Efficacy and Safety of Biosimilar CT-P17 Versus Reference Adalimumab in Subjects With Rheumatoid Arthritis

24-Week Results From a Randomized Study

Jonathan Kay; Janusz Jaworski; Rafal Wojciechowski; Piotr Wiland; Anna Dudek; Marek Krogulec; Slawomir Jeka; Agnieszka Zielinska; Jakub Trefler; Katarzyna Bartnicka-Maslowska; Magdalena Krajewska-Wlodarczyk; Piotr A. Klimiuk; Sang Joon Lee; Yun Ju Bae; Go Eun Yang; Jae Kyoung Yoo; Daniel E. Furst; Edward Keystone

Disclosures

Arthritis Res Ther. 2021;23(51) 

In This Article

Results

Subject Disposition and Baseline Characteristics

Subjects were recruited between December 5, 2018, and April 25, 2019 (last subject week 24 visit: October 8, 2019). Of the 648 subjects who were randomized, 324 to each of the CT-P17 and EU-adalimumab groups (Figure 1), 612 (94.4%) completed study treatment up to week 24 (CT-P17, 305/324 [94.1%]; EU-adalimumab, 307/324 [94.8%]). Nineteen (5.9%) and 17 (5.2%) subjects discontinued study treatment in the CT-P17 and EU-adalimumab groups, respectively. Withdrawal by subject was the most frequent reason for discontinuation (CT-P17, 9 [2.8%] subjects; EU-adalimumab, 7 [2.2%] subjects), followed by TEAEs (CT-P17, 6 [1.9%]; EU-adalimumab, 7 [2.2%]). Of the 36 (5.6%) subjects who discontinued study treatment, 25 (3.9%) terminated the study (CT-P17, 15 [4.6%]; EU-adalimumab, 10 [3.1%]) and 11 (1.7%) (CT-P17, 4 [1.2%]; EU-adalimumab, 7 [2.2%]) continued participation in the study.

Figure 1.

Subject disposition (ITT population). aSubject discontinued CT-P17 treatment due to significant dose delay due to adverse event. bTwo subjects discontinued EU-adalimumab treatment due to subject decision due to adverse event. EU-adalimumab, European Union-approved adalimumab; ITT, intention-to-treat

Baseline demographics and disease characteristics were balanced between treatment groups (Table 1). Median age was 53.5 and 54.0 years for CT-P17 and EU-adalimumab, respectively. Most subjects were female (CT-P17, 76.9%; EU-adalimumab, 81.8%) and were mainly enrolled by sites in Eastern European countries, particularly Poland (231 [71.3%] subjects for both groups). Most subjects had high disease activity (SDAI score > 26). Stratification factors, SDAI score category, and country were well balanced between groups.

Efficacy

Primary Efficacy Analysis. The ACR20 response rate at week 24 (Figure 2a) was 82.7% (n = 268/324) for both the CT-P17 and EU-adalimumab groups (ITT population). The 95% confidence interval (CI) of − 5.94 to 5.94 for the estimate of treatment difference was entirely within the predefined equivalence margin of − 15 to 15% (EMA assumption), demonstrating therapeutic equivalence between treatment groups. Results for the PP population supported those for the ITT population (CT-P17, 87.0% [n = 248/285]; EU-adalimumab, 87.0% [n = 240/276]), with the 95% CI of − 5.60 to 5.78 for the estimate of treatment difference. Likewise, for both analysis populations, 90% CIs for the estimate of treatment difference (− 4.98 to 4.98 in the ITT population and − 4.70 to 4.86 in the PP population) were entirely within the asymmetric equivalence margin of − 12 to 15% (FDA assumption), thereby also demonstrating therapeutic equivalence between treatment groups. Sensitivity analysis using logistic regression with covariates for the primary endpoint provided similar results, − 5.75 to 5.86 (ITT population) and − 5.07 to 5.93 (PP population) for 95% CI.

Figure 2.

Secondary efficacy endpoints up to week 24 (ITT population). ACR20 response rate up to week 24 (a). ACR20, ACR50, and ACR70 response rates at week 24 (b). Mean change from baseline in DAS28-CRP up to week 24 (c). Mean change from baseline in CDAI value up to week 24 (d). Mean change from baseline in SDAI value up to week 24 (e). ACR, American College of Rheumatology; ACR20, 20% improvement according to American College of Rheumatology criteria; ACR50, 50% improvement according to American College of Rheumatology criteria; ACR70, 70% improvement according to American College of Rheumatology criteria; CDAI, Clinical Disease Activity Index; DAS28-CRP, Disease Activity Score in 28 joints C-reactive protein; EU-adalimumab, European Union-approved adalimumab; ITT, intention-to-treat; SDAI, Simplified Disease Activity Index

Secondary and Additional Efficacy Analyses. The proportions of subjects achieving ACR20, ACR50, and ACR70 responses up to week 24 were similar between the CT-P17 and EU-adalimumab groups (Figure 2a, b; Supplementary Table 3, Additional file 1). Mean values of and change from baseline in DAS28-CRP (Figure 2c), CDAI (Figure 2d), and SDAI (Figure 2e) were comparable between groups up to week 24, as were EULAR (CRP) response rates and SDAI, CDAI, DAS28 (CRP), and Boolean remission rates (Table 2). Mean hybrid ACR scores increased from week 2 to week 24 and were similar between groups (Supplementary Table 3, Additional file 1). Mean SF-36 physical and mental component scores increased from baseline to week 24; mean increases up to week 24 were similar between groups. At week 24, mean (SD) change from baseline in the SF-36 physical component score was 7.869 (7.4184) for CT-P17 (n = 309) and 8.213 (8.0179) for EU-adalimumab (n = 312). At week 24, mean (SD) change from baseline in the SF-36 mental component score was 5.879 (9.8480) for CT-P17 (n = 309) and 6.585 (9.7404) for EU-adalimumab (n = 312).

Pharmacokinetic Analysis

The mean adalimumab C trough was comparable between groups in the PK population, although values were slightly higher in the CT-P17 than in the EU-adalimumab group (Supplementary Table 4, Additional file 1). Mean C trough increased gradually from baseline to week 22 for both groups (Supplementary Figure 1, Additional file 1).

Usability Analysis

Mean scores for each domain of the PRE-SIAQ and POST-SIAQ were comparable between treatment groups (Supplementary Table 5, Additional file 1). All subjects in the population in which usability was assessed completed self-injection successfully.

Safety

Overall, the proportion of subjects experiencing ≥ 1 TEAE was similar between treatment groups (CT-P17, 169 [52.2%] subjects; EU-adalimumab, 184 [56.8%] subjects) (Table 3). Most TEAEs were grade 1 or 2 in intensity. TEAEs considered by the investigator to be study drug-related were reported by 187 (28.9%) subjects, with similar proportions between treatment groups (CT-P17, 88 [27.2%]; EU-adalimumab, 99 [30.6%]) (Table 3). A similar proportion of subjects in each group experienced TEAEs leading to study drug discontinuation; of these, 2 (0.6%) and 4 (1.2%) subjects, respectively, experienced TEAEs that were considered study drug related. The most frequently reported TEAEs in the CT-P17 group were nasopharyngitis and upper respiratory tract infection (17 [5.2%] subjects each) and ISR (16 [4.9%]); in the EU-adalimumab group, these were ISR (22 [6.8%]) and nasopharyngitis and upper respiratory tract infection (20 [6.2%] each) (Table 3). Treatment-emergent serious adverse events (TESAEs) were reported for 10 (3.1%) subjects in the CT-P17 group and 16 (4.9%) in the EU-adalimumab group (Table 3). Study drug-related TESAEs were reported for 9 subjects overall (CT-P17, 5 [1.5%]; EU-adalimumab, 4 [1.2%]) (Supplementary Table 6, Additional file 1). No deaths were reported up to week 24.

TEAEs classified as hypersensitivity/allergic reactions, ISRs, or infections were experienced by similar proportions of subjects in each group (Table 3). Conversion to positive interferon-γ release assay, up to week 24, was experienced by 12 (3.7%) and 17 (5.2%) subjects in the CT-P17 and EU-adalimumab groups, respectively. Latent tuberculosis was reported in 12 (3.7%) and 15 (4.6%) subjects in the CT-P17 and EU-adalimumab groups, respectively; for 7 (2.2%) and 10 (3.1%) of these subjects, this was considered study drug-related. All these subjects began tuberculosis prophylaxis, except for the single subject in each group who terminated study participation. Two (0.6%) subjects in the EU-adalimumab group reported active tuberculosis and discontinued study treatment. One (0.3%) subject experienced a TEAE classified as malignancy (breast cancer) in the CT-P17 group (Table 3); however, the site investigator considered this event to be unrelated to study drug.

Small imbalances were identified in the proportions of subjects reporting TEAEs classified in the SOC of gastrointestinal disorders (CT-P17, 24 [7.4%] subjects; EU-adalimumab, 16 [4.9%] subjects), nervous system disorders (CT-P17, 19 [5.9%] subjects; EU-adalimumab, 9 [2.8%] subjects), and metabolism and nutrition disorders (CT-P17, 12 [3.7%] subjects; EU-adalimumab, 6 [1.9%] subjects) (Supplementary Table 7, Additional file 1). However, among these SOCs, other than for two grade 3 TEAEs that were considered unrelated to study drug in the EU-adalimumab group (1 nervous system disorder of carotid arteriosclerosis, and 1 metabolism and nutrition disorder of hypertriglyceridemia), all TEAEs were grade 1–2 in intensity.

Mean (SD) 100-mm VAS scores for local site pain measurements decreased over time. Results at each visit were comparable between treatment groups. At week 0, mean (SD) VAS scores for local site pain were 6.64 (10.887) for CT-P17 and 4.85 (7.300) for EU-adalimumab, while mean VAS scores at week 24 had decreased to 4.45 (8.393) for CT-P17 and to 4.32 (8.651) for EU-adalimumab.

Immunogenicity

At baseline, 11 (3.4%) and 6 (1.9%) subjects were ADA-positive and 4 (1.2%) and 1 (0.3%) subjects were NAb-positive in the CT-P17 and EU-adalimumab groups, respectively (Supplementary Table 8, Additional file 1). At week 24, 93 (28.7%) and 116 (35.8%) subjects were ADA-positive and 83 (25.6%) and 103 (31.8%) subjects were NAb-positive in the CT-P17 and EU-adalimumab groups, respectively. Overall, immunogenicity was slightly lower numerically for the CT-P17 group than for the EU-adalimumab group throughout the study.

ADA Subgroup Analysis

The proportions of subjects achieving an ACR20 response at week 24 were similar between the CT-P17 and the EU-adalimumab treatment groups in both the ADA-positive and ADA-negative subgroups (Supplementary Table 9, Additional file 1). Mean C trough was lower in the ADA-positive subgroup than in the ADA-negative subgroup for both treatment groups (Supplementary Figure 1 and Supplementary Table 4, Additional file 1). A lower proportion of subjects in the ADA-negative subgroup experienced ≥1 TEAE than did those in the ADA-positive subgroup (49.7% and 59.8%, respectively); however, with a limited number of events, there was no apparent correlation between the presence of ADA and the incidence of TESAEs, TEAEs classified as hypersensitivity/reactions, or TEAEs classified as ISRs (Supplementary Table 10, Additional file 1).

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