What data exists for the recently approved tocilizumab biosimilar (Tofidence)?

Comment by InpharmD Researcher

Fully published clinical trials for the recently approved tocilizumab biosimilar (BAT1806/BIIB800; tocilizumab-bavi; Tofidence™) are limited to its phase 1 trial, which found tocilizumab-bavi to have similar pharmacokinetic parameters to reference tocilizumab (Actemra®) with a similar safety profile and low intersubject variability. Its phase 3 trial (POS0287), which only has 24- and 52-week results published in the form of abstracts, compared tocilizumab-bavi and reference tocilizumab in patients with moderate to severe rheumatoid arthritis and inadequate response to methotrexate. Results observed comparable safety and immunogenicity profiles as well as equivalent efficacy response rates, as deemed by the FDA’s requirement for equivalency. Due to its recent approval, available guidelines do not yet include recommendations for the tocilizumab biosimilar product.

Background

While multiple guidelines provide recommendations for the use of tocilizumab to treat rheumatoid and juvenile idiopathic arthritis, none have recommendations for the biosimilar agent. The most recent guideline publication was from 2022, which would not have been updated with the recent FDA approval of Tofidence [1], [2], [3]

Due to the lack of published data on the Phase 3 trial evaluating the interchangeability between Tofidence (tocilizumab-bavi; BAT1806/BIIB800) and reference tocilizumab (TCZ), the manufacturer Biogen was contacted to request further information regarding the Phase 3 trial leading to FDA approval of Tofidence. The medical information department further disclosed that the requested data cannot be shared at the current time point but did reference the published poster/abstract on preliminary results. Specifically, a 2022 phase 3 randomized, double-blinded, active-controlled trial, as part of the biosimilar development program, evaluated the efficacy, pharmacokinetics (PK), safety, and immunogenicity of BAT1806/BIIB800 in comparison with European Union (EU)-sourced TCZ in subjects with moderate to severe rheumatoid arthritis with inadequate response to methotrexate (MTX). [4], [5], [6]

A total of 621 eligible patients recruited from 55 centres in China and Europe were randomized (2:1:1) to one of three treatment groups: (1) BAT1806/BIIB800 up to Week 48 (n= 312), (2) TCZ up to Week 48 (n= 155), or (3) TCZ up to Week 24, followed by BAT1806/BIIB800 from Week 24 to Week 48 (n= 154), administered intravenously every 4 weeks at a dose of 8mg/kg. Baseline characteristics were similar across all treatment groups. Results demonstrated comparable proportions of subjects achieving an American College of Rheumatology (ACR)20 response in BAT1806/BIIB800 vs.TCZ groups, both at Week 12 (68.97% vs. 64.82%) and Week 24 (69.89% vs. 67.94%). The corresponding differences between ACR response rates were 4.15% (95% confidence interval [CI] -3.63 to 11.93) at week 12, and 1.94% (90% CI -4.04 to 7.92; 95% CI -5.18 to 9.07) at Week 24, which achieved the pre-defined equivalence margin per FDA (90% CI -12.0%/+15%). Additionally, serum trough levels (15.8 vs. 15.4 mcg/mL), incidence of treatment-emergent adverse events (TEAEs; 64.4% vs. 63.4%), and proportion of antidrug antibody (ADA)-positive patients (20.5% vs. 13.6%) were found to be similar between the biosimilar and reference products. [5], [6]

Subsequent treatment period 2 reporting results from Weeks 24 to 48 included 90 (92.9%), 142 (92.2%), and 145 (93.5%) in groups 1, 2, and 3, respectively. Proportions of ACR20 responders continued to increase up to 253/280 (90.4%), 121/134 (90.3%), and 122/139 (87.8%) for groups 1, 2, and 3, respectively. Again, the incidence of serious TEAEs was similar between treatment groups (2.8% vs. 3.5% vs. 2.8%), and no death occurred. ADAs were reported at least once in 21.0%, 16.2%, and 18.6% of subjects in treatment groups 1, 2, and 3, respectively; of these subjects, all but 1 in the TCZ group tested positive for neutralizing antibodies. Collectively, results from the phase 3 trials concluded comparable efficacy, safety, immunogenicity, and PK profiles between BAT1806, TCZ/BAT1806, and TCZ. In individuals switching from TCZ to BAT1806, no safety or clinically relevant immunogenicity issues were observed. [5], [6]

References:

[1] Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update [published correction appears in Ann Rheum Dis. 2023 Mar;82(3):e76]. Ann Rheum Dis. 2023;82(1):3-18. doi:10.1136/ard-2022-223356
[2] American College of Rheumatology. Juvenile Idiopathic Arthritis Guideline. Accessed October 13, 2023. https://rheumatology.org/juvenile-idiopathic-arthritis-guideline
[3] Onel KB, Horton DB, Lovell DJ, et al. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging. Arthritis Care Res (Hoboken). 2022;74(4):505-520. doi:10.1002/acr.24839
[4] Personal correspondence. Biogen. Medical Information. October 13, 2023.
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[5] Leng X, Leszczynski P, Jeka S, et al. POS0287 A Phase III, Randomised, Double-Blind, Active-Controlled Clinical Trial To Compare Bat1806/Biib800, A Proposed Tocilizumab Biosimilar, With Tocilizumab Reference Product In Subjects With Moderate To Severe Rheumatoid Arthritis With An Inadequate Response To Methotrexate Therapy. Annals of the Rheumatic Diseases 2022;81:388.
[6] Leng X, Leszczynski P, Jeka S, Liu S, Liu H, Miakisz M, Gu J, Kilasonia L, Stanislavchuk M, Yang X, Zhou Y, Dong Q, Mitroiu M, Addison J, Zeng X. Fifty-two-week Results from a Phase 3, Randomized, Double-blind, Active-controlled Clinical Trial to Compare BAT1806/BIIB800, a Proposed Tocilizumab Biosimilar, with a Tocilizumab Reference Product in Subjects with Moderate to Severe RA with an Inadequate Response to Methotrexate [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9).
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Please summarize clinical trials for the recently approved tocilizumab biosimilar. Please also include any guideline recommendations on use of the biosimilar product.

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Table 1 for your response.

 

A Phase I Clinical Study Comparing the Tolerance, Immunogenicity, and Pharmacokinetics of Proposed Biosimilar BAT1806 and Reference Tocilizumab in Healthy Chinese Men

Design

Phase I, randomized, double-blind, single-dose, three-arm, parallel study

N= 129

Objective

To explore the bioequivalence of a proposed biosimilar BAT1806 (TofidenceTM) to its reference products marketed in the EU and US (RoActemra-EU and Actemra-US) among healthy Chinese men. The tolerance, immunogenicity, and pharmacokinetics (PK) of the three drugs were also investigated.

Study Groups

BAT1806 (n= 45)

RoActemra-EU (n= 42)

Actemra-US (n= 42)

Inclusion Criteria

Healthy males aged 18 to 55 years, body mass index 18.0 to 28.0 kg/m2, total body weight between 55 to 85 kg, normal test outcomes or clinically unremarkable results for blood and urine routine tests as well as hepatic and renal function tests during enrollment, absolute neutrophil count of ≥ 1.8 × 109/L and platelet count of ≥ 125 × 109/L

Exclusion Criteria

Clinically significant laboratory abnormalities or other clinically indicated diseases, participated in other clinical trials or donated blood in the past 3 months, positive tuberculosis assay results, contact with a patient with tuberculosis or presenting with suspected symptoms of tuberculosis in the past 3 months

Methods

 Patients fasted for at least 8 hours prior to biosimilar administration and were randomized (1:1:1) to receive a single intravenous drip of 4 mg/kg BAT1806, RoActemra-EU, or Actemra-US for 60 min (± 6 min)

Duration

 57 days

Outcome Measures

Pharmacokinetics: the concentration-time data included time to peak (Tmax), the maximum observable serum concentration (Cmax), clearance (CL), half-life (t 1/2), volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞)

Positive for drug antibodies, positive for neutralizing antibodies, intersubject variability

Baseline Characteristics

  

BAT1806 (n= 45)

RoActemra-EU (n= 42)

 Actemra-US (n= 42)  

Age, years

 37.4 35.1 36  

Weight, kg

 67.04 67.57 66.73  

Body mass index, kg/m2

 23.03 23.71 23.39  

Results

Endpoint

BAT1806 (n= 45)

RoActemra-EU (n= 42)

Actemra-US (n= 42)

p-Value

Pharmacokinetic parameter

AUC0-∞, mcg*h/mL

AUC0-t, mcg*h/mL

Cmax, mcg/mL

Tmax, h

t1/2, h

CL, L/h

Vz, L

AUCextrapolation

 

10,840

10,260

88.28

2

89.81

0.02457

3.184

5.35

 

11,080

10,580

96.28

3

82.08

0.02421

2.867

4.51

 

10,690

10,390

91.29

4

72.57

0.02482

2.599

2.80

 

0.73

0.78

0.03

N/A

N/A

N/A

N/A

N/A

Positive for drug antibodies by Day 57

Positive for neutralizing antibodies by Day 57

19 (42.2%)

14 (31.1%)

10 (23.8%)

9 (21.4%)

12 (28.6%)

12 (28.6%)

0.15

0.57

Intersubject variability ranged from 14.5% to 21.5%.

Adverse Events

A total of 27 participants in the BAT1806 group, 34 participants in the RoActemra-EU group, and 32 participants in the Actemra-US group experienced treatment-related and treatment-emergent adverse events (TEAEs). The most frequently observed treatment-related adverse events were a decrease in neutrophil and white blood cell counts.

Study Author Conclusions

 The PK characteristics of BAT1806 were similar to those of the reference products, RoActemra-EU and Actemra-US. Both BAT1806 and the reference products exhibited low intersubject variability and similar safety profiles.

InpharmD Researcher Critique

The study states that intersubject variability between 14.5% to 21.5% is considered low variability. However, the difference at its peak is over one-fifth of a difference, and could be interpreted as having a concerning amount of variability.



References:

Zhang H, Wang H, Wei H, et al. A Phase I Clinical Study Comparing the Tolerance, Immunogenicity, and Pharmacokinetics of Proposed Biosimilar BAT1806 and Reference Tocilizumab in Healthy Chinese Men. Front Pharmacol. 2021;11:609522. Published 2021 Jan 25. doi:10.3389/fphar.2020.609522