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

Discussion

This study demonstrated equivalent efficacy of CT-P17 to EU-adalimumab in the proportion of subjects achieving an ACR20 response at week 24. This primary endpoint was met in both the ITT and PP analysis populations for both the EMA (− 15 to 15%, 95% CI) and the FDA (− 12 to 15%, 90% CI) statistical assumptions. Comparable efficacy of CT-P17 and EU-adalimumab was demonstrated for secondary endpoints up to week 24. PK parameters were also comparable between groups, although mean C trough was slightly higher for CT-P17 than for EU-adalimumab. The usability of CT-P17, assessed by ability to complete successful self-injections and subject-reported outcomes, was comparable to that of EU-adalimumab. The overall safety profile of CT-P17 was similar to that of EU-adalimumab, although there were small imbalances between the CT-P17 and EU-adalimumab groups for some SOCs.

In our study, the ACR20 response rate at week 24, using high-concentration (100 mg/ml) formulations of CT-P17 and EU-adalimumab, was 82.7% in both treatment groups (ITT population). These observed ACR20 response rates are only slightly above the range of ACR20 responses for reference adalimumab (50 mg/ml) and adalimumab biosimilars in other adalimumab biosimilar studies, in which ACR20 response rates at week 24 or week 26 ranged between 63.9 and 82.5% (Supplementary Figure 2, Additional file 1).[21–25] However, our study did not compare the high-concentration formulation to the low-concentration formulation of adalimumab.

We also investigated the influence of immunogenicity status on the proportion of subjects achieving an ACR20 response at week 24. Overall, a slightly lower proportion of ADA-positive subjects achieved an ACR20 response at week 24 than did ADA-negative subjects (81.4% vs 85.1%), consistent with previous reports for reference adalimumab and adalimumab biosimilars.[13,26] However, within subject subgroups by ADA status, ACR20 response rates were similar between CT-P17 and EU-adalimumab treatment groups, in line with similar data reported previously for adalimumab biosimilars.[26,27]

In this study, we observed slightly higher mean Ctrough values in the CT-P17 group compared with the EU-adalimumab group. In a separate study, ADA formation was associated with increased clearance and lower serum adalimumab concentrations.[13] However, in this study, AUC and clearance were not evaluated, so this could not be examined directly. It is possible that the differences may be associated with the lower proportion of ADA-positive subjects in the CT-P17 versus EU-adalimumab group. Indeed, in our study, Ctrough was generally lower in the ADA-positive than in the ADA-negative subgroup; Ctrough values became more similar between groups when compared within these subgroups. Nevertheless, Ctrough values of the ADA-positive subgroup were within the therapeutic level of adalimumab (5 to 8 μg/ml).[13] In addition, our findings are in keeping with previous reports for adalimumab biosimilars.[26,28]

The overall safety profile of CT-P17 in this study was consistent with the known safety profile of reference adalimumab.[13] In both treatment groups, the most frequently reported study drug-related TEAEs were ISRs, consistent with information provided in the EU-adalimumab summary of product characteristics.[13] ISRs, as well as the other protocol-specified TEAESIs of hypersensitivity/allergic reactions and infections, were experienced by similar proportions of subjects in each treatment group. There were small imbalances, at the SOC level, in the proportions of subjects reporting TEAEs for gastrointestinal disorders, nervous system disorders, and metabolism and nutrition disorders. These TEAEs were mostly grade 1–2 in intensity and, at the Preferred Term level, absolute differences between groups in the number of subjects experiencing a given TEAE were small. When analyzed by ADA status, the incidence of TEAEs, but not of TESAEs, was higher for ADA-positive than for ADA-negative subjects; there was no apparent correlation between the presence of ADAs and hypersensitivity/allergic reactions or ISRs.

This is the first report of a phase III clinical trial comparing CT-P17 to reference adalimumab. Strengths of this study include its randomized, double-blind design, and the use of well-established outcome measures. Equivalent efficacy of CT-P17 and EU-adalimumab was established using both symmetric and asymmetric equivalence margins, as agreed to by the EMA and the FDA, respectively. In addition to the data reported from comparing these treatments up to week 24, this study will provide valuable information regarding the efficacy and safety of transitioning from EU-adalimumab to CT-P17 (during treatment period 2).

Limitations of this study include the relatively short follow-up period (24 weeks) reported herein; however, this study is ongoing and efficacy and safety data up to week 52 will be reported. Although sufficient testing was done for regulatory purposes, comprehensive PK data were not collected. While treatment groups were well balanced by stratification factors including country, subjects from Eastern European countries, particularly Poland, accounted for most of the study population. The races of subjects enrolled in this study included white, mestizo, and Native Peruvian. This could limit the global generalizability of the findings; however, this should be viewed in the context of the global scope of the CT-P17 clinical development program that included American Indian or Alaska Native, Black or African American, and Asian subjects, among which there were no differences in clinical responses.[11,16,29] Also, since this was a comparative study to demonstrate equivalence of CT-P17 to EU-adalimumab, it did not aim to evaluate the drugs across other ethnic groups.

The original reference adalimumab was developed as a low-concentration (50 mg/ml) formulation containing citrate. Subsequently, a high-concentration (100 mg/ml), citrate-free formulation of reference adalimumab has been developed.[13,14] While the high-concentration CT-P17 formulation is similar to the newer formulation of reference adalimumab,[13,14] it differs from the low-concentration (50 mg/ml) adalimumab biosimilars that are currently approved.[12,30–33] The high-concentration formulations of both CT-P17 and reference adalimumab offer the potential to administer high-dose (80 mg/0.8 ml) induction treatment to patients with inflammatory bowel disease with a reduced number of injections. In addition, the citrate-free buffer may benefit patients by reducing discomfort during injection.[12,15]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....