Reference Adalimumab Research Articles

Safety of adalimumab biosimilar MSB11022 (acetate-buffered formulation) in patients with moderately-to-severely active rheumatoid arthritis

ObjectivesTo compare the safety, efficacy, and immunogenicity of MSB11022 (acetate-buffered formulation), an adalimumab biosimilar, with the reference product.MethodAURIEL-RA study was a phase 3, multicenter, randomized, double-blind, parallel group trial (NCT03052322). Patients with moderately-to-severely active rheumatoid arthritis (RA) with an inadequate response to methotrexate were randomized 1:1 to MSB11022 or reference adalimumab. The primary endpoint was the incidence of treatment-emergent adverse events of special interest (AESIs) (predefined as hypersensitivity) up to week 52. The key secondary endpoint was ACR20 (≥ 20% improvement in American College of Rheumatology core set measurements from baseline) at week 12. Other efficacy endpoints, quality of life, immunogenicity, and pharmacokinetic parameters were evaluated up to week 52. Secondary safety endpoints were evaluated up to week 52 and at a 4-month safety follow-up.ResultsIn total, 288 patients were randomized. The proportion of patients experiencing ≥ 1 treatment-emergent AESI up to week 52 was similar between trial arms: 6 patients (4.2%; 95% CI 1.56, 8.91) receiving MSB11022, and 8 patients (5.5%; 95% CI 2.41, 10.58) receiving reference adalimumab. No clinically meaningful differences in efficacy, quality of life, or immunogenicity were seen between treatment arms up to week 52. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the follow-up period.ConclusionsThese results suggest MSB11022 and reference adalimumab are similar in patients with moderately-to-severely active rheumatoid arthritis in terms of safety, immunogenicity, and efficacy. AURIEL-RA provides evidence to support the similarity of MSB11022 and adalimumab.Key Points• Incidences of hypersensitivity events were similar for MSB11022 (modified buffer) and reference adalimumab.• There was no difference in local reactions between MSB11022 (modified buffer) and reference adalimumab.• AURIEL-RA confirms the equivalence in efficacy and immunogenicity of MSB11022 (modified buffer) and reference adalimumab.

A Review of Adalimumab Biosimilars for the Treatment of Immune-Mediated Rheumatic Conditions

Adalimumab is a recombinant fully human monoclonal antibody targeting soluble and transmembrane TNF alpha. It is approved for the treatment of immune-mediated rheumatic, gastroenterological, dermatological, and ophthalmological conditions and this therapeutic versatility has made it the top-selling drug worldwide since 2012. Not surprisingly, following the patent expiration of the originator drug, biopharmaceutical companies invested in the development of biosimilar versions of adalimumab and six have already received marketing authorisation: ABP 501, GP2017, and BI 695501 in Europe and in the USA (though the manufacturer of the latter requested authorisation withdrawal in Europe), and SB5, FKB327, and MSB11022 in Europe. This manuscript reviews published data on approved adalimumab biosimilars, including analytical and biofunctional results from preclinical assessments; pharmacokinetics after administration in healthy subjects (Phase I trials); and efficacy, safety, and immunogenicity from pivotal (Phase III) clinical trials. Data on switching from reference adalimumab to biosimilars, and predicted cost-savings from available budget impact models, will also be addressed.

Real-Life Tolerability and Effectiveness of Adalimumab Biosimilar in Rheumatoid Arthritis: ASPIRE Registry Data.

IntroductionThe TNF-α blocker adalimumab is a well-proven therapy for rheumatoid arthritis (RA). A biosimilar adalimumab (ZRC-3197; Exemptia™), a ‘fingerprint match’ to reference adalimumab, has been approved for prescription in India since 2014. Here, we report on the effectiveness and tolerability of this biosimilar adalimumab (bADA) from the Adalimumab Biosimilar Patient Registry [ASPIRE; ISRCTN16838474], which contains data from real-life RA patients from India.MethodsASPIRE is a post-marketing, observational registry that evaluates real-world experience across multiple centres in India. Patients with moderate to severe RA who were prescribed bADA 40 mg subcutaneously every fortnight were enrolled. Patients with complete data available until 24 weeks of bADA treatment were extracted and analyzed for standard disease activity measures and reported adverse events.ResultsThe registry included 149 patients with RA who had a median age of 41 (22–67) years; 65% of the patients were female. Disease outcome measures, i.e. ESR, DAS-ESR and VAS-pain scores, showed gradual and significant decreases (p < 0.0001 for all) in 73 analyzable patients who received 24 weeks of bADA therapy. ACR20, ACR50 and ACR70 responses were achieved in 48%, 48% and 34% of patients after 24 weeks of therapy, respectively, and about 58% and 15% of patients were moderate and good EULAR responders, respectively. Physician and patient ratings for the overall global assessment of efficacy and tolerability were ‘good’ to ‘excellent’ for the majority of the patients (≥ 96%). No new safety signals were observed when analyzing this registry data.ConclusionReal-life data from this post-marketing observational analysis demonstrate the clinical effectiveness and tolerability of 24 weeks of adalimumab biosimilar therapy in Indian patients with RA. This report also reflects upon the treatment strategies and prescription patterns for such therapies in Indian clinical practice.Trial RegistrationISRCTN16838474.FundingCadila Healthcare Limited, India.

PBI8 COST SAVING OPPORTUNITY TO A HEALTH-SYSTEM ADALIMUMAB BIOSIMILAR TRANSITION PROGRAMME ACCOUNT WITHIN THE UK

To determine the overall potential twelve-month savings opportunity when accounting for both drug acquisition cost savings and operational cost incurred in a theoretical UK account transition programme setting. A simulated UK health system account was devised based on a cohort of 250 adult patients with a total annual usage volume of 6,500 units of the 40mg reference adalimumab biologic. Operational costs incurred for an individual patient transition were assumed to be £62.40 based on current NHS guidance. The reference adalimumab biologic price was assumed to be at list price with no further discounting with other biosimilar formulations at a discount of 50% and 65%. The account scenario was based on an immediate transition programme (assuming full patient consent for change in formulation had previously been obtained). At a discount of 50%, a potential full year effect saving of £1.14m could be achieved increasing to £1.49m at a 65% discount. Allowing for the operational transition costs of £15,600 (staff time, counselling, training and other related issues) for this cohort, savings could be expected to be similar after operational cost outlay. Operational costs are an important factor to consider when planning a transition programme. These costs will invariably be required to be an upfront cost impact but the longer-term savings through competitive pricing outweigh this initial investment. To maximise these savings, mechanisms between the payer and the clinical account need to be in place to allow for rapid adoption.

Demonstration of functional similarity of a biosimilar adalimumab SB5 to Humira®

A biosimilar is a biological medicinal product that is highly similar to an authorized biological product in terms of quality, biological activity, safety and efficacy. SB5 was developed by Samsung Bioepis as a biosimilar referencing adalimumab, and was authorized by the European Commission (EC) in August 2017 (Imraldi®). Extensive characterization studies were performed to demonstrate functional similarity of SB5 to reference adalimumab (Humira®, AbbVie Inc. and AbbVie Deutschland GmbH & Co. KG). SB5 and Humira® showed highly similar soluble TNF-α binding and neutralizing activity, as well as transmembrane TNF-α binding activity and reverse signaling induced in the membrane TNF-α expressing cell line. Both products exhibited similar binding of the Fc gamma receptors and Fc-related effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In addition, additional mechanisms of action induced by TNF-α, such as cytokine release and expression of adhesion molecules, were analyzed and shown to be similar between SB5 and Humira®. Taken together, our results demonstrate that SB5 and Humira® are highly similar in terms of their functional characteristics.

FKB327: An Adalimumab Biosimilar.

FKB327 (Hulio®) is a biosimilar of the reference monoclonal anti-TNFα antibody adalimumab, and is approved in the EU for use in the same indications as reference adalimumab. FKB327 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and pharmacokinetic equivalence was shown in healthy volunteers and patients with moderate-to-severe rheumatoid arthritis (RA) despite methotrexate therapy. FKB327 demonstrated equivalent clinical efficacy to that of reference adalimumab in patients with moderate-to-severe RA, and similar tolerability, safety and immunogenicity profiles. Switching from reference adalimumab to FKB327 had no impact on efficacy, safety or immunogenicity.

GP2017, an adalimumab biosimilar: pharmacokinetic similarity to its reference medicine and pharmacokinetics comparison of different administration methods

ABSTRACT Background: To compare the pharmacokinetics of Sandoz biosimilar adalimumab (GP2017) with reference adalimumab (Humira) in healthy volunteers (PK similarity study) and to compare the pharmacokinetics of GP2017 administered by autoinjector (AI) or prefilled syringe (PFS; delivery study). Methods: Healthy male subjects were randomized to receive a single 40 mg subcutaneous injection of GP2017, US-licensed or EU-authorized reference adalimumab (US/EU-Humira; PK similarity study) or a single 40 mg subcutaneous injection of GP2017 via AI or PFS (delivery study). Pharmacokinetics, safety, and immunogenicity were assessed over 72 days post-injection. Results: The geometric mean ratios (90% confidence intervals) for Cmax and AUC0–inf were 1.05 (0.99–1.11) and 1.04 (0.96–1.13) for GP2017/EU-Humira and 1.00 (0.94–1.06) and 1.08 (1.00–1.18) for GP2017/US-Humira, all within the prespecified margin of 0.80–1.25 (PK similarity study). Pharmacokinetic parameters of GP2017 matched between AI and PFS (delivery study). Safety and immunogenicity were similar across groups in both studies. Conclusion: PK similarity between GP2017, EU- and US-Humira was demonstrated. The safety profile of GP2017 was consistent with previous reports for Humira. These results contribute to the ‘totality-of-the-evidence’ supporting biosimilarity of GP2017 to Humira. PK and tolerability were equivalent for GP2017 dosed by AI or PFS. Trial registration: PK similarity study EudraCT no. 2015-000579-28; Delivery study: EudraCT no. 2014–002879-29

P431 Validation of a therapeutic drug monitoring test to measure the adalimumab biosimilar SB5 in comparison with the reference adalimumab

Validation of therapeutic drug monitoring (TDM) tests is an essential requirement for using these tools to help assess reasons for non-response. The arrival of biosimilars has prompted a need to validate that existing TDM tests are suitable to determine drug levels for all versions of a given molecule. The adalimumab (ADL) biosimilar SB5 (IMRALDI®, Biogen) was authorised by the European Commission in August 2017, and has recently become available for prescription in several European countries. Promonitor®-ADL test is routinely used to monitor IBD patients treated with ADL. In this study, we validated the suitability and performance of Promonitor-ADL CE-marked TDM test for quantifying SB5 serum concentrations in comparison to reference adalimumab (HUMIRA®, Abbvie). The study evaluated imprecision and bias applied to the reference ADL and SB5 biosimilar. The validation study was in line with the design requirements established in the Clinical and Laboratory Standards Institute (CLSI) guideline EP10-A3 for the determination of imprecision and bias. Imprecision was evaluated using three replicates of five human serum sample matrices representative of clinically relevant ADL concentrations and spanning the measurement range of Promonitor-ADL.1 Validations were ran on one instrument with one kit lot by one operator over six non-consecutive operating days and one run per testing day, with an acceptance criterium of CV% ≤20%. The Lower Limit of Quantification (LLOQ) of Promonitor-ADL was determined according to CLSI guideline EP17-A2. The imprecision of Promonitor-ADL was calculated by estimating the components of variance due to within-run and between-day factors meet the accuracy goals proposed at all concentration levels of SB5 vs. HUMIRA (CV% between 5% and 12%). The assessment of accuracy showed that Promonitor-ADL equally measures the active moiety of HUMIRA or SB5. The test is able to quantify SB5 in the measurement range of 0.9 to 10.9 μg/ml with a bias estimate of −0.124 (1%) to 0.897 (10%) μg/ml and an overall imprecision of 5% to 11%. The measurement range includes the recommended clinical decision points. LLOQ of the test to determine ADL was determined to be 0.36 μg/ml. This study demonstrates that Promonitor-ADL test can measure either the reference ADL drug or the biosimilar SB5 (IMRALDI) with equivalent sensitivity, precision and accuracy. Reference 1. Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology 2017;153:827–34.

P664 SB5 and reference adalimumab show cross-immunogenicity in patients with inflammatory bowel disease or rheumatoid arthritis

P664 SB5 and reference adalimumab show cross-immunogenicity in patients with inflammatory bowel disease or rheumatoid arthritis

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.

GP2017: An Adalimumab Biosimilar.

GP2017 (adalimumab) is a biosimilar anti-TNF-α antibody. It is approved in the EU for use in all indications for which reference adalimumab is approved. GP2017 has similar physicochemical and functional properties to those of reference adalimumab, and the pharmacokinetic similarity of the agent has been shown in healthy male volunteers. GP2017 demonstrated clinical efficacy equivalent to that of reference adalimumab in patients with moderate to severe plaque psoriasis or rheumatoid arthritis; the tolerability, safety and immunogenicity profiles of the two agents were also similar. Multiple switching between GP2017 and reference adalimumab (up to four times) had no impact on efficacy, tolerability or immunogenicity. The role of reference adalimumab in the management of autoimmune inflammatory conditions is well established and GP2017 provides an effective biosimilar alternative for patients requiring adalimumab therapy.

SB5: An Adalimumab Biosimilar.

SB5 (Imraldi®) is a biosimilar of the reference anti-TNF monoclonal antibody adalimumab. It is approved for use in the following indications for which reference adalimumab is approved: rheumatoid arthritis (RA), juvenile idiopathic arthritis [polyarticular juvenile idiopathic arthritis (pJIA) and enthesitis-related arthritis (ERA)], axial spondyloarthritis [ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)], psoriatic arthritis (PsA), psoriasis, pediatric plaque psoriasis, hidradenitis suppurativa (HS), Crohn's disease, pediatric Crohn's disease, ulcerative colitis (UC), and non-infectious uveitis. SB5 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and the pharmacokinetic similarity of these agents has been shown in healthy volunteers and patients with RA. SB5 demonstrated clinical efficacy considered equivalent to that of reference adalimumab in patients with RA, and was generally well tolerated in this population. The safety and tolerability profile of SB5 was similar to that of reference adalimumab, as was the immunogenicity profile. Switching from reference adalimumab to SB5 had no impact in terms of efficacy, safety or immunogenicity. The role of reference adalimumab in the management of RA, pJIA, ERA, AS, nr-axSpA, PsA, psoriasis, pediatric plaque psoriasis, HS, Crohn's disease, UC and non-infectious uveitis is well established and SB5 provides an effective biosimilar alternative for patients requiring adalimumab therapy.

Comparative functional and pharmacological characterization of Sandoz proposed biosimilar adalimumab (GP2017): rationale for extrapolation across indications

ABSTRACTBackground: Biosimilars are approved biologics that match reference medicine in quality, safety, and efficacy. The development of Sandoz proposed biosimilar adalimumab (SPBA; GP2017) involved a target-directed, iterative state-of-the-art quality-by-design development program. Here, we describe the functional and pharmacological characterization of SPBA and its proposed mechanism of action in immune-mediated inflammatory diseases.Methods: Sensitive in vitro binding and functional characterization studies, and nonclinical evaluations (pharmacokinetics, pharmacodynamics, and safety/toxicology) were performed as part of a stepwise approach to confirm the biosimilarity of SPBA with reference adalimumab.Results: Matching values were reported for SPBA and reference adalimumab in binding assays involving tumor necrosis factor (TNF)-α, complement 1q and human immune effector cell Fcγ receptor subtypes in cell-based bioassays for Fc receptor function (complement- and antibody-dependent cytotoxicity), and in apoptosis inhibition. Furthermore, SPBA and reference adalimumab were equivalent in terms of membrane TNF binding and induction of reverse signaling. Pharmacokinetics of SPBA and reference adalimumab were comparable in rabbits, and the two biologics were equally effective in a human TNF transgenic mouse model of polyarthritis.Conclusion: SPBA matches reference adalimumab with regards to target binding, functional, pharmacokinetic, and pharmacodynamic properties at the nonclinical level supporting its approval in all indications of the reference adalimumab.

A new CHO (Chinese hamster ovary)-derived cell line expressing anti-TNFα monoclonal antibody with biosimilar potential.

Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that mediates the homeostasis of immune responses; its exacerbated production is associated with the pathogenesis of autoimmune and chronic inflammatory diseases. Anti-TNFα drugs have revolutionized the treatment of inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Currently, a worldwide race is on stage for the production of biosimilars moved by patent expiration of monoclonal antibodies (mAbs), such as anti-TNFα adalimumab. Our goal was to develop the first stage of an adalimumab biosimilar candidate with potential for national production, through the generation of a productive and stable cell line and assess its functionality. The robotic system ClonePix was used for screening and isolation of colonies from transfected CHO-S stable pools plated in semisolid medium. Selected clones were expanded based on growth and productivity. Purified mAbs from different clones were tested for binding and functional activity. The binding affinity of the denominated adabut clones to TNFα and FcRγ did not differ statistically when compared to reference adalimumab. One functional activity assay demonstrated the antibody neutralization capacity of the cytotoxicity induced by TNFα in L929 murine fibroblasts. A second assay confirmed adabut as an antagonist of the TNFα activity by the inhibition of the cell adhesion molecule expression in HUVEC cultures. The binding and functional activity analyses performed with selected adabut clones in comparison to reference adalimumab represent an important status of "non-inferiority," part of the process required for a biosimilar development. We generated and selected high-quality adabut clones which mAbs may be further developed as the first in-house made Brazilian biosimilar, demonstrating a success case for our incipient biotechnology industry, or also modified as biobetters, thus representing an innovative strategy for the patients' welfare.

Long-term Efficacy, Safety, and Immunogenicity Data From a Phase III Confirmatory Study Comparing GP2017, a Proposed Biosimilar, With Reference Adalimumab

Long-term Efficacy, Safety, and Immunogenicity Data From a Phase III Confirmatory Study Comparing GP2017, a Proposed Biosimilar, With Reference Adalimumab

Su1893 - Evaluation of the Pharmacokinetic Profiles of SB5 and Reference Adalimumab

Su1893 - Evaluation of the Pharmacokinetic Profiles of SB5 and Reference Adalimumab

P377 Evaluation of the pharmacokinetic profiles of SB5 and reference adalimumab

P377 Evaluation of the pharmacokinetic profiles of SB5 and reference adalimumab

Grades, status, and titles

<h3>Background</h3> Adalimumab, an anti TNF-α agent, has been proven to be safe and effective in treatment of ankylosing spondylitis (AS). A biosimilar adalimumab was approved for use by Indian regulators in 2014. It is a “fingerprint match” of the reference adalimumab in terms of purity, potency, safety and clinical efficacy.^1,2 ln the absence of availability of adalimumab in India, this biosimilar adalimumab currently serves as an accessible, cost-effective option for treatment of AS patients. <h3>Objectives</h3> This retrospective analysis evaluates effectiveness of biosimilar adalimumab (bADA), in terms of disease activity, safety and outcomes in real-life Indian AS patients treated for initial 24 weeks and then followed for next 24 weeks off biologic treatment. <h3>Methods</h3> Medical records of AS patients with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) &gt;4, who were prescribed bADA therapy between January to December 2015 were analysed. For patients, who stopped bADA treatment after 24 weeks, standard AS outcome-measurement scores including ESR, CRP, BASDAI, BASFI, and Health Assessment Questionnaire (HAQ) at baseline, week 24 and at week 48 were measured to evaluate ongoing efficacy, were compared using paired Student9s T-test. Patients were allowed to continue methotrexate and salazopyrin as part of routine medical care. <h3>Results</h3> During the study period, 52 AS patients were prescribed bADA 40 mg s/c; 24 of these patients, who had stopped treatment after 6 months, were considered for this analysis. Mean age for this group was 36.57±10.81 years; 10 females. At the end of 24 weeks9 treatment, there were significant reductions in levels of inflammatory markers ESR, CRP, as well as in BASDAI, BASFI and HAQ scores. Eight patients continued to receive methotrexate and 8 patients sulfasalazine as concomitant medications. After week 48 (24 weeks post stoppage), BASDAI and BASFI scores did not deteriorate despite discontinuation of bADA treatment. The patients9 HAQ scores were also indicative of similar trends of continuing improved health status post the therapy. <h3>Conclusions</h3> Biosimilar adalimumab therapy was effective in treating AS patients. The disease activity and health assessment scores continued to remain stable with no worsening after the stoppage of treatment for 6 months, indicating a post-therapy effectiveness in these patients with no reported adverse event. <h3>References</h3> Bandyopadhyay S, et al. Biosimilars. 2015;5:1–18. Jani RH et al. int J Rheum Dis. 2015 Jul 14. <h3>Disclosure of Interest</h3> None declared