89–103.78)
99.19
(93.22–105.53)
Cmax (μg/mL) 88.28 (14.5) 96.28 (17.6) 91.29 (16.4) 0.03 91.71
(86.90–96.79)
96.25
(91.70–101.03)
95.28
(90.04–100.82)

Adapted from: Zhang et al. 2021.

*GeoMean (CV%)

Bioequivalence by ANOVA if the 90%  confidence intervals (CIs) for the ratio of geometric means (GMRs) of the treatments compared were contained within the pre-defined equivalence margin (80-125%).

ANOVA=analysis of variance; AUC0-t=area under the curve from zero to the final quantifiable concentration; AUC0–∞=area under the curve from zero to infinity;  Cmax=maximum observable serum concentration; GMR=geometric mean ratio.

Safety data from the Phase I clinical study2

Summary of common TEAEs
Number (%) of subjects
TOFIDENCE
(n=45)
EU-Actemra
(n=42)
US-Actemra
(n=42)
Overall
(N=129)
p*
Number of participants with treatment-related TEAEs 27 (60.0) 34 (81.0) 32 (76.2) 93 (72.1)0.07
Investigations 21 (46.7) 26 (61.9) 27 (64.3) 74 (57.4)0.19
Neutrophil count decreased 12 (26.7) 20 (47.6) 25 (59.5) 57 (44.2)0.007
White blood cell count decreased 7 (15.6) 12 (28.6) 16 (38.1) 35 (27.1)0.06
Alanine aminotransferase increased 6 (13.3) 10 (23.8) 7 (16.7) 23 (17.8)0.43
Aspartate aminotransferase increased 7 (15.6) 8 (19.0) 3 (7.1) 18 (14.0)0.26
Blood bilirubin increased 0 (0.0) 5 (11.9) 4 (9.5) 9 (7.0)0.07
Metabolism and nutrition disorders 11 (24.4) 15 (35.7) 8 (19.0) 34 (26.4)0.20
Hypertriglyceridemia 9 (20.0) 11 (26.2) 6 (14.3) 26 (20.2)0.39
Hyperuricemia 3 (6.7) 4 (9.5) 4 (9.5) 11 (8.5)0.85
Blood and lymphatic system disorders 2 (4.4) 3 (7.1) 0 (0.0) 5 (3.9)0.23
Cardiac disorders 0 (0.0) 4 (9.5) 1 (2.4) 5 (3.9)0.06
Infections and infestations 1 (2.2) 3 (7.1) 1 (2.4) 5 (3.9)0.40

 

Adapted from: Zhang et al. 2021.

p*, the number (%) of subjects with common TEAEs were compared among the three groups. Neutrophil count (p*=0.007). Other treatment-related emergent adverse events (p*>0.05).

Summary of immunogenicity assessment2
(number (%) of subjects with positive antibodies)

Parameter Time
(day)
TOFIDENCE
(n=45)
EU-Actemra
(n=42)
US-Actemra
(n=42)
Overall
(n=129)
p*
ADA 0 2 (4.4) 0.0 0.0 2 (1.6) 0.15
15 3 (6.7) 3 (7.1) 3 (7.1) 9 (7.0) 0.99
43 11 (24.4) 9 (21.4) 9 (21.4) 29 (22.5) 0.92
57 19 (42.2) 10 (23.8) 12 (28.6) 41 (31.8) 0.15
NAb 0 1 (2.2) 0.0 0.0 1 (0.8) 0.39
15 3 (6.7) 3 (7.1) 3 (7.1) 9 (7.0) 0.99
43 10 (22.2) 6 (14.3) 8 (19.0) 24 (18.6) 0.63
57 14 (31.1) 9 (21.4) 12 (28.6) 35 (27.1) 0.57

Adapted from: Zhang et al. 2021.

The positive rates of ADA and NAb were compared among the three groups.

ADA=antidrug antibody; NAb=neutralizing antibody.

Phase III Clinical Study

Summary of safety and immunogenicity outcomes from the TOFIDENCE clinical trial program3,4

Weeks 0-24 (Treatment Period 1)3 Weeks 24-48 (Treatment Period 2) and up to Week 52 (Safety Set)4
n (%) TOFIDENCE
(n=312)
Actemra*
(n=309)
TOFIDENCE
(n=290)
Actemra*
TOFIDENCE
(n=142
Actemra*
(n=145)
TEAE 201 (64) 196 (63) 162 (56) 92 (65) 90 (62)
Treatment-related TEAE 148 (47) 151 (49) 112 (39) 64 (45) 59 (41)
Serious TEAE 11 (4) 13 (4) 8 (3) 5 (4) 4 (3)
Treatment-related serious TEAE 2 (1) 7 (2) 2 (<1) 1 (<1) 1 (<1)
Fatal TEAE 3 (1) 1 (<1) 0 0 0
ADA-positive 64 (21) 42 (14) 61 (21) 23 (16) 27 (19)
NAb-positive 64 (21) 42 (14) 61 (21) 23 (16) 26 (18)

Adapted from: Zhang et al. 2021.

*Actemra is represented by EU-approved tocilizumab in the study.

TEAE=treatment-emergent adverse event.

Safety set included all randomly assigned patients that had received study drug in Treatment Period 1 or Treatment Period 2, respectively.

Treatment Period 1

  • 7 subjects in the rTCZ group reported 12 related serious TEAEs, 4 probably treatment-related and 8 possibly treatment-related
  • 2 subjects in the TOFIDENCE group reported related serious TEAEs, 1 probably treatment-related and 1 possibly treatment-related (ovarian carcinoma - fatal)
  • 4 subjects experienced a fatal TEAE
    - 1 in the rTCZ group (possibly related)
    - 3 in the TOFIDENCE group (2 unrelated, 1 possibly related)

Treatment Period 2

  • 4 subjects in the rTCZ group reported 5 serious TEAEs, 1 possibly treatment-related
  • 5 subjects in the rTCZ to TOFIDENCE group reported 5 serious TEAEs, 1 possibly treatment-related
  • 8 subjects in the TOFIDENCE group reported 9 serious TEAEs, 2 possibly treatment-related

Common TEAEs by preferred term in Treatment Period 13

 

Adapted from: Leng, et al. 2024

*Actemra is represented by EU-approved tocilizumab in the study.

Nonserious TEAEs with an occurrence below 5% in either group are not reported here.

Total reports of any adverse event were comparable between TOFIDENCE 66% (n=206) and Actemra 65% (n=201)3

The occurrence of all TEAEs was 64% (n=201) for TOFIDENCE and 63% (n=196) for Actemra3

Common treatment-related TEAEs by preferred term in
Treatment Period 13

Adapted from: Zhang et al. 2024.

*Actemra is represented by EU-approved tocilizumab in the study.

Nonserious TEAEs with an occurrence below 5% in either group are not reported here.

None of the individual reported serious TEAEs (or treatment-related serious TEAEs) had an incidence higher than 0.5% across all enrolled participants that had received study drug.

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ALT=alanine aminotransferase; DMARD=disease-modifying anti-rheumatic drug; NAb=neutralizing antibody; TEAE=treatment-emergent adverse event.

 

References
  1. TOFIDENCE Prescribing Information, Cambridge, MA: Biogen.
  2. Zhang H, Wang H, Wei H, et al. A phase l clinical study comparing the tolerance, immunogenicity, and pharmacokinetics of proposed biosimilar BAT1806 and reference tocilizumab in healthy Chinese men. Front Pharmacol. 2021;11:609522.
  3. Leng X, Leszczynski P, Jeka S, et al. Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial. Lancet Rheumatol. 2024;6(1):e40-e50.
  4. Leng X, Leszczyński P, Jeka S, et al. A phase 3, randomized, double-blind, active-controlled clinical trial to compare BAT1806/BIIB800, a tocilizumab biosimilar, with tocilizumab reference product in participants with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate: treatment period 2 analysis (week 24 to week 48). Arthritis Res Ther. 2024;26(1):157. doi:10.1186/s13075-024-03375-w