Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 versus reference tocilizumab: a randomized, double-blind, single-dose phase I study

ABSTRACT

Background

CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab (EU-tocilizumab) in healthy Asian adults.

Research design and methods

This double-blind, multicenter, parallel-group trial randomized healthy adults (1:1) to receive a single (162 mg/0.9 mL) subcutaneous dose of CT-P47 or EU-tocilizumab. The primary endpoint (Part 2) was PK equivalence by area under the concentration – time curve (AUC) from time zero to last quantifiable concentration (AUC_0–last), AUC from time zero to infinity (AUC_0–inf), and maximum serum concentration (C_max). PK equivalence was concluded if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the 80–125% equivalence margin. Additional PK endpoints, immunogenicity, and safety were evaluated.

Results

In Part 2, 289 participants were randomized (146 CT-P47; 143 EU-tocilizumab); 284 received study drug. AUC_0–last, AUC_0–inf, and C_max were equivalent between CT-P47 and EU-tocilizumab: 90% CIs for the ratios of gLSMs were within the 80–125% equivalence margin. Secondary PK endpoints, immunogenicity, and safety were comparable between groups.

Conclusions

CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults.

Clinical trial registration

www.clinicaltrials.gov identifier is NCT05188378.

Plain Language Summary

Tocilizumab is a biologic medicine used to treat inflammatory diseases including rheumatoid arthritis. Biosimilars are drugs that are highly similar to an already approved, ‘reference’ biologic medicine. This means that they do not have any differences from the reference product in factors including structure, biologic function, efficacy, and safety, that might affect how well they work in patients. Biosimilars are often available at a lower cost than reference drugs, so their use can provide patients with better access to expensive treatments. There are no approved biosimilars of tocilizumab so far: CT-P47 is currently in development as a potential tocilizumab biosimilar.

In the main part of this study, 289 healthy Asian volunteers were randomly allocated to receive a single injection of either CT-P47 or the reference drug, European Union-approved tocilizumab (EU-tocilizumab). The main aim of the study was to find out whether CT-P47 and EU-tocilizumab were equivalent in terms of pharmacokinetics (drug absorption, distribution, metabolism, and excretion by the body). This is part of a standard process required by regulatory authorities to ensure that biosimilars work as well as their reference drugs. Analysis of blood samples taken over 43 days showed that the pharmacokinetic profiles of CT-P47 and EU-tocilizumab were equivalent, after the volunteers received a single dose of either drug. Safety and immunogenicity (immune responses made to the drug) were also comparable between CT-P47 and EU-tocilizumab. While only healthy Asian adults were included, further research comparing CT-P47 with reference tocilizumab will help to ensure that the findings from the study can be applied to broader populations.

KEYWORDS:

• Biosimilar
• CT-P47
• immunogenicity
• pharmacokinetics
• safety
• tocilizumab

1. Introduction

Tocilizumab is a recombinant, humanized, monoclonal antibody of the immunoglobulin G1k class that targets the cognate interleukin (IL)-6 receptor both in its soluble and membrane-bound forms [1,2]. In doing so, it inhibits the IL-6-mediated signal transduction involved in the pathogenesis of certain lymphoproliferative disorders and immune-mediated inflammatory diseases [1]. Reference tocilizumab (intravenous [IV] formulation) received regulatory approval in Europe in 2009 and in the United States (US) in 2010 [3,4], and a subcutaneous (SC) formulation was subsequently approved [2,5]. Indications for the SC formulation comprise rheumatoid arthritis (RA), juvenile idiopathic arthritis, giant cell arteritis, and systemic sclerosis-associated interstitial lung disease (in the US only) [2,5].

Over the last two decades, biologics have changed the face of treatment for immune-mediated inflammatory diseases [6,7]; however, their relatively high costs in the context of resource-constrained healthcare systems continue to limit patient access [7,8]. Biosimilars approved in highly regulated areas, such as by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA), are biologic products with no clinically meaningful differences from an approved reference product in factors including structure, biological activity, safety, efficacy, and immunogenicity. Biosimilarity is demonstrated through the totality of the evidence gained through a comprehensive set of comparative analytical, non-clinical, and clinical studies [9,10]. Since biosimilars are generally available at a lower cost than their reference products, cost savings can be leveraged to improve patient access to biologic treatments, or allocated to advances in the same therapeutic area or elsewhere within healthcare systems [7]. At present, no biosimilars of tocilizumab have obtained regulatory approval from the FDA or EMA [11,12], although results of phase I studies comparing IV- or SC-administered candidate tocilizumab biosimilars with the reference product have been published [13–16]. CT-P47 is among the candidate tocilizumab biosimilars currently in clinical development [17], for administration by SC or IV routes.

A first-in-human, phase I trial of CT-P47 has been conducted (ClinicalTrials.gov: NCT05188378). This was a two-part, randomized, double-blind, multicenter, parallel-group study. The objective of Part 1 was to evaluate the safety of CT-P47, compared with that of European Union-approved reference tocilizumab (EU-tocilizumab); the results are briefly described herein. Part 2, the focus of this report, aimed to assess the pharmacokinetic (PK) equivalence of CT-P47 and EU-tocilizumab in healthy adults. Immunogenicity and safety were also evaluated.

2. Participants and methods

2.1. Study design

This two-part, randomized, double-blind, parallel-group, phase I trial (ClinicalTrials.gov: NCT05188378) was conducted in healthy individuals at seven centers in the Republic of Korea in Part 2 (Supplementary Table S1) and at a single center in Part 1.

Screening took place between Day −28 and Day −2. Participants were admitted to the study center on Day −1 or Day 1, depending on the timing of screening and study center availability. Participants remained at the center until assessments were completed 24 h post-dose. Remaining assessments (up to Day 43; end of study [EOS]) were conducted on an outpatient basis.

Participants were randomized (1:1) to CT-P47 or EU-tocilizumab. Randomization numbers were generated by an interactive web response system and allocated to participants sequentially, based on a computer-generated randomization list prepared by unblinded statisticians prior to the study. Randomization was balanced by permuted blocks, using randomly selected block sizes of two and four. Randomization was stratified by Day −1 body weight (<70 kg versus 70–<90 kg versus ≥90 kg), sex (male versus female), and study center (for Part 2 only). Participants and investigators involved in study assessments were blinded to treatment assignment.

On Day 1, participants received a single SC injection (162 mg/0.9 mL) of CT-P47 (Celltrion, Incheon, Republic of Korea) or EU-tocilizumab (Roche, Basel, Switzerland) administered into the outer upper arm via a prefilled syringe (PFS). Injections were administered by unblinded study center staff. Participants were blinded to treatment assignment through the use of curtains, blindfolds, and concealed sharps bins. Study drugs were administered under fasting conditions. Participants fasted for ≥8 h prior to study drug administration, and until 4 h post-dose. Water was permitted, except for 1 h either side of study drug administration.

The study was conducted in accordance with the legal and regulatory requirements of the Republic of Korea, the International Council for Harmonisation Guideline for Good Clinical Practice, and the principles of the Declaration of Helsinki. Participants provided written informed consent prior to study enrollment. The study protocol, informed consent form, and any other written materials provided to participants were approved by Institutional Review Boards at each study center (Supplementary Table S1) prior to study initiation.

2.2. Participants

Full eligibility criteria can be found in the Supplementary Methods. In brief, eligible individuals were adults aged 19–55 years (inclusive) who were healthy (defined as having no clinically relevant abnormalities identified by a detailed medical history, full physical examination, and clinical laboratory tests). Eligible participants had a body mass index (BMI) of 18.5–28.0 kg/m² (inclusive) and weighed ≥60–≤100 kg (males) or ≥50–≤100 kg (females). Key exclusion criteria included a history or presence of clinically significant atopy or hypersensitivity/allergic reactions to study drug excipients or monoclonal antibodies; a history or presence of systemic or local infections, gastrointestinal conditions, or malignancy (except adequately treated squamous or basal cell carcinoma of the skin); laboratory abnormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, absolute neutrophil count, or platelet count at screening or Day −1; and a history of exposure to tocilizumab, candidate tocilizumab biosimilars, or IL-6-targeted drugs.

2.3. Study endpoints

The primary study endpoint (assessed during Part 2 of the study) was the PK equivalence of CT-P47 and EU-tocilizumab, as determined by the area under the concentration – time curve from time zero to infinity (AUC_0–inf), the area under the concentration – time curve from zero to the last quantifiable concentration (AUC_0–last), and the maximum serum concentration (C_max). Additional PK variables were evaluated as secondary endpoints, including time to maximum serum concentration (T_max), terminal half-life (t_1/2), percentage of the area under the concentration – time curve from time zero to infinity obtained by extrapolation (%AUC_ext), terminal elimination rate constant (λ_z), apparent total body clearance (CL/F), apparent volume of distribution during the terminal phase (V_z/F), and serum tocilizumab concentrations at each timepoint. Immunogenicity was evaluated at Days 1, 13, and 43 (EOS). Safety was monitored throughout the study.

2.4. Study assessments

Blood samples for the PK evaluation were taken on Day 1 (pre-dose and 8 h post-dose) and at all subsequent visits: Days 2, 3, 4, 5, 6, 7, 8, 10, 13, 16, 19, 22, 29, 36, and EOS. Serum tocilizumab concentrations were determined using an electrochemiluminescence (ECL) method (Meso Scale Discovery, Meso Scale Diagnostics, Rockville, MD, US). For the calculation of PK variables, concentrations below the lower limit of quantification (BLQ; 0.08 µg/mL) prior to study drug administration (or soon after administration, before the first measurable concentration) were set to zero. Post-dose concentrations that were BLQ, measurable concentrations after consecutive BLQ values, and all other incidences of BLQ values were set to missing. PK variables were calculated by non-compartmental methods using Phoenix WinNonlin version 8.3 (Pharsight, St Louis, MO, US).

Serum samples for immunogenicity evaluation were taken on Day 1 (pre-dose) and at Days 13 and 43. Anti-drug antibodies (ADAs) and ADA titers were detected using a validated ECL bridging assay, with a sensitivity of 3.021 ng/mL. Confirmed ADA-positive samples were further analyzed for neutralizing antibodies (NAbs) using a validated ECL assay with affinity capture elution, with a sensitivity of 148.787 ng/mL.

Safety assessments included monitoring of adverse events (AEs), hypersensitivity, and prior/concomitant medications throughout the study. Clinical laboratory assessments (hematology, clinical chemistry, and urinalysis) were conducted during screening (Day −28 to −2), at Days −1, 2, 6, 13, 29, and EOS. Treatment-emergent adverse events (TEAEs) were AEs that occurred or worsened after study drug exposure. Treatment-emergent adverse events of special interest (TEAESIs) were infection, hypersensitivity (including anaphylaxis), injection-site reactions (ISRs), hepatic events, hemorrhage, gastrointestinal perforation, malignancy, and demyelinating disorders (see Supplementary Methods). TEAEs were coded using the Medical Dictionary for Regulatory Activities version 25.0. Severity was graded using the Common Terminology Criteria for Adverse Events version 5.0. Local injection-site pain was measured within 15 min after study drug administration using a 100-mm visual analog scale (VAS).

2.5. Statistical analysis

The primary analysis assessed the PK equivalence of CT-P47 and EU-tocilizumab, based on the primary endpoints AUC_0–inf, AUC_0–last, and C_max. An analysis of covariance was used to analyze log-transformed primary endpoints, with treatment as a fixed effect and Day −1 body weight, sex, and study center as covariates. For each primary endpoint, the difference in least-squares means was backtransformed to determine the ratio of geometric least-squares means (gLSMs) and corresponding 90% confidence intervals (CIs). Equivalence between CT-P47 and EU-tocilizumab was concluded if the 90% CI was entirely contained within the predefined equivalence margin of 80–125%.

For Part 2, sample size calculations showed that a sample size of 242 participants (121 per group) was required to achieve 90% power to demonstrate PK equivalence. Calculations were based on an equivalence margin of 80–125%, two one-sided tests at an alpha level of 0.05, a coefficient of variation of 53%, and an expected gLSM ratio of 1.03. In anticipation of a 10% dropout rate, randomization of 270 participants (135 per group) was planned. No formal statistical inferences were made in Part 1 of the study; therefore, a sample size justification based on a formal statistical hypothesis was not relevant, and randomization of approximately 30 participants was planned.

The analysis sets are explained in Supplementary Methods; participants who were ADA positive at baseline were included in the PK analyses. Categorical variables were summarized as n (%). Continuous variables were summarized using descriptive statistics. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, US).

3. Results

3.1. Results of Part 1 of the study

In Part 1 of the study, the first participant was randomized on 5 January 2022, and the last participant’s final visit was on 6 April 2022. In total, 29 participants were randomized and received study drug (CT‑P47, N = 14; EU-tocilizumab, N = 15); one participant in the CT-P47 group withdrew consent and discontinued the study after the Day 29 visit. Baseline characteristics for the randomized participants are shown in Supplementary Table S2. All participants successfully received the full volume of study drug administered via PFS, and comparable proportions of participants experienced TEAEs in each treatment group (Supplementary Table S3).

The remainder of this report presents data from Part 2 of the study.

3.2. Participant disposition

In Part 2 of the study, the first participant was randomized on 22 December 2021, and the last participant’s final visit was on 2 May 2022. Overall, 289 participants were randomized: 146 to the CT-P47 group and 143 to EU-tocilizumab (Figure 1). Of these, 284 participants received study drug, and 278 completed the study. Six (2.1%) participants discontinued the study after study drug administration. Five participants withdrew consent, two in the CT-P47 group and three in the EU-tocilizumab group. One participant in the CT-P47 group experienced a treatment-emergent serious adverse event (TESAE) of coronavirus disease 2019 (COVID-19), leading to discontinuation from the study due to isolation at a treatment center. However, this was not captured as a TEAE leading to study drug discontinuation since the direct cause of discontinuation from the study was isolation, meaning that the participant could not attend the study site for the remaining scheduled study visits, rather than the TESAE of COVID-19.

Figure 1. Participant flow diagram (Part 2).

^aThe participant experienced COVID-19, considered unrelated to study drug and of grade 2 in intensity. This was documented as a TESAE due to admission to a community treatment center for isolation purposes; as a result, the participant was unable to complete the study and discontinued on Day 29.

COVID-19 = coronavirus disease 2019. EU-tocilizumab = European Union-approved reference tocilizumab. TESAE = treatment-emergent serious adverse event.

Baseline demographics and characteristics were comparable between groups (Table 1). All participants were Asian, and 76.1% were male. At screening, median (range) body weight was 70.4 (50.4–96.7) kg and 69.5 (51.3–98.0) kg in the CT-P47 and EU-tocilizumab groups, respectively. Correspondingly, median (range) BMI was 23.85 (18.8–27.9) kg/m² and 24.00 (18.6–28.0) kg/m².

Table 1. Baseline demographics and characteristics (intent-to-treat set; Part 2).

	CT-P47 (N = 146)	EU-tocilizumab (N = 143)
Age (years), median (range)	26 (19–50)	26 (19–51)
Sex, n (%)^a
Male	112 (76.7)	108 (75.5)
Female	34 (23.3)	35 (24.5)
Body weight at Day −1, n (%)^a,b
<70 kg	71 (48.6)	74 (51.7)
70–<90 kg	69 (47.3)	66 (46.2)
≥90 kg	6 (4.1)	3 (2.1)
Weight at screening (kg), median (range)	70.4 (50.4–96.7)	69.5 (51.3–98.0)
Height at screening (cm), median (range)	171.7 (151.1–189.0)	172.1 (153.3–197.7)
BMI at screening (kg/m^2), median (range)	23.85 (18.8–27.9)	24.0 (18.6–28.0)
Site number, n (%)^a
1	13 (8.9)	14 (9.8)
2	18 (12.3)	17 (11.9)
3	19 (13.0)	21 (14.7)
4	27 (18.5)	27 (18.9)
5	27 (18.5)	25 (17.5)
6	21 (14.4)	20 (14.0)
7	21 (14.4)	19 (13.3)
Asian race, n (%)	146 (100.0)	143 (100.0)
Non-Hispanic or Non-Latino ethnicity, n (%)	146 (100.0)	143 (100.0)
Smoking history, n (%)
Yes	57 (39.0)	59 (41.3)
No	89 (61.0)	84 (58.7)
Average cigarette consumption for smokers (cigarettes/day), median (range)	8 (2–10)	8 (1–10)

^aStratification factor for randomization.

^bFor participants whose Day −1 assessments were omitted, screening body weight was used.

BMI = body mass index. EU-tocilizumab = European Union-approved reference tocilizumab.

3.3. Pharmacokinetics

Mean serum tocilizumab concentrations were comparable between the CT-P47 and EU-tocilizumab groups throughout the study (Figure 2). Primary and secondary PK variables were comparable between treatment groups (Table 2). The PK equivalence between CT-P47 and EU-tocilizumab was demonstrated for the primary PK endpoints, AUC_0–inf, AUC_0–last, and C_max (Table 3). The 90% CIs for the ratios of gLSMs were within the predefined equivalence margin of 80–125%.

Figure 2. Mean (SD) serum concentrations of CT-P47 and EU-tocilizumab (PK set; Part 2).

Note: Values below the lower limit of quantification were set to zero.

EU-tocilizumab = European Union-approved reference tocilizumab. PK = pharmacokinetic. SD = standard deviation.

Table 2. Summary of PK variables (PK set; Part 2).

	CT-P47 (N = 144)	EU-tocilizumab (N = 140)
AUC0–inf (day*μg/mL)
n	138^a	136^a,b
Mean (SD)	94.34 (40.95)	85.98 (36.23)
AUC0–last (day*μg/mL)
n	144	139^a
Mean (SD)	92.57 (40.28)	84.26 (35.42)
Cmax (μg/mL)
n	144	140
Mean (SD)	10.33 (4.01)	9.83 (3.58)
Tmax (day)
n	144	140
Median (range)	3.99 (1.00–8.98)	3.99 (1.00–6.99)
t1/2 (day)
n	138^a	136^a,b
Mean (SD)	1.65 (0.68)	1.67 (0.70)
%AUCext (%)
n	138^a	136^a,b
Mean (SD)	1.26 (4.22)	1.29 (3.33)
λz (1/day)
n	138^a	136^a,b
Mean (SD)	0.4555 (0.09603)	0.4539 (0.1031)
CL/F (L/h)
n	138^a	136^a,b
Mean (SD)	0.1020 (0.1325)	0.09874 (0.07281)
Vz/F (L)
n	138^a	136^a,b
Mean (SD)	6.10 (11.41)	5.70 (4.91)

^aλ_z and its associated variables (i.e. t_1/2, AUC_0–inf, %AUC_ext, CL/F, and V_z/F) were not evaluable for nine participants: eight participants (CT-P47, n = 5; EU-tocilizumab, n = 3) were excluded from the AUC_0–inf analysis owing to adjusted coefficients of determination (adjusted R²) <0.85; one participant in the CT-P47 group did not have ≥3 PK evaluations after C_max; thus, AUC_0–inf was not evaluable.

^bOne participant in the EU-tocilizumab group was excluded from all PK analyses other than C_max and T_max due to increased serum tocilizumab concentrations observed after 360 h post-dose. These results were not considered physiologically plausible; no reasons for the impact on these PK parameters could be identified.

%AUC_ext = percentage of area under the concentration – time curve from time zero to infinity obtained by extrapolation. λ_z = terminal elimination rate constant. AUC_0–inf = area under the concentration – time curve from time zero to infinity. AUC_0–last = area under the concentration – time curve from zero to the last quantifiable concentration. CL/F = apparent total body clearance. C_max = maximum serum concentration. EU-tocilizumab = European Union-approved reference tocilizumab. PK = pharmacokinetic. SD = standard deviation. t_1/2 = terminal half-life. T_max = time to maximum serum concentration. V_z/F = apparent volume of distribution during the terminal phase.

Table 3. Statistical analysis of the primary PK endpoints (PK set; Part 2).

	CT-P47 (N = 144)	EU-tocilizumab (N = 140)
AUC0–inf (day*μg/mL)
n	138^a	136^a,b
gLSM	79.37	73.54
Ratio (90% CI) of gLSMs	107.92 (98.04–118.80)
AUC0–last (day*μg/mL)
n	144	139^b
gLSM	77.55	72.52
Ratio (90% CI) of gLSMs	106.93 (97.36–117.43)
Cmax (μg/mL)
n	144	140
gLSM	8.89	8.63
Ratio (90% CI) of gLSMs	103.00 (94.67–112.06)

Note: An analysis of covariance was performed using the natural log-transformed PK variables as the dependent variable, treatment as a fixed effect, and stratification factors (Day −1 body weight, sex, and study center) as covariates.

^aλ_z and its associated variables (i.e. t_1/2, AUC_0–inf, %AUC_ext, CL/F, and V_z/F) were not evaluable for nine participants: eight participants (CT-P47, n = 5; EU-tocilizumab, n = 3) were excluded from the AUC_0–inf analysis owing to adjusted coefficients of determination (adjusted R²) <0.85; one participant in the CT-P47 group did not have ≥3 PK evaluations after C_max;; thus, AUC_0–inf was not evaluable.

^bOne participant in the EU-tocilizumab group was excluded from all PK analyses other than C_max and T_max due to increased serum tocilizumab concentrations observed after 360 h post-dose. These results were not considered physiologically plausible; no reasons for the impact on these PK parameters could be identified.

%AUC_ext = percentage of area under the concentration – time curve from time zero to infinity obtained by extrapolation. λ_z = terminal elimination rate constant. AUC_0–inf = area under the concentration – time curve from time zero to infinity. AUC_0–last = area under the concentration – time curve from zero to the last quantifiable concentration. CI = confidence interval. CL/F = apparent total body clearance. C_max = maximum serum concentration. EU-tocilizumab = European Union-approved reference tocilizumab. gLSM = geometric least-squares mean. PK = pharmacokinetic. t_1/2 = terminal half-life. T_max = time to maximum serum concentration. V_z/F = apparent volume of distribution during the terminal phase.

3.4. Immunogenicity

Prior to study drug administration, one (0.7%) participant in each group was ADA positive (Supplementary Table S4). Comparable proportions of participants had ≥1 positive post-baseline ADA result in the CT-P47 and EU-tocilizumab groups (13.9% and 20.7%, respectively). No participant had positive NAb results prior to study drug administration, while comparable proportions of participants in each treatment group had ≥1 positive post-baseline NAb result (11.8% in the CT-P47 group and 14.3% in the EU-tocilizumab group). At the EOS visit (Day 43), there was no distinct difference in the pattern of ADA titer levels between the two treatment groups; mean (SD) titer levels were 1,511.25 (1,540.47) and 1,842.05 (5,100.83) in the CT-P47 and EU-tocilizumab groups, respectively.

Given that most participants were ADA negative throughout the study, PK analyses by ADA status should be viewed with caution; however, mean serum tocilizumab concentrations were slightly higher in the ADA-negative subset than in the ADA-positive subset, for both the CT-P47 and EU-tocilizumab groups, over the study period (Supplementary Figure S1). Primary PK variables were generally lower in the ADA-positive versus ADA-negative subset; secondary PK variables were comparable between subsets (Supplementary Table S5). Within ADA subsets, primary and secondary PK variables were comparable between treatment groups.

3.5. Safety

All participants who received the study drug received a full 162 mg dose. Overall, 237 TEAEs were reported in 55 (38.2%) and 72 (51.4%) participants in the CT-P47 and EU-tocilizumab groups, respectively (Table 4). Correspondingly, study drug-related TEAEs were reported by 47 (32.6%) and 61 (43.6%) participants. By system organ class, TEAEs of investigations were most frequently reported (CT-P47: 17 [11.8%]; EU-tocilizumab: 23 [16.4%]) (Supplementary Table S6). Neutrophil count decreased was the most commonly reported TEAE overall (CT-P47: 14 [9.7%]; EU-tocilizumab: 15 [10.7%]) (Supplementary Table S7). The majority of TEAEs were grade 1–2 in intensity. Four (2.8%) and eight (5.7%) participants in the CT-P47 and EU-tocilizumab groups, respectively, experienced TEAEs with a most severe intensity of grade 3. Correspondingly, three (2.1%) and four (2.9%) participants experienced TEAEs with a most severe intensity of grade 4 (Table 4 and Supplementary Table S8). All grade 3 events were considered related to study drug (Supplementary Table S8). All grade 4 TEAEs were due to laboratory abnormalities and were not considered related to study drug, other than for one (0.7%) participant in each group with neutropenia, and one (0.7%) participant in the EU-tocilizumab group with blood creatine phosphokinase increased (Supplementary Table S8).

Table 4. Summary of TEAEs (safety set; Part 2).

	CT-P47 (N = 144)	EU-tocilizumab (N = 140)
Total number of TEAEs	103	134
Participants with ≥1 TEAE, n (%)	55 (38.2)	72 (51.4)
≥1 study drug-related TEAE	47 (32.6)	61 (43.6)
≥1 grade 3 TEAE	4 (2.8)	8 (5.7)
≥1 grade 4 TEAE	3 (2.1)	4 (2.9)
Participants with ≥1 TESAE, n (%)	2 (1.4)	1 (0.7)
Participants with ≥1 TEAE leading to study drug discontinuation, n (%)	0	0
Participants with ≥1 TEAE leading to death, n (%)	0	0
Participants with ≥1 TEAESI, n (%)
Infection^a	10 (6.9)	25 (17.9)
Study drug-related	5 (3.5)	17 (12.1)
Hepatic event^b	4 (2.8)	5 (3.6)
Study drug-related	2 (1.4)	2 (1.4)
Injection-site reaction^c	4 (2.8)	5 (3.6)
Study drug-related	4 (2.8)	5 (3.6)
Hypersensitivity (including anaphylaxis)^c	4 (2.8)	2 (1.4)
Study drug-related	4 (2.8)	2 (1.4)
Hemorrhage^c	2 (1.4)	0
Study drug-related	1 (0.7)	0
Demyelinating disorder	0	0
Gastrointestinal perforation	0	0
Malignancy	0	0

^aAll grade 1–2 in intensity.

^bAll grade 1–2 in intensity, other than one study drug-related grade 3 TEAE of aspartate aminotransferase increased in the EU-tocilizumab group, and two grade 4 TEAEs in one participant in the EU-tocilizumab group (alanine aminotransferase increased and aspartate aminotransferase increased; both considered not related to study drug).

^cAll grade 1 in intensity. EU-tocilizumab = European Union-approved reference tocilizumab. TEAE = treatment-emergent adverse event. TEAESI = treatment-emergent adverse event of special interest. TESAE = treatment-emergent serious adverse event.

TESAEs were experienced by two (1.4%) and one (0.7%) participants in the CT-P47 and EU-tocilizumab groups, respectively (Table 4). Those in the CT-P47 group were of grade 2 in intensity: one participant tested positive for COVID-19 and subsequently discontinued the study due to isolation at a treatment center. The participant received non-steroidal anti-inflammatory drugs and cough remedy and was later discharged. In the second case, a participant experienced pain in an extremity following a car accident. This participant received acupuncture and electrotherapy and completed the study. Both events were considered to be unrelated to study drug. The TESAE in the EU-tocilizumab group was a headache of grade 3 intensity. The participant was hospitalized and received symptomatic treatment with analgesics, tranquilizers, antidepressants, antiemetics, and antihypertensives. The event was considered possibly related to study drug and the participant completed the study. There were no TEAEs leading to discontinuation of the study drug or death (Table 4).

There were no TEAESIs of demyelinating disorder, gastrointestinal perforation, or malignancy (Table 4). Infections were the most frequently reported TEAESI, occurring in 10 (6.9%) and 25 (17.9%) participants in the CT-P47 and EU-tocilizumab groups, respectively. Comparable proportions of participants in each group experienced TEAESIs of hepatic event, ISR, and hypersensitivity. All ISRs were grade 1 in intensity, and the most frequently reported sign or symptom was injection-site erythema, reported in one (0.7%) and three (2.1%) participants in the CT-P47 and EU-tocilizumab groups, respectively. Injection-site urticaria was reported for one participant in each group. All other signs and symptoms of ISR – injection-site induration, irritation, pain, pruritus, and rash – were reported for one participant in either group. The reported signs and symptoms of hypersensitivity reactions were myalgia, vascular headache, nausea, and rash. Each occurred in 1–2 participants per treatment group, and all were grade 1 in intensity and considered related to study drug. All participants recovered without treatment and no cases of anaphylaxis according to Sampson criteria [18] were identified. TEAESIs of hemorrhage were reported in two (1.4%) participants in the CT-P47 group only, comprising a study drug-unrelated puncture-site bruise due to a blood collection procedure and hematuria considered related to study drug; both events were of grade 1 in intensity and the participants recovered without treatment. All TEAESIs were grade 1–2 in intensity, other than three hepatic events that occurred in two participants in the EU-tocilizumab group. One participant experienced an increased AST level (grade 3; considered possibly related to study treatment), and the other experienced increased AST and ALT levels (both grade 4; confirmed to be the result of alcohol consumption and therefore considered unrelated to study treatment). Both participants recovered without treatment.

There were no differences between groups in mean changes from baseline in hematology, clinical chemistry, and urinalysis laboratory variables, other than for creatine kinase. At some timepoints from Day 13, large changes from baseline in creatine kinase levels were seen. This was due to a small number of participants who had increased creatine kinase at some timepoints; however, mean creatine kinase levels were comparable between treatment groups throughout the study period, with the exception of Days 13 and 43.

Overall, neutrophil count decreased and creatine phosphokinase increased were the most frequently reported grade 3 and 4 laboratory abnormalities, respectively (Supplementary Table S9). Neutrophil count decreased was reported in 14 (9.7%) and 23 (16.4%) participants in the CT-P47 and EU-tocilizumab treatment groups, respectively; correspondingly, creatine phosphokinase increased was reported for seven (4.9%) and two (1.4%) participants. In all cases, participants recovered by EOS.

Mean (SD) local injection-site pain scores on the 100-mm VAS were comparable between groups (CT-P47: 7.08 [15.13]; EU-tocilizumab: 7.00 [12.56]).

4. Discussion

Following the administration of a single dose to healthy Asian adults, the primary study endpoint was met, demonstrating PK equivalence between the proposed tocilizumab biosimilar CT-P47 and EU-tocilizumab. Part 1 of the study identified no safety issues with CT-P47 administration; in Part 2, secondary PK variables, immunogenicity, and safety were comparable between treatment groups.

While the IV and SC formulations are available for reference tocilizumab [2,5], the current study evaluated the SC administration of CT-P47 and EU-tocilizumab. This is aligned with FDA and EMA guidance for PK evaluation in cases where the reference product has multiple administration routes [10,19]. Elimination of tocilizumab is concentration dependent, with non-linear, target-mediated clearance dominant over linear, non-target-mediated clearance at the lower serum concentrations achieved with SC versus IV administration [5,20]. Thus, SC administration in this study facilitated the comparison of target-mediated elimination between CT-P47 and EU-tocilizumab.

The primary study endpoints were also selected in accordance with regulatory guidance [10,19]. In the current study, 90% CIs of the ratio of gLSMs for AUC_0–inf, AUC_0–last, and C_max were entirely contained within the predefined 80–125% equivalence margin, demonstrating the equivalence between CT-P47 and EU-tocilizumab in terms of PK.

Rates of immunogenicity were low and comparable between CT-P47 and EU-tocilizumab in this study, in keeping with the low risk of ADA development identified by a pooled analysis of SC and IV tocilizumab clinical trials in patients with RA [21]. While most participants were ADA negative throughout the current study, meaning that comparisons should be interpreted with caution, serum concentrations and primary PK variables were slightly lower in the ADA-positive than in the ADA-negative subset. PK variables were comparable between CT-P47 and EU-tocilizumab within subsets by ADA status.

A single SC administration of CT-P47 was well tolerated in this study, with the overall safety profile comparable between CT-P47 and EU-tocilizumab. Most of the reported TEAEs were grade 1–2 in intensity, and all grade 4 TEAEs were related to laboratory abnormalities and resolved by EOS without the participants requiring treatment. While numerically higher proportions of participants in the EU-tocilizumab versus the CT-P47 group experienced TEAEs (51.4% versus 38.2%), study drug-related TEAEs (43.6% versus 32.6%), or TEAESIs of infection (17.9% versus 6.9%), the between-group differences appeared to be mainly accounted for by the incidence of COVID-19 (13.6% versus 5.6%). Considering that various factors other than the effects of a single drug administration impact the likelihood of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [22–24] and that the study was conducted during a period of high COVID-19 incidence in the Republic of Korea (December 2021–May 2022) [25], it is unlikely that these differences between treatment groups resulted from the nature of the study drugs.

Neutrophil count decreased was the most frequent TEAE in this study, with comparable incidence between groups. This frequency is aligned with low neutrophil counts being reported as marked laboratory abnormalities in studies of reference tocilizumab [26,27]. Low neutrophil counts are also a consideration for dosing included in the EU-tocilizumab prescribing information [5]. In the current study, no signs or symptoms of infection were reported in participants experiencing decreased neutrophil counts. The incidence of TEAESIs of hepatic event, ISR, and hypersensitivity was relatively low, and was comparable between groups. The incidence of TEAESIs of ISR was generally similar to that observed in a phase I study which compared another candidate tocilizumab biosimilar with the reference product (4.8% overall) [15].

Strengths of the current study include the 43-day sampling period (exceeding five half-lives for SC administration of tocilizumab [5]), which was designed to allow PK variables to be adequately described, including during the late elimination phase. The study was also conducted at seven centers, whereas published studies evaluating other candidate tocilizumab biosimilars were conducted at two or fewer centers [13–16]. A potential limitation of the current study is that all participants were Asian and most were male, which could limit the generalizability of the findings to other groups. This is particularly significant when considering the RA patient population, which is predominantly female [28]. However, randomization in this study was stratified by sex, and regulatory documents report no impact of ethnic origin or sex on PK in patient populations, and only limited potential differences in efficacy by ethnicity [5,29]. Therefore, we do not think that these factors compromise the key findings of this study, given that the study's aim was to evaluate PK equivalence. The participants in the current study were also relatively young, with a median age of 26 years; thus, future studies enrolling more diverse populations would be beneficial to enhance the generalizability of the findings.

While this study had a two-arm design and did not include US-licensed reference tocilizumab as a comparator, the demonstration of PK equivalence between CT-P47 and EU-tocilizumab provides adequate PK similarity data for the SC formulation to support applications for EMA and FDA regulatory review. Following the demonstration of PK equivalence between CT-P47 and EU-tocilizumab and the comparability of immunogenicity and safety in this study, a phase III clinical trial is underway. This will compare the efficacy and safety of IV-administered CT-P47 and EU-tocilizumab in patients with moderate-to-severe active RA [30].

5. Conclusions

This study demonstrated the equivalence of CT-P47 and EU-tocilizumab in terms of PK, following administration of a single SC dose to healthy Asian adults. Immunogenicity and safety were also comparable between CT-P47 and EU-tocilizumab. Future studies will extend the generalizability of information available about CT-P47 treatment to broader populations.

Declaration of interests

Josef S. Smolen has received grants for his institution from AbbVie, AstraZeneca, Janssen, Lilly, Novartis, and Roche, and has received honoraria for consulting or speaking engagements from AbbVie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB. Gerd R. Burmester has received honoraria for consulting and lectures from Amgen, AbbVie, BMS, Celltrion, Chugai, Lilly, MSD, Pfizer, Sanofi, and Roche. SungHyun Kim, YunJu Bae, DaBee Jeon, JaeKyoung Yoo, GoEun Yang, and JiHun Bae are employees of Celltrion, Inc. Edward Keystone has received research funding from Amgen, Merck, and Pfizer Pharmaceuticals; has had consulting agreements or held advisory board membership for AbbVie, Amgen, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc., Janssen Inc., Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, and Samsung Bioepsis; and had speaker honoraria agreements with Amgen, AbbVie, Celltrion, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Pfizer Pharmaceuticals, Sandoz, and Sanofi Genzyme. Kyung-Sang Yu, Byungwook Kim, Dongseong Shin, Min Kyu Park, Jun Gi Hwang, Min-Gul Kim, Hyewon Chung, JongLyul Ghim, and Jae-Yong Chung have nothing to disclose, other than sponsorship of the current study by Celltrion. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors contributed to study design and data analysis or interpretation. KSY, BWK, DSS, MKP, JGH, MGK, HWC, JLG, JYC, SHK, YJB, DBJ, JKY, GEY, and JHB contributed to data collection. All authors reviewed and critically revised the manuscript, approved the final version for publication, and agree to be accountable for the accuracy and integrity of the work.

Acknowledgments

We thank all participants and investigators involved in the study. The study was registered at ClinicalTrials.gov with the identifier NCT05188378. Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, collating author comments, copyediting, fact checking, and referencing, was provided by Beatrice Tyrrell, DPhil, CMPP, at Aspire Scientific Ltd (Bollington, UK). Funding for medical writing support for this article was provided by Celltrion, Inc. (Incheon, Republic of Korea).

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2023.2212155.

Additional information

Funding

This manuscript was funded by Celltrion, Inc. (Incheon, Republic of Korea).