THU0184 Impact of immunogenicity on clinical efficacy and administration related reaction in tnf inhibitors: a pooled-analysis from three biosimilar studies in patients with rheumatoid arthritis

Abstract

BackgroundSB4, SB2, and SB5 are biosimilars of reference etanercept, infliximab, and adalimumab, respectively. The phase III randomised, double-blind clinical studies comparing the efficacy and safety of each biosimilar with its reference product had similar study designs, patient demographics, and the same primary endpoint of the ACR20 response rate. In each study immunogenicity was measured using a validated ECL assay tagged with the biosimilar.ObjectivesTo assess the immunogenicity of three TNFi and examine the potential impact of anti-drug antibodies (ADAbs) on efficacy and injection site reactions (ISR) or infusion related reactions (IRR) by a pooled analysis of three biosimilar studies.1–3 Data to the time of the primary endpoint for each study (week 24 for etanercept and adalimumab studies and week 30 for infliximab study) are presented.MethodsData from patients who had immunogenicity results from each phase III study were pooled. Efficacy (ACR responses, clinical response [defined as good or moderate EULAR response], change in disease activity [DAS28, SDAI, CDAI]) and ISR/IRR were evaluated in relation to the presence of ADAb (at least one ADAb positive result up to when the primary endpoint was measured).ResultsThe analysis included 1710 patients and the incidence of ADAb by treatment group is presented in the table 1.Across treatment groups, efficacy was greater in patients without ADAb compared to those with ADAb. In all treatments combined, the ACR20 response rate was lower in the presence of ADAb (OR 2.06, 95% CI: 1.63–2.60, p<0.0001) (figure 1) and the mean improvement in DAS28 was significantly greater in patients without ADAb (estimated difference: 0.383, 95% CI: 0.24–0.52, p<0.0001). The ADAb effect on reducing ACR20 response rates as well as other efficacy parameters was similarly observed in other treatment groups.In all treatments combined, the presence of ADAb was associated with increased ISR/IRR (OR 1.73, 95% CI: 1.02–2.96, p=0.043), predominantly with the infliximab combined (OR 2.67, 95% CI: 1.04–6.89, p=0.041) rather than the etanercept combined (OR 1.72, 95% CI: 0.38–7.77, p=0.478) and adalimumab combined (OR 1.00, 95% CI: 0.35–2.88, p=0.998).Abstract THU0184 – Table 1Incidence of Anti-drug Antibody (n/n’)TreatmentSB4ETNSB2INFSB5ADA ADAb Incidence2/299 (0.7%)39/297 (13.1%)158/287 (55.1%)145/292 (49.7%)88/266 (33.1%)86/269 (32.0%)TreatmentSB4+ETNSB2+INFSB5+ADABiosimilars combinedRP combinedAll treatments combinedADAb Incidence41/596 (6.9%)303/579 (52.3%)174/535 (32.5%)248/852 (29.1%)270/858 (31.5%)518/1710 (30.3%)ADA, adalimumab reference product; ADAb, anti-drug antibody; ETN, etanercept reference product; INF, infliximab reference product; RP: reference productAbstract THU0184 – Figure 1Effect of Anti-drug Antibody on ACR20 Response RatesConclusionsIn a pooled analysis, the development of ADAbs to TNFi is associated with reduced clinical efficacy and increased incidence of ISR/IRR in patients with RA.References[1] Emery, et al. Ann Rheum Dis2017Jan;76(1):51–57.[2] Choe, et al. Ann Rheum...

Nonmedical Switching From Originators to Biosimilars: Does the Nocebo Effect Explain Treatment Failures and Adverse Events in Rheumatology and Gastroenterology?

“…Because biologics are complex, micro-heterogeneous molecules that are highly sensitive to changes in both raw materials and manufacturing conditions, differences between biosimilars and their originator products can and do exist [82][83][84]. Although the clinical effect of these differences are not fully known, it is reasonable to postulate that the differences can cause individuals to respond differently to each molecule and raises the distinct possibility of altered outcomes that cannot be ignored [83,85]. Potential immunogenic responses should also be acknowledged; because biosimilars are not exact copies of their originators, it has been suggested that switching to a biosimilar may trigger an immunogenic response to subtle differences in epitopes between biosimilar and the originator [4,84,86], potentially leading to loss of efficacy or adverse events in individual patients [85].…”

“…Although the clinical effect of these differences are not fully known, it is reasonable to postulate that the differences can cause individuals to respond differently to each molecule and raises the distinct possibility of altered outcomes that cannot be ignored [83,85]. Potential immunogenic responses should also be acknowledged; because biosimilars are not exact copies of their originators, it has been suggested that switching to a biosimilar may trigger an immunogenic response to subtle differences in epitopes between biosimilar and the originator [4,84,86], potentially leading to loss of efficacy or adverse events in individual patients [85]. Furthermore, some studies have demonstrated that patients who develop an immunogenic response against an originator biologic should not be switched to its biosimilar owing to cross-reactivity and thus a similar loss of treatment response [87][88][89][90].…”

“…Furthermore, some studies have demonstrated that patients who develop an immunogenic response against an originator biologic should not be switched to its biosimilar owing to cross-reactivity and thus a similar loss of treatment response [87][88][89][90]. To our knowledge, only one pooled analysis has assessed the associations between immunogenicity and adverse outcomes [85], and future studies are needed to fully assess the implications of immunogenic consequences on efficacy and safety following a nonmedical switch but also responses that go beyond immunogenicity (e.g., nocebo effect).…”

Safety evaluation of adalimumab in immune-mediated inflammatory disorders: a rheumatological point of view

“…Recently, Emery et Al. showed that AAA against TNF inhibitors were associated with reduced clinical efficacy [26]. The PREMIER study revealed a better clinical outcome if adalimumab was prescribed with methotrexate [27,28].…”