Interchangeability for Biologics is a Legal Distinction in the USA, Not a Clinical One.

Biologics are increasingly vital medicines that significantly reduce morbidity as well as mortality, yet access continues to be an issue even in apparently wealthy countries, such as the USA. While patient access is expected to improve with the introduction of biosimilars, misperceptions in a significant part based on terminology continue to make a sustained contribution by biosimilars difficult. Patients are and will continue to suffer needlessly if biosimilars continue to be impugned. Consequently, it is increasingly urgent that semantics are clarified, and in particular, the implication that interchangeable biologics are better biosimilars dismissed. This paper distinguishes between the real differences between biologics that matter clinically to patients and discusses the actual meaning of a US Food and Drug Administration designation of interchangeability for a biosimilar product. This will help highlight where there is need for further Food and Drug Administration education and which stakeholders likely need that education the most.

Radiographic progression based on baseline characteristics from TNF inhibitor biosimilar studies in patients with rheumatoid arthritis.

OBJECTIVE: Phase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA). Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction. METHODS: Patients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product. Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson's correlation coefficient with the change in modified Total Sharp Score. Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression. RESULTS: A total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%. The 3 baseline predictors of radiographic progression, based on Pearson's correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA). A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA (P < 0.001). CONCLUSIONS: In this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies. Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach. CLINICAL TRIAL REGISTRATION NUMBERS: EudraCT 2012-005026-30. Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results EudraCT 2012-005733-37. Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results EudraCT 2013-005013-13. Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results.

Real World SB4 (Etanercept Biosimilar) Use in Patients With Psoriasis: Data from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

Psoriasis is a chronic, systemic, inflammatory skin disease with a risk of comorbidities and a potential high impact on patients’ quality of life.

Pooled analysis of TNF inhibitor biosimilar studies comparing radiographic progression by disease activity states in rheumatoid arthritis.

OBJECTIVE: To evaluate the relationship between disease activity and radiographic progression in rheumatoid arthritis, three phase III studies of SB4, SB2 and SB5 (biosimilars of etanercept, infliximab and adalimumab) were pooled to assess radiographic progression by disease activity status. METHODS: Patients from each study with radiographic data were pooled and grouped based on disease activity state (remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)), determined by disease activity score based on 28-joint count (DAS28) per erythrocyte sedimentation rate, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) at different time points. Mean change in modified Total Sharp Score (mTSS) and the proportion of radiographic non-progressors of higher disease activity groups (LDA, MDA and HDA) in reference to remission were summarised descriptively, with comparison of ORs using logistic models. RESULTS: 1265 patients were included. In all treatments combined, the 1 year mean change in mTSS was 0.03, 0.4, 0.3 and 1.3 and proportion of radiographic non-progressors was 79.8%, 78.1%, 74.1% and 58.4% in the week 24/30 DAS28-determined remission, LDA, MDA and HDA groups, respectively. ORs (95% CIs) of the proportion of non-progressors were lowest in the HDA group in reference to remission (0.35 (0.23 to 0.54)), followed by MDA (0.72 (0.50 to 1.05)) and LDA (0.90 (0.55 to 1.48)) groups. Similar trends were observed when disease activity was assessed using SDAI or CDAI. CONCLUSION: A pooled analysis of radiographic assessment data from three biosimilar studies showed that radiographic progression is small overall but increases with worse disease activity. TRIAL REGISTRATION NUMBERS: NCT01895309, NCT01936181 and NCT02167139.

SB5 shows cross-immunogenicity to adalimumab but not infliximab: results in patients with inflammatory bowel disease or rheumatoid arthritis.

BACKGROUND: The primary objective of this study was to analyze the cross-reactivity of antidrug antibodies to reference adalimumab (ADL) and SB5 (adalimumab biosimilar) in patients with inflammatory bowel disease (IBD) or rheumatoid arthritis (RA). METHODS: Sera from patients with IBD and RA with or without antibodies to adalimumab (ATA+ or ATA-, respectively) were tested for cross-reactivity with SB5 and ADL. Functional inhibition of tumor necrosis factor-α binding was measured. Sera from patients with antibodies to reference infliximab (ATI+) were examined for cross-reactivity to SB5. Sera were tested by enzyme-linked immunosorbent assay. RESULTS: All 30 anti-ADL ATA+ sera from patients with IBD and all 4 anti-SB5 ATA+ sera from patients with RA were cross-reactive with ADL and SB5 (range of mean concentrations: IBD, 20.99-21.31 µg/ml; RA, 16.46-17.48 µg/ml). In general, there was no significant difference between mean ATA titers. A strong correlation was detected in all ATA+ samples (rho = 0.997 to >0.999; p < 0.001 each). However, ATA- sera were not reactive to either ADL or SB5. anti-ADL ATA+ sera similarly neutralized functional activity of ADL and SB5; no functional inhibition was observed with ATA- sera. ATI+ sera did not cross-react with SB5. CONCLUSIONS: ADL and SB5 show cross-immunogenicity in sera from patients with IBD or RA, supporting shared immune-dominant epitopes. ATI+ sera did not cross-react with SB5, suggesting different immunogenic epitopes between infliximab and SB5.

Usability and safety of SB5 (an adalimumab biosimilar) prefilled syringe and autoinjector in patients with rheumatoid arthritis.

OBJECTIVE: To demonstrate comparability between administration of the adalimumab biosimilar, SB5, via prefilled syringe (PFS) and autoinjector (AI) pen based on injection site pain, patient preference, and safety in rheumatoid arthritis (RA) patients. METHODS: In this phase 2, open-label study (NCT02565810; EudraCT Number 2014-004887-39), adult RA patients self-administered 40 mg SB5 subcutaneously via PFS at weeks 0 and 2, followed by AI at weeks 4, 6, 8, and 10. Patients rated injection site pain from 0 (no pain) to 10 (severe pain) using a visual numeric scale immediately and 15-30 min post-injection at weeks 0, 2, 4, and 6. Equivalence between PFS and AI was concluded if the 97.5% confidence interval (CI) of the difference in the injection site pain scores at weeks 2 and 6 was contained within the equivalence margin of ±5. Overall impression and preference for PFS and AI were also evaluated. Safety was assessed up to 20 weeks after the first injection. RESULTS: Of 49 patients enrolled, 48 completed the study. Mean injection site pain scores were equivalent between PFS and AI immediately (2.3 vs 2.0; 97.5% CI = -0.99-0.30) and 15-30 min post-injection (0.8 vs 0.7; 97.5% CI = -0.47-0.25). The overall impression of both devices was comparable. The overall preference of AI was higher than PFS. Treatment-emergent adverse events (TEAE) were mild-to-moderate. There were no severe or serious TEAEs reported during the study. CONCLUSIONS: In RA patients, SB5 showed equivalent injection site pain and comparable safety when administered via PFS and AI.

Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheumatoid Arthritis: Fifty-Two-Week Phase III Randomized Study Results.

OBJECTIVE: The 24-week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate-to-severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks. METHODS: In this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week). At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group). Efficacy, safety, and immunogenicity were evaluated up to 52 weeks. RESULTS: The full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group). The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study. ACR20 response rates ranged from 73.4% to 78.8% at week 52. Radiographic progression was minimal and comparable across treatment groups. The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition. CONCLUSION: SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment-emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy.

Phase III Randomized Study of SB5, an Adalimumab Biosimilar, Versus Reference Adalimumab in Patients With Moderate-to-Severe Rheumatoid Arthritis.

OBJECTIVE: SB5 is a biosimilar agent for adalimumab (ADA). The aim of this study was to evaluate the efficacy, pharmacokinetics (PK), safety, and immunogenicity of SB5 in comparison with reference ADA in patients with rheumatoid arthritis (RA). METHODS: In this phase III, randomized, double-blind, parallel-group study, patients with moderately to severely active RA despite treatment with methotrexate were randomized 1:1 to receive SB5 or reference ADA at a dosage of 40 mg subcutaneously every other week. The primary efficacy end point was the response rate based on the American College of Rheumatology 20% improvement criteria (ACR20) at week 24 in the per-protocol set (completer analysis). Additional end points included efficacy, PK, safety, and immunogenicity assessments. RESULTS: Of the 544 patients randomized to receive a study drug, the full analysis set comprised 542 patients (269 in the SB5 group, 273 in the reference ADA group) and the per-protocol set comprised 476 patients (239 receiving SB5, 237 receiving reference ADA). The ACR20 response rate at week 24 in the per-protocol set was equivalent between those receiving SB5 and those receiving reference ADA (72.4% and 72.2%, respectively); the difference in the ACR20 response rate (0.1%, [95% confidence interval -7.83%, 8.13%]) was within the predefined equivalence margin (±15%). Similar results were seen in the full analysis set (missing data being considered a nonresponse). The SB5 and reference ADA treatment groups were comparable across other end points, including the ACR 50% and ACR 70% improvement response rates, Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate, PK data, incidence of treatment-emergent adverse events, and the antidrug antibody response. Subgroup analyses showed that the efficacy and safety of SB5 and reference ADA were comparable regardless of antidrug antibody status. CONCLUSION: The ACR20 response rate at week 24 was equivalent between patients treated with the biosimilar agent SB5 and those treated with reference ADA. SB5 and reference ADA were both well tolerated, with comparable safety profiles, in patients with RA.

52-week results of the phase 3 randomized study comparing SB4 with reference etanercept in patients with active rheumatoid arthritis.

Objective: To compare the 52-week efficacy and safety of SB4 [an etanercept biosimilar] with reference etanercept (ETN) in patients with active RA. Methods: In a phase 3, randomized, double-blind, multicentre study, patients with moderate to severe RA despite MTX treatment were randomized to receive 50 mg/week of s.c. SB4 or ETN up to week 52. Efficacy assessments included ACR response rates, 28-joint DAS, Simplified and Clinical Disease Activity Indices and changes in the modified total Sharp score (mTSS). Safety and immunogenicity were also evaluated. Results: A total of 596 patients were randomized to receive either SB4 (n = 299) or ETN (n = 297) and 505 (84.7%) patients completed 52 weeks of the study. At week 52, the ACR20 response rates in the per-protocol set were comparable between SB4 (80.8%) and ETN (81.5%). All efficacy results were comparable between the two groups and they were maintained up to week 52. Radiographic progression was also comparable and the change from baseline in the mTSS was 0.45 for SB4 and 0.74 for ETN. The safety profile of SB4 was similar to that of ETN and the incidence of anti-drug antibody development up to week 52 was 1.0 and 13.2% in the SB4 and ETN groups, respectively. Conclusion: Efficacy including radiographic progression was comparable between SB4 and ETN up to week 52. SB4 was well tolerated and had a similar safety profile to that of ETN. Trial registration number: ClinicalTrials.gov NCT01895309, EudraCT 2012-005026-30.

Long-term efficacy and safety in patients with rheumatoid arthritis continuing on SB4 or switching from reference etanercept to SB4.

OBJECTIVES: SB4 (Benepali, Brenzys) is a biosimilar of reference etanercept (ETN). In a randomised, double-blind, 52-week study, SB4 demonstrated comparable efficacy and safety to ETN in patients with rheumatoid arthritis (RA). The open-label extension period evaluated long-term efficacy, safety and immunogenicity when continuing SB4 versus switching from ETN to SB4. METHODS: In the randomised, double-blind phase, patients received weekly subcutaneous administration of 50 mg SB4 or ETN with background methotrexate for up to 52 weeks. Patients in the Czech Republic and Poland who completed the 52-week visit were enrolled in the open-label extension period and received SB4 for 48 additional weeks. Efficacy, safety and immunogenicity were assessed up to week 100. RESULTS: Of 245 patients entering the extension period, 126 continued to receive SB4 (SB4/SB4) and 119 switched to SB4 (ETN/SB4). American College of Rheumatology (ACR) response rates were sustained and comparable between SB4/SB4 and ETN/SB4 with ACR20 response rates at week 100 of 77.9% and 79.1%, respectively. Other efficacy results, including radiographic progression, were also comparable between the groups. After week 52, rates of treatment-emergent adverse events were 47.6% (SB4/SB4) and 48.7% (ETN/SB4); one patient/group developed non-neutralising antidrug antibodies. No cases of active tuberculosis or injection-site reactions were reported during the extension period. One patient (SB4/SB4) died of hepatic cancer. CONCLUSIONS: SB4 was effective and well tolerated over 2 years in patients with RA. Efficacy, safety and immunogenicity were comparable between the SB4/SB4 and ETN/SB4 groups, showing no risk associated with switching patients from ETN to SB4. TRIAL REGISTRATION NUMBER: NCT01895309; 2012-005026-30.

A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy.

OBJECTIVES: To compare the efficacy and safety of SB4 (an etanercept biosimilar) with reference product etanercept (ETN) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: This is a phase III, randomised, double-blind, parallel-group, multicentre study with a 24-week primary endpoint. Patients with moderate to severe RA despite MTX treatment were randomised to receive weekly dose of 50 mg of subcutaneous SB4 or ETN. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 24. Other efficacy endpoints as well as safety, immunogenicity and pharmacokinetic parameters were also measured. RESULTS: 596 patients were randomised to either SB4 (N=299) or ETN (N=297). The ACR20 response rate at week 24 in the per-protocol set was 78.1% for SB4 and 80.3% for ETN. The 95% CI of the adjusted treatment difference was -9.41% to 4.98%, which is completely contained within the predefined equivalence margin of -15% to 15%, indicating therapeutic equivalence between SB4 and ETN. Other efficacy endpoints and pharmacokinetic endpoints were comparable. The incidence of treatment-emergent adverse events was comparable (55.2% vs 58.2%), and the incidence of antidrug antibody development up to week 24 was lower in SB4 compared with ETN (0.7% vs 13.1%). CONCLUSIONS: SB4 was shown to be equivalent with ETN in terms of efficacy at week 24. SB4 was well tolerated with a lower immunogenicity profile. The safety profile of SB4 was comparable with that of ETN. TRIAL REGISTRATION NUMBERS: NCT01895309, EudraCT 2012-005026-30.