What do guidelines and primary literature say regarding tocilizumab and its available biosimilars?

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) 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. Similarly, MSB11456 (tocilizumab-aazg; Tyenne®) was reported to be pharmacokinetically similar to US-licensed tocilizumab, as well as comparable efficacy and safety to EU-licensed tocilizumab. Due to recent approvals, available guidelines do not yet include recommendations for any 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.
[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 3 studies investigating the researchable question:

What do guidelines and primary literature say regarding tocilizumab and its available biosimilars?

Level of evidence

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



Please see Tables 1-3 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

 

Pharmacokinetics of a proposed tocilizumab biosimilar (MSB11456) versus US-licensed tocilizumab: results of a randomized, double-blind, single-intravenous dose study in healthy adults

Design

Prospective, randomized, double-blind, two-arm, parallel-group, single-dose study

N= 128

Objective

To assess pharmacokinetic (PK) equivalence of intravenous MSB11456 to US-licensed tocilizumab

Study Groups

MSB11456 (n= 62)

Tocilizumab (n= 66)

Inclusion Criteria

Healthy patients aged ≥18 to ≤55 years; body mass index (BMI) ≥18.5 to ≤30.0 kg/m2

Exclusion Criteria

History or presence of clinically significant atopic allergy or anaphylactic reactions; significant concurrent disease; previously exposed to tocilizumab or any other IL-6 acting drug

Methods

Patients in Poland were randomized in a 1:1 ratio to either a single one-hour 8 mg/kg IV infusion of either MSB11456 or tocilizumab. In total, 21 blood samples were collected from each subject on day 1 before start of infusion (0 hour) and 0.5, 1 (immediately after end of infusion), 2, 4, 8, and 12 hours post-start of the infusion, and different temporal points up until day 48 of treatment.

Duration

48 days

Outcome Measures

Primary: PK parameter area under the concentration–time curve (AUC) from time zero to the last quantifiable concentration (AUC0–last)

Secondary: maximum observed concentration (Cmax) and AUC from time zero to infinity (AUC0–inf)

Baseline Characteristics

 

MSB11456 (n= 62)

Tocilizumab (n= 66)

Age, years

35.5 ± 9.5 32.8 ± 9

Female

21 (33.9%) 19 (28.8%)

White

62 (100%) 66 (100%)

Weight, kg

77.10 ± 9.3 76.53 ± 10.1

BMI, kg/m2

25.15 ± 2.7 25.14 ± 2.8

≥1 medical history*

33 (53.2%) 32 (48.5%)

* No medical history was considered to be of clinical significance

Only one subject (MSB11456 group) was ADA-positive prior to dosing.

Results

Endpoint

MSB11456 (n= 62)

Tocilizumab (n= 66)

PK parameters following a 1-h infusion

Cmax, mcg/mL

AUC0–last, h*mcg/mL

AUC0–inf, h*mcg/mL

t1/2, h

CL, mL/h

tmax, h

 

176 ± 21.5

29,179 ± 4,242

32,343 ± 5,185

204 ± 35.1

19.5 ± 3.34

2.00

 

174 ± 28.4

28,316 ± 4,608

31,449 ± 5,655

203 ± 36.9

20.0 ± 3.91

2.00

Post-infusion ADA positivity

Day 29 ADA positivity

Day 48 ADA positivity

91.9%

88.7%

12.9%

98.5%

87.9%

10.6%

Endpoint

GLSM

90% CI

Ratio of GLSM for MSB1456/tocilizumab

AUC0–last, h*mcg/mL

Cmax, mcg/mL

AUC0–inf, h*mcg/mL

 

103.34

101.48

103.15

 

98.53 to 108.37

97.23 to 105.92

97.86 to 108.73

Abbreviations: ADA, anti-drug antibodies; AUC, area under the concentration–time curve; AUC0–inf, AUC from time zero to infinity; AUC0–last, AUC from time zero to the time of the last quantifiable concentration; CI, confidence interval; CL, total clearance; Cmax, maximum observed serum concentration; tmax, time to maximum observed serum concentration; t1/2, terminal elimination half-life; GLSM, geometric least squares mean; TEAE, treatment-emergent adverse event

Adverse Events

Common Adverse Events (MSB11456 vs. tocilizumab): 61.3% vs. 57.6% overall experienced at least one TEAE. Most commonly reported: Grade 3 or 4 neutropenia (32.3% vs. 21.2%) and headache (16.1% vs. 13.6%). Neutropenic events were considered treatment-related, while headaches were considered unrelated.

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Pharmacokinetic similarity of MSB11456 and US-licensed tocilizumab was demonstrated, with comparable immunogenicity and safety profiles, supporting MSB11455 as a biosimilar to US-licensed tocilizumab.

InpharmD Researcher Critique

The limited sample size, use of healthy subjects, and short-term follow-up reduces generalizability to a larger patient population, as the study may not have sufficiently captured more rare adverse events.

References:

Tomaszewska-Kiecana M, Ullmann M, Petit-Frere C, Monnet J, Dagres C, Illes A. Pharmacokinetics of a proposed tocilizumab biosimilar (MSB11456) versus US-licensed tocilizumab: results of a randomized, double-blind, single-intravenous dose study in healthy adults. Expert Rev Clin Immunol. 2023;19(4):439-446. doi:10.1080/1744666X.2023.2174104

 

Comparison of the efficacy and safety of a proposed biosimilar MSB11456 with tocilizumab reference product in subjects with moderate-to-severe rheumatoid arthritis: results of a randomised double-blind study

Design

Multicenter, randomized, double-blind, multinational, parallel-group study

N= 604

Objective

To evaluate the efficacy, immunogenicity and safety of MSB1156 compared with European Union (EU)- approved tocilizumab in patients with moderate-to-severe active rheumatoid arthritis (RA) who had experienced an inadequate clinical response to at least one disease-modifying antirheumatic drug (DMARD) and were receiving a stable dose of methotrexate

Study Groups

MSB11456 (n= 302)

Reference tocilizumab (n= 302)

Inclusion Criteria

Age ≥18 years, body weight <100 kg, diagnosis of RA with disease duration ≥6 months and moderate-to-severe disease activity, treated with methotrexate for ≥12 consecutive weeks at a stable dose of 10-25 mg/week, previous inadequate clinical response to one or more conventional synthetic DMARD (csDMARD; discontinued at least 8 weeks prior) or biologics (discontinued at least 12 weeks prior)

Exclusion Criteria

American College of Rheumatology (ACR) functional class IV; received more than two previous biologics for RA; previous use of tocilizumab, an interleukin (IL)-6 acting drug, targeted synthetic DMARD or high potency opioid analgesic; use of nonsteroidal anti-inflammatory drugs within 4 weeks; use of oral corticosteroids >10 mg/day prednisone or equivalent within 6 weeks

Methods

Patients were randomized (1:1) to receive 24 weekly subcutaneous 162 mg injections of either MSB11456 or EU-approved tocilizumab into the lower abdomen starting on day 1. All patients continued stable dose of methotrexate (10-25 mg/week) and stable dose of corticosteroids (≤10 mg/day) and received a stable dose of folic acid (≥5 mg/week total folate dose).

At week 24, patients remaining on study treatment entered the double-blind extended period. Patients originally in the MSB11456 group were randomized to continue treatment with MSB11456, and patients originally in the EU-approved tocilizumab group were randomized (1:1) to continue their weekly treatment with EU-approved tocilizumab or transition to MSB11456.

Equivalence between treatments was considered if the 95% confidence interval (European Medicines Agency)/90% confidence interval (US Food and Drug Administration) for the difference in mean change from baseline to week 24 in Disease Activity Score-28 Joint Count with erythrocyte sedimentation rate (DAS28-ESR) between treatments was entirely within prespecified equivalence intervals (−0.6 to 0.6 and −0.6 to 0.5, respectively).

Duration

August 3, 2020 to June 6, 2022

Follow-up: 52 weeks; 55 weeks for safety and immunogenicity

Outcome Measures

Primary: change from baseline in DAS28-ESR at week 24

Secondary: 20% improvement in ACR core set measures (ACR20) at week 24; change from baseline in DAS28-ESR at week 12; 50%/70% improvement in ACR core set measures (ACR50/70); change from baseline in DAS28-CRP; treatment-induced anti-drug antibodies (ADA) positivity

Double-blind extended period: change from baseline to week 52 in DAS28-ESR and DAS28-CRP

Baseline Characteristics

 

MSB11456 (n= 302)

Reference tocilizumab (n= 302)

 

Age, years

51.2 ± 12.7 53.2 ± 11.3  

Female

82.8% 82.1%  

White

100% 100%  

Body mass index, kg/m2

26.9 ± 4.7 26.2 ± 4.6  

Functional class

1

2

3


8.3%

76.5%

15.2%


5.6%

81.5%

12.9%

 

Previous use of biologics

9.3%

8.6%

 

DAS28-ESR*

Low

Moderate

High


0.3%

5.3%

94.4%


0

7.3%

92.7%

 

DAS28-CRP

5.44 ± 0.90

5.42 ± 0.90

 

Clinical Disease Activity Index (CDAI)†

Low

Moderate

High


0.3%

5.3%

94.4%


0.3%

7.0%

92.7%

 

Simplified Disease Activity Index (SDAI)‡

Low

Moderate

High


0.3%

10.9%

88.7%


0.3%

11.9%

87.7%

 

*DAS28-ESR: low ≤2.6 to <3.2; moderate ≤3.2 to ≤5.1; high >5.1

†CDAI: low <2.8 to ≤10; moderate <10 to ≤22; high >22

‡SDAI: low <3.3 to ≤11; moderate <11 to ≤26; high >26

Results

Endpoint

MSB11456 (n= 302)

Reference tocilizumab (n= 302)

Difference (95% CI unless otherwise specified)

LS mean change from baseline to week 24 in DAS28-ESR

-3.53 ± 0.11 -3.54 ± 0.11 0.01 (-0.16 to 0.18) (-0.19 to 0.22)*

ACR20 response rate at week 24

244 (80.8%) 256 (84.8%) -3.94 (-9.97 to 2.11)

LS mean change from baseline to week 12 in DAS28-ESR

-3.13 ± 0.10 -3.12 ± 0.10 -0.01 (-0.21 to 0.19)

LS mean change from baseline to week 24 in DAS28-CRP

-2.78 ± 0.07 -2.83 ± 0.07 0.05 (-0.12 to 0.22)

ACR50 response rate at week 24

183 (60.6%) 188 (62.3%) -1.59 (-9.29 to 6.15)

ACR70 response rate at week 24

118 (39.1%) 116 (38.4%) 0.73 (-7.01 to 8.45)

Treatment-induced ADA positivity reported

24-week treatment period

55-week overall treatment period

 

95%

98.7%

 

92.4%

98.1%

N/A

Double-blind extended period

MSB11456 (n= 302) Reference tocilizumab (n= 302)

Reference tocilizumab/MSB11456 (n= 139)

LS mean change from baseline to week 52 in DAS28-ESR

-4.00 ± 0.09 -3.80 ± 0.12 -4.05 ± 0.12

LS mean change from baseline to week 52 in DAS28-CRP

-3.14 ± 0.08 -3.06 ± 0.10 -3.21 ± 0.10

CI, confidence interval; LS, least squares

*(90% CI)(95% CI)

Adverse Events

Common Adverse Events: increased alanine aminotransferase (9.3% vs. 11.6%), COVID-19 (6% vs. 5.6%), neutropenia (6% vs. 5%), leukopenia (5.6% vs. 4.6%), increased aspartate aminotransferase (4.6% vs. 5.3%)

Serious Adverse Events: any (9.3% vs. 9.9%), treatment-related (1% vs. 1%)

Percentage that Discontinued due to Adverse Events: 7.3% vs. 5.6%

Study Author Conclusions

Therapeutic equivalence was demonstrated for efficacy endpoints, and safety and immunogenicity analyses support the similarity of the two treatments. The results of this study strengthen the evidence that the proposed biosimilar MSB11456 and EU-approved tocilizumab exert similar clinical effects.

InpharmD Researcher Critique

The strict exclusion criteria may limit the generalizability of the results. It should be noted that EU-approved tocilizumab was utilized as the reference product in this study, not US-approved tocilizumab. However, an equivalence analysis for the primary outcome was conducted based on U.S. Food & Drug Administration criteria.



References:

Zubrzycka-Sienkiewicz A, Klama K, Ullmann M, et al. Comparison of the efficacy and safety of a proposed biosimilar MSB11456 with tocilizumab reference product in subjects with moderate-to-severe rheumatoid arthritis: results of a randomised double-blind study. RMD Open. 2024;10(1):e003596. Published 2024 Feb 5. doi:10.1136/rmdopen-2023-003596