Comparative Clinical Efficacy and Safety of the Proposed Biosimilar ABP 710 With Infliximab Reference Product in Patients With Rheumatoid Arthritis

Mark C. Genovese; Juan Sanchez-Burson; MyungShin Oh; Eva Balazs; Jeffrey Neal; Andrea Everding; Tomas Hala; Rafal Wojciechowski; Gary Fanjiang; Stanley Cohen

Disclosures

Arthritis Res Ther. 2020;22(60) 

In This Article

Results

Patient Disposition

Subject disposition is summarized in Figure 1. A total of 558 patients (279 in the ABP 710 treatment group and 279 in the infliximab RP treatment group) were randomized at 75 centers across 9 countries. Overall, 484 out of 558 (86.7%) patients completed the study through week 22 and were re-randomized; 74 (13.3%) patients discontinued the study prior to week 22 and were not re-randomized. For both treatment groups, the most common reason for discontinuing the study prior to week 22 was due to AEs (11 [3.9%] patients in the ABP 710 treatment group and 14 [5.0%] patients in the infliximab RP treatment group). Of the 484 patients who were re-randomized at week 22, 244 were initially randomized to ABP 710 and, thus, continued to receive ABP 710 (ABP 710/ABP 710 treatment group); 121 were initially randomized to infliximab RP and were re-randomized to continue receiving infliximab RP (RP/RP treatment group); and 119 initially randomized to infliximab RP were re-randomized to receive ABP 710 (RP/ABP 710 treatment group). Overall, 435 (78.0%) of the 558 patients who were initially randomized completed the study, and 123 (22.0%) patients discontinued the study. For both treatment groups, the most common reason for discontinuing the study was due to AEs (21 [7.5%] patients in the ABP 710 treatment group and 20 [7.2%] patients in the RP treatment group). The ITT analysis set included 558 patients, the PP analysis set included 471 patients, and the safety analysis set included 556 patients.

Figure 1.

Patient disposition

Baseline Demographics and Clinical Characteristics

The majority of patients were female (78.3%) and white (95.3%), with a mean age of 54.9 years (range 19–77 years) and a mean of 8.53 years (range 0.3–45.0 years) since diagnosis (Table 1). Overall, baseline demographics and clinical characteristics were similar across treatment groups with a mean (standard deviation [SD]) baseline DAS28-CRP score of 5.58 (0.912) for ABP 710 and 5.60 (0.893) for infliximab RP. Clinical characteristics at week 22 for the 484 re-randomized patients were also similar across treatment groups with a mean (SD) DAS-CRP score of 5.54 (0.890) for ABP 710/ABP 710, 5.59 (0.900) for RP/RP, and 5.54 (0.913) for RP/ABP 710.

Concomitant and Previous Medications

Prior use of biologics for RA and baseline RA medications were balanced across groups; the majority of patients (ABP 710, 72.4%; infliximab RP, 71.0%) were treatment-naive for prior use of biologics for RA. Oral corticosteroids were used at baseline by 55.6% and 52.0% of patients in the ABP 710 and infliximab RP groups, respectively. Percentages of corticosteroid use at baseline were also similar among re-randomized groups with 54.9%, 52.1%, and 51.3% of ABP 710/ABP 710, RP/RP, and RP/ABP 710 treatment groups, respectively. Baseline mean MTX doses were similar across treatment groups with 17.54 (4.835) mg/week and 17.19 (4.938) mg/week for ABP 710 and infliximab RP, respectively, and 17.51 (4.951), 17.02 (4.703), and 17.50 (5.218) mg/week for ABP 710/ABP 710, RP/RP and RP/ABP 710, respectively.

Clinical Efficacy

ACR20 at Week 22. At week 22, 68.1% (190/279) of patients in the ABP 710 group and 59.1% (165/279) of patients in the infliximab RP group met the ACR20 response criteria. The estimated RD of ACR20 was 9.37% with a 2-sided 90% CI of 2.67%, 15.96%. The 90% CI exceeded the upper bound of the prespecified equivalence margin (− 15%, 15%). Post hoc analyses of ACR20 at week 22 were used to adjust for the impact of random imbalance in baseline demographic and disease characteristic between the two treatment arms (Table 2). The resulting estimate of RD was reduced to 7.18%, and the 90% CI was narrowed to 0.75%, 13.62%, within the margin of − 15%, 15%.

ACR20, ACR50, and ACR70 Across Time. ACR20, ACR50, and ACR70 response rates with 95% CIs by treatment group through week 22 and post week 22 are summarized in Figure 2a. Over the entire study, the maximum RD of ACR20 occurred at the week 22 time point, with narrow differences before and directly after this time point. Results show that efficacy was consistently maintained throughout the study and that a single transition from infliximab RP to ABP 710 did not impact efficacy.

Figure 2.

a Percentage of patients achieving ACR20, ACR50, and ACR70 by study week, ± 95% CI. ACR20, ACR50, and ACR70 is the 20, 50, and 70%, respectively, improvement from baseline in American College of Rheumatology core set measurements. b Mean ± 95% CI change from baseline DAS28-CRP by study week. c Percentage of Hybrid ACR improvement from baseline ± 95% CI. Hybrid ACR was calculated when all seven ACR components were non-missing. For post week 22, only re-randomized subjects were included

DAS28-CRP. At week 22, the mean change from baseline in DAS28-CRP was − 2.06 for both groups, with a difference between treatment groups (two-sided 90% CI) of − 0.01 (− 0.20%, 0.17%), further substantiating clinical efficacy equivalence between ABP 710 and infliximab RP. Mean change from baseline in DAS28-CRP decreased similarly throughout the study in both groups, indicating similar reduced disease activity (Figure 2b). For reference, European League Against Rheumatism (EULAR) previously defined a change in DAS28 of 0.6 as the minimal clinically important difference;[13] the differences between treatment groups were well within this margin throughout the study. In addition, the single transition from infliximab RP to ABP 710 did not impact efficacy.

Hybrid ACR. Results for analysis of hybrid ACR through the entire study by treatment groups are shown in Figure 2c. Hybrid ACR by treatment groups followed the same pattern of response throughout the study with overlapping 95% CIs between the treatment groups at all time points. Results show that efficacy was consistently maintained throughout the study. In addition, the single transition from infliximab RP to ABP 710 did not impact efficacy.

Safety

Through week 22, 50.7% of all patients had ≥ 1 treatment-emergent AE (TEAE) during the study and the percentages of patients who reported TEAEs were similar among patients in the ABP 710 and RP groups (51.8% and 49.6%, respectively) (Table 3). Post week 22, 55.7% of all patients had ≥ 1 TEAE during the study and the percentages of patients who reported TEAEs were similar among patients in the ABP 710/ABP 710, RP/RP, and RP/ABP 710 groups (53.9%, 57.0%, and 58.0%, respectively) (Table 4).

TEAEs reported in ≥ 5% of patients in any treatment group were reported at similar rates in the three treatment groups (ABP 710/ABP 710; RP/RP; RP/ABP 710). In general, the subject incidence rates for these frequently reported AEs were similar across the treatment groups, and no safety signal was associated with a single transition from infliximab RP to ABP 710. The only event with at least a 5% difference between treatment groups was pharyngitis, which was reported in 2 (0.8%), 2 (1.7%), and 7 (5.9%) patients in the ABP 710/ABP 710, RP/RP, and RP/ABP 710 treatment groups, respectively.

For the three treatment groups, the highest subject incidence rates of AEs were in the System Organ Class of infections and infestations. Discontinuation of IP or study due to ≥ 1 AE in the ABP 710/ABP 710, RP/RP, and RP/ABP 710 treatment groups occurred in 12 (5.0%), 4 (3.3%), and 4 (3.4%) patients, respectively. A total of 30 (6.2%) patients reported having AEs of grade ≥ 3 post week 22 and the percentages of patients were similar between the ABP 710/ABP 710 (n = 18; 7.5%), RP/RP (n = 7; 5.8%), and RP/ABP 710 (n = 5; 4.2%) groups. No fatal AEs were reported post week 22. Overall, there were no differences between groups that were ≥ 5% for the percentage of patients who experienced a TEAE.

Immunogenicity

Through week 22, 556 patients had ≥ 1 evaluable ADA result and were included in the antibody analysis. For the ABP 710 and infliximab RP groups, 16 (5.8%) and 11 (4.0%) patients, respectively, tested positive for pre-existing binding antibodies and no patients tested positive for pre-existing neutralizing antibodies. The number of patients with a binding negative or no result at baseline who tested positive for binding antibodies at week 22 post baseline was similar in each group (ABP 710, n = 149 [57.1%]; RP, n = 160 [60.0%]). A total of 102 (18.3%) patients tested positive for neutralizing ADAs by week 22, which was also similar to that for each treatment group (ABP 710, n = 47 [18.0%]; RP, n = 55 [20.8%]). A total of 186 (38.7%) of patients who were re-randomized (96 [39.8%] in the ABP 710/ABP 710 treatment group, 45 [37.2%] in the RP/RP treatment group, and 45 [37.8%] in the RP/ABP 710 treatment group) were negative for binding ADAs at week 22, had a negative or no result before week 22, and had a post week 22 ADA result by week 50. Of these, 66 (35.5%) patients (29 [30.2%] in the ABP 710/ABP 170 treatment group, 19 [42.2%] in the RP/RP treatment group, and 18 [40.0%] in the RP/ABP 710 treatment group) tested positive for binding ADAs post week 22. Six patients (3 [3.1%] patients in the ABP 710/ABP 710 treatment group, 1 [2.2%] subject in the RP/RP treatment group, and 2 [4.4%] patients in the RP/ABP 710 treatment group) tested positive for neutralizing ADAs post week 22. Descriptive results for ADAs by visit and treatment indicate that the incidence of ADAs was similar in patients across all groups throughout the course of the study (Table 5).

Pharmacokinetic Results

Of the 558 randomized patients, 556 had at least one evaluable result for serum concentration of ABP 710 or infliximab RP at any visit and were included in the PK analysis. PK results revealed that trough serum concentrations were similar between groups across all study weeks, indicating that exposure was similar between treatment groups. The geometric mean trough serum concentrations and geometric coefficient of variation at week 22 were 1126.98 ng/ml (291.55%) and 1184.40 ng/ml (327.94%) for ABP 710 and infliximab RP, respectively, with similar concentrations across groups at all time points up to week 22 with geometric mean ratio values ranging from 0.91 to 1.05, indicating that ABP 710 and infliximab RP have similar PK following multiple-dose administration in patients with RA. The geometric mean trough serum concentrations with geometric coefficient of variation post transition at week 50 were 4028.52 ng/ml (245.05%; ABP 710/ABP 710), 3432.72 ng/ml (437.30%; RP/RP), and 2948.96 ng/ml (587.56%; RP/ABP 710) with similar concentrations across groups at all time points with geometric mean ratio values ranging from 0.90 to 1.25 for comparisons of ABP 710/ABP 710 and RP/RP treatment groups and from 0.72 to 1.15 for comparisons of RP/ABP 710 and RP/RP treatment groups.

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