A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inferiority clinical trial to compare efficacy and safety of biosimilar adalimumab (CinnoRA®) to the reference product (Humira®) in patients with active rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease of unknown pathophysiology leading to peripheral and symmetrical joint synovitis. The primary systemic manifestations are pain, morning stiffness, fatigue, and weight loss [1‐3]. In progressive forms, it may lead to cartilage damage, joint destruction, and joint swelling resulting in impaired physical function and premature morbidity [4‐6]. RA mostly develops in the fourth and fifth decades of life, with 80% of the cases occurring between 35 and 50 years of age. The worldwide prevalence of RA is about 0.5–1.0% with a female/male ratio of 2.5:1.0 [7, 8]. Although the presence of chronic inflammation has been proposed as a contributing factor, the exact mechanism of developing RA is still unknown [9].

The management of RA aims primarily at improving patients’ quality of life (QoL), achieving low disease activity based on American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria, and ultimately remission [1, 10]. The treatment options for RA include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (sDMARDs) and biological DMARDs (bDMARDs). RA treatment has developed considerably in recent years, with the early use of methotrexate (MTX) and the addition of targeted bDMARDs in patients with an inadequate response to MTX [10, 11]. In fact, concomitant use of bDMARDs and MTX has been associated with the greatest clinical outcomes in trials and has been approved as the standard of care for patients with moderate-to-severe disease [12]. The stage and severity of the joint condition, the balance between possible adverse effects and expected benefits, and patients’ preferences are amongst the influential factors in choosing a DMARD. MTX is the most frequently administered sDMARD and is used either as monotherapy or in combination with other anti-rheumatic drugs. The early onset of action and superior efficacy makes MTX the synthetic agent of choice in the treatment of RA [5, 13]. Similarly, biological agents such as anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies are effective in suppressing disease activity, inhibiting structural deterioration and maintaining physical function. Adalimumab, a fully humanized immunoglobulin (IgG1) monoclonal antibody is produced in genetically modified Chinese hamster ovary cells (CHO). Adalimumab consists of two identical heavy and two identical light chains that bind specifically to the transmembrane TNF, thus blocking the interaction of TNF-α with its receptor [4, 14‐16]. Adalimumab was first approved by the US Food and Drug Administration (FDA) in December 2002 for the treatment of RA and is currently approved for the following indications: RA, juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), pediatric CD, ulcerative colitis (UC), psoriasis (PsO), pediatric plaque PsO, hidradenitis suppurativa (HS), and non-infectious uveitis [17, 18].

Biosimilars are biotherapeutic products that are similar to the licensed biological reference products in terms of quality, efficacy, and safety, but often are provided at a lower price [19, 20]. CinnoRA® was developed by CinnaGen Company (Alborz, Iran) as a biosimilar to the innovator adalimumab product (Humira®). This study aimed to evaluate the non-inferiority of test-adalimumab (CinnoRA®) to the reference product in terms of efficacy, tolerability, and safety in patients with active RA.

A total of 216 subjects were screened across 10 hospitals in Iran, of whom 136 patients were considered eligible for participation in this study. Patients were enrolled in the CinnoRA® or Humira® arms (68 subjects in each arm) and 64 patients in each group completed the 24-week study period. Four patients in the CinnoRA® group withdrew from the study for the following reasons: adverse drug reactions (ADR, n = 2), positive PPD test (n = 1), and poor compliance (n = 1). Similarly, four patients in the Humira® group left the trial because of ADR (n = 3) and poor compliance (n = 1). The study profile is shown in Fig. 1.

Patients who were randomized to the CinnoRA® or Humira® arms had comparable baseline characteristics. The mean age of the participants in the CinnoRA® and Humira® groups was 48.29 ± 12.72 and 47.59 ± 11.48 years, respectively. The mean DAS in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) was 5.51 ± 1.24 in the CinnoRA® arm and 5.47 ± 1.28 in the Humira® arm. The baseline characteristics are summarized in Table 1.

At week 12, the DAS28-ESR values were 2.95 ± 1.30, and 2.96 ± 1.41 in the CinnoRA® and Humira® groups, respectively (P value = 0.97); at week 24 the DAS28-ESR values were 2.58 ± 1.06 in the CinnoRA® arm vs. 2.55 ± 1.14 in the Humira® group (p value = 0.88).

According to the PP population, the proportion of patients fulfilling moderate and good EULAR response criteria based on the DAS28-ESR at week 12 was 42.42% and 54.55% in the CinnoRA® arm compared to 37.88% and 51.52% in the Humira® group, respectively (cumulative 12-week good and moderate EULAR response in the PP population 97% in the CinnoRA® vs. 89% in the Humira® arm; p value = 0.08; CI for the difference = −0.9 to 16). At 24 weeks, 28.13% and 70.31% in the CinnoRA® vs. 31.25% and 67.19% in the Humira® arm met the criteria for moderate and good EULAR response, respectively (cumulative 24-week good and moderate EULAR response in the PP population 98% in the CinnoRA® vs. 98% in the Humira® arm; p value = 1; CI for the difference = −4 to 4). Similarly, in the ITT population, 41.18% and 36.73% achieved moderate EULAR response at 12 weeks in the CinnoRA® and Humira® arms, respectively, and 52.94% in the CinnoRA® arm and 50.00% in the Humira® arm achieved good EULAR response at 12 weeks (cumulative 12-week good and moderate EULAR response in the ITT population 94% in the CinnoRA® vs. 87% in the Humira® arm; p value = 0.14; CI for the difference = −2 to 17). At 24 weeks, moderate EULAR response was attained in 26.47% of patients in the CinnoRA® arm compared to 29.41% in the Humira® arm. However, good EULAR response was achieved in 66.18% of patients in the CinnoRA® arm and 63.24% in the Humira® arm (cumulative 24-week good and moderate EULAR response in the ITT population 93% in the CinnoRA® vs. 93% in the Humira® arm; p value = 1; CI for the difference = −9 to 9). Based on the prespecified margin of 20%, non-inferiority of test-adalimumab to the reference product in terms of the proportion of patients achieving good or moderate EULAR response was confirmed at both the 12-week and 24-week time points (Fig. 2, Table 2).

The median (IQR) HAQ scores at 12 and 24 weeks were 0.25 (0.88) and 0.25 (0.63) in the CinnoRA® arm vs. 0.38 (0.88) and 0.19 (0.63) in the Humira® arm, respectively. The difference between treatment arms was not statistically significant at the respective time points (12 weeks, p value = 0.87; 24 weeks, p value = 0.48).

The proportion of patients achieving ACR20, ACR50, and ACR70 responses at the 12-week time point were 85%, 61%, and 28% in the CinnoRA® arm compared to respective values of 76%, 48%, and 36% in the Humira® arm. At week 24, 92%, 77%, and 47% of the patients in the CinnoRA® arm achieved ACR20, ACR50, and ACR70 responses, respectively, which was similar to those observed in the Humira® arm (89%, 75%, and 53%, respectively). No statistically significant difference was observed between treatment arms at either the 12-week or the 24-week time point (all p values >0.05, Fig. 3).

The incidence of adverse effects was comparable between patients who received test-adalimumab compared to those who took the reference product. Overall, a total of 24 patients (35.29%) in the CinnoRA® arm vs. 30 (44.12%) patients in the Humira® arm reported at least one adverse event. The most prevalent adverse events were local (8.82% with CinnoRA®, 17.65% with Humira®) and respiratory (8.82% with CinnoRA®, 20.59% with Humira®) adverse effects (Table 3).

Randomized clinical trials demonstrating comparable efficacy, safety and tolerability of the biosimilar and innovator products are absolutely necessary as well as analytical evidence to establish similar physicochemical and biological actions of the products. Biosimilars improve the availability of more affordable products while offering similar efficacy and safety to the reference product [18, 25‐27]. The perception of biosimilarity has been changed over recent years, especially in rheumatology. In September 2016, AMJEVITA™ (Amgen®, Thousand Oaks) was approved by the FDA, as a biosimilar adalimumab for treatment of seven inflammatory diseases. Similarly, Exemptia™, another adalimumab biosimilar, was approved in India. Etanercept and infliximab biosimilars were also authorized in various indications. In May 2016, Inflectra™ was approved by the European Medicines Agency (EMA) and the FDA as an infliximab biosimilar for all indications of the reference infliximab, including RA, AS, PsA, PsO, CD, and UC. In the case of etanercept, the biosimilar HD203 was recently approved in South Korea. In addition, Samsung Bioepis’s SB4, known as BRENZYS™ (Samsung Bioepis Co., Ltd., Korea) received regulatory approval from the Korean Ministry of Food and Drug Safety (MFDS), the European Commission (EC), and the Australian Therapeutic Goods Administration (TGA) to be used as a biosimilar alternative to etanercept [18, 28].

In this randomized, double-blind, parallel-group, non-inferiority study, the efficacy and safety of CinnoRA® were compared with those of adalimumab in the treatment of adult patients with active RA. Several studies have assessed the efficacy of 40 mg adalimumab administered subcutaneously every other week, in terms of ACR criteria and DAS-based EULAR response. In the study of Bombardieri et al., the efficacy of adalimumab was evaluated in RA patients for a 12-week period. By the end of week 12, about 60% and 33% of patients achieved ACR20 and ACR50 responses, respectively. Based on EULAR criteria, 76% of patients attained a moderate response and 23% attained a good response. In addition, 12% of patients reached clinical remission, achieving a DAS28 less than 2.6 [29, 30]. In another study, Huang et al. assessed the efficacy and safety of adalimumab in combination with MTX by administrating 40 mg adalimumab every other week for 12 weeks. The results of this multicenter, randomized, double-blind, placebo-controlled clinical trial indicated that 57% of patients achieved ACR20 and 32.2% of them achieved ACR50 responses [31]. In line with previous studies, we evaluated the percentage of patients with moderate-to-good DAS-based EULAR response, which was our primary outcome measure. Additionally, we compared the number of patients reaching ACR 20, ACR50, and ACR70 responses, along with ESR, CRP, and HAQ status. The percentage of our patients achieving moderate and good EULAR responses increased significantly in both the CinnoRA® and the Humira® arms, and the difference between the two arms was not statistically significant. Further, the percentage of patients reaching ACR20, ACR50, and ACR70 increased significantly during the 6-month period. In the retrospective study of Takeuchi et al. investigating the ability of adalimumab to reduce disease activity in 167 patients with RA, the mean DAS28-ESR score decreased from 5.3 ± 1.3 at baseline to 3.5 ± 1.5 at week 52 (p < 0.0001), which is consistent with our findings [32].

Furst et al. conducted a double-blind, placebo-controlled study and assigned patients into groups receiving either adalimumab 40 mg subcutaneously every other week or placebo. The study aimed to evaluate the efficacy of adalimumab when given with standard antirheumatic therapy over 24 weeks in patients with active RA, who were not adequately responding to such therapies. Similarly, a 24-week follow-up period was considered to evaluate the efficacy and safety of test-adalimumab in rheumatic patients [33].

Aletaha et al. chose the 3-month time point as a critical decision point in the treatment of patients with RA. It seems that patients who have significantly improved by 3 months are more likely to reach their treatment target by 6 months. In fact, achieving responses at 3 months is a good indicator of remission at 12 months, whereas patients with poor responses at 3 months will probably benefit from changing the treatment [34]. In agreement with previous studies, patients in our study who had noticeable improvements at 3 months also had better remission status. Patients in the CinnoRA® arm responded to treatment within a shorter period of time; however, this difference was not statistically significant. In the study of Burmester et al. in rheumatic patients receiving adalimumab for approximately 5 years, the mean HAQ-disability index score decreased in the first 6 months and then remained steady till the end of the study [35]. Similarly, in our study the mean HAQ score decreased significantly in both treatment arms and the difference between the groups was not statistically significant. In fact, as an important therapeutic goal, adalimumab improved social and physical functions in rheumatic patients.

In the safety analyses of the study of Takeuchi et al., the most frequently noted adverse events during one year of treatment with adalimumab were reactions at the drug administration site, with a frequency of 11.40/100 patient-years [32]. Safety was evaluated based on the adverse events reported by patients. All the adverse events were summarized according to the Medical Dictionary for Regulatory Activities system organ class (MedDRA SOC). We did not notice any significant difference in the incidence of injection site reactions as the most prevalent adverse events between treatment arms, and our findings were consistent with previous studies. Despite having a negative PPD test at the beginning of the study, one of the patients had a positive PPD test 8 weeks later that was probably due to close contact with a patient infected with TB close to the time of study enrollment.

Based on our findings, CinnoRA®, as a biosimilar adalimumab, was shown to be non-inferior to Humira® in the treatment of adult patients with active RA.