Biosimilar Research Articles

Discussion on the Quality Similarity Assessment of Bevacizumab Biosimilar

Discussion on the Quality Similarity Assessment of Bevacizumab Biosimilar

Professor Daniel I.C. Wang: A Legacy of Education, Innovation, Publication, and Leadership.

Professor Daniel I.C. Wang: A Legacy of Education, Innovation, Publication, and Leadership.

Mandatory switching to biosimilars would be cost saving

Mandatory switching to biosimilars would be cost saving

Biosimilars to Infliximab Show Slow Uptake in U.S.

Treating inflammatory bowel disease incurs significant cost, much of which is related to medical therapy. The introduction of biosimilars was expected

Update on Biosimilar Insulins: A US Perspective.

The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar® (insulin glargine) and Admelog® (insulin lispro) have undergone extensive testing, and have gained significant use by patients in the US. Despite the availability of these follow-on products, the price of insulin has remained stubbornly high. New regulatory guidance under the Biologics Price Competition and Innovations Act that came into effect in March 2020 introduced an abbreviated pathway for the approval of biosimilar insulins and introduced the option to apply for interchangeability of the biosimilar insulin with the reference product. This abbreviated clinical testing may open the doors for numerous follow-on insulin products, with unknown supply-chain and fiscal ramifications. This review will highlight the development process of biosimilar insulin in the US and the recent regulatory changes that can aid this process. We will also discuss challenges for prescribers and patients who are navigating this ever-changing landscape. These new regulations for biosimilar insulins will have ramifications for patients, healthcare providers, and third-party payers, though the direction and scope of these changes is unclear.

Identification of recombinant insulin analogues by peptide mapping method

Insulin human, containing 51 amino acids, is a small polypeptide hormone that regulates blood glucose homeostasis. Patients with insulin-dependent diabetes mellitus require insulin therapy through the administration of exogenous insulin to avoid ketoacidosis. Utilizing various genetic engineering techniques, pharmaceutical companies have developed a variety of rapid- or long-acting insulin analogues. Analytical methods for various types of insulin and insulin analogues are gradually being included in the United States Pharmacopeia (USP) and the European Pharmacopeia (Ph. Eur.), but not yet in the Chinese Pharmacopeia. Usually these insulin analogues only differ by 1 to 3 amino acids, which is too subtle to distinguish by most of analytical methods currently available. In this study a peptide mapping technique was employed to screen insulin analogues for quality assessment. Peptide mapping is capable of identifying single amino acid changes resulted from events such as errors in the reading of complementary DNA sequences or point mutations. Here we analyzed 6 insulin preparations including insulin human, insulin lispro, insulin aspart, insulin detemir, insulin glargine and insulin glulisine using peptide mapping analysis. The peptide fingerprints of the insulin products we tested all corresponded well to those of the standard materials. Our peptide mapping method is more accurate in identifying the subtle differences between the insulin analogues than chromatography is. We concluded that peptide mapping is a valuable initial screening tool for quality assessment of insulin analogues. In the future, we intend to continue to develop this technology for post-marketing surveillance of other biopharmaceuticals and biosimilars, such as somatropin, erythropoietin and G-CSF.

AB0274 USE OF TNF-INHIBITORS BIOSIMILARS IN CHRONIC INFLAMMATORY ARTHRITIDES: A THREE-YEAR EXPERIENCE IN A LARGE MONOCENTRIC COHORT OF PATIENTS FROM THE NORTH-EAST ITALY

Background::In recent years several biosimilars (BS) of tumour necrosis factor inhibitors (TNF-i) were introduced. At the Padova University Hospital the first BS of etanercept (bsETN) was available in October 2016 and the BS of adalimumab (bsADA) was available in November 2018.Objectives:The objectives of the study were to evaluate the rate of bioriginator-biosimilar (BO-BS) switch in all patients with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and axial spondiloarthritis (axSpA) in the cohort of the Padova University Hospital and to examine factors favouring BO-BS switch. Secondly, we investigated survival of BO-BS switch and BO treatment and factors associated with longer treatment survival.Methods:We considered all patients on ETN originator (boETN) treatment when the first bsETN was available (1st October 2016) and all patients on ADA originator (boADA) when bsADA was available (1st November 2018). Patients were followed until 30 August 2019 and were classified as BO-BS switchers if they underwent a switch from either boETN or boADA to BS during the follow-up, otherwise they were considered as continuing BO treatment. Factors associated with BO-BS switch were tested with a multivariable regression analysis. To test the survival of the BO-BS switch and of the BO treatment, Cox regression analysis was used including all variables achiving a p<0.10 in univariate analysis tested with Log-rank test and Kaplan-Meier curves.Results:Among 1208 patients (553 RA, 433 PSA, 215 axSpA), 560 (46.3%) patients switched to bsETN (391) or bsADA (169). Mean disease duration was 16 (14.2) years and mean duration of the bDMARD treatment was 96.3 (56.8) months. After adjustment for potential confounders, factors associated with BO-BS switch were a longer disease duration, a shorter duration of previous bDMARD treatments and diagnosis (Tab.1) RA patients had almost a 3 fold increased likelihood of being switched to BS compared to PSA and axSPA, while difference between PSA and axSPA was not significant.Following Cox regression analysis we observed a longer drug survival in BO-BS switchers compared to those continuing with BO (HR 1.38; 95% C.I. 1.2-1.58; p<0.001) (Fig. 1). A longer drug survival was also associated with a longer disease duration (.15years: HR 1.75; 95% C.I. 1.5-2; p<0.001), longer mean duration of previous bDMARDs (.5years: HR 4.1; 95% C.I. 3.5-4.7; p<0.001), and diagnosis (RA vs PSA: HR 1.22; 95% C.I. 1.02-1.47; p=0.030; RA vs axSpA: HR 0.89 95% C.I. 0.067-0.97; p=0.023; PSA vs axSpA: HR 0.66; 95% C.I. 0.57-0.77; p<0.001) (Fig 2).Figure 1.Kaplan-Meier curves for treatment survival, Log-rank test.Figure 2.Kaplan-Meier curves for treatment survival in all patients, Log-rank tesConclusion:BO-BS switch was undertaken in almost half of the patients. Patients with longer disease duration and longer bDMARD duration, were the most likely to be switched successfully to BS. BO-BS switching does not affect the survival of the treatment, indeed, it provides sustained effectiveness particularly if undertaken in patients with stable disease activity.Table 1.Factors associated with BO-BS switch, multivariate regression analysis.Disclosure of Interests:DAVIDE ASTORRI: None declared, Francesca Ometto: None declared, LARA FRISO: None declared, BERND RAFFEINER: None declared, Costantino Botsios: None declared, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS

FRI0630-HPR ONE-YEAR FOLLOW-UP OF A NURSE-LED TEAM INTERVENTION EFFECTIVE IN REDUCING THE NOCEBO EFFECT WHEN SWITCHING FROM ORIGINATOR INFLIXIMAB TO A BIOSIMILAR.

Background:Nonspecific subjective adverse effects and symptoms (NSAE/NSS), usually considered as related to a nocebo effect (NE), have been identified as a barrier to the acceptability of switches from biologic originators (BO) to biosimilars (BS) in rheumatology. A multidisciplinary team intervention with a prominent role of nurses has provided a reduction of the NE assessed in the short-term during a systematic switch from originator Infliximab (OI) to the biosimilar infliximab SB2 (ref.1).Objectives:To assess the intervention outcomes after one-year follow up in comparison with a historical cohort.Methods:The intervention was developed after a literature search and semi-directive interviews of patients, and included consensual communication towards patients, with a prominent role of nurses (Ref.1). All patients with chronic inflammatory rheumatic diseases (CIRD) treated by OI were included and followed-up in routine care. The outcomes were I) SB2 retention rate (RR) II) SB2 discontinuation rate due to a presumed NE, defined as lack of efficacy with no objective criteria for increased inflammation or non-objective and non-specific adverse event, either occurring after the switch and disappearing after back-switch or change of biologic. Criteria for NSAE/NSS in the historical cohort were the same lack of efficacy or subjective adverse events and disappearance after change of biologic BD. Medium-term (12 months) SB2 outcomes were assessed and compared with I) the data obtained in the short-term (34 weeks) II) the data from an historical cohort of CIRD patients treated by OI in the same rheumatology department, using Kaplan-Meier survival curve.Results:Forty-five patients were prospectively included for the switch from March 2018 to August 2018: 17 with rheumatoid arthritis (RA), 28 with spondylarthritis (SpA); 55% were women, mean age was 53.2 (SD: 2,1), and mean time under OI was 113.5 (SD9.3). For the historical cohort, the 52 patients treated with OI between December 2016 and January 2017 were included and their data collected at baseline and one year. Fifty-nine percent were women, mean age at inclusion was 50.25 (1.2), and mean time under OI was 94.8 (9.4).SB2 RR did not differ from the OI RR in the historical cohort: 91.2% and 96.2% respectively at 34 weeks (p = 0.41); 84.4% and 88.5% respectively at 12 months (p = 0.52) (figure 1). The SB2 RR was significantly higher than in three other European cohorts at 34 weeks (mean RR 73.6%, p<0.05, ref.1) but not at 12 months (mean RR 80.9%, ref.2,3,4).SB2 and OI discontinuations due to NSAE/NSS at 34 weeks were 2,2 % and 1.9% respectively; at 12 months 6,6% and 1.9% respectively (p= 0.6).Conclusion:An intervention based on a tailored communication with a prominent role of nurses was effective in reducing the NE when switching from OI to SB2 in the short term, compared with an historical cohort and other European cohorts. The one-year follow-up showed no statistical difference in RR or NE compared with our historical cohort. The present study shows that appropriate interventions may be developed to improve the outcome of switches to biosimilars.Figure 1:Treatment withdrawal free survival curves (SB2 in switched cohort and OI in historical cohort).Kaplan Meir survival curves. Comparison with Log-Rank test between OI to SB2 cohort and historical OI cohort, p = 0.520. OI : original infliximab.

Evaluation of adverse events associated with filgrastim originator and biosimilar using a spontaneous reporting system database.

Biosimilar products of filgrastim have become available for improved sustainability of cancer care; however, the real-world safety profile remains unknown. The purpose of this study was to clarify the adverse events associated with filgrastim originator and its biosimilar using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2014-2018 were extracted. We calculated the reporting odds ratio and 95% confidence interval for each adverse event. We obtained 584 reports of adverse events associated with filgrastim originator and 102 reports with its biosimilar. Signals were detected for bone marrow failure and febrile neutropenia with both filgrastim originator and its biosimilar; whereas those for drug resistance and hypoxia only involved filgrastim originator, and those for interstitial lung disease only involved its biosimilar. The safety profiles of filgrastim originator and its biosimilar were partly different. Further studies are needed to confirm these findings.

Learning the How & Why of Biosimilars

Learning the How & Why of Biosimilars

Biosimilars, a new era in rheumatology in Spain

Biosimilars, a new era in rheumatology in Spain

Statistical Assessment of Biosimilarity Based on the Relative Distance Between Follow-on Biologics for Time-to-Event Endpoints

The two-arm parallel design that is commonly used to assess biosimilarity has the drawback that it does not take into account the inherent variability within the reference products. The three-arm parallel design was proposed to solve this problem. The purpose of this article was to extend the previous results to the time-to-event endpoints in the exponential model, the Cox proportional hazard model, and the restricted mean survival time. The relative distance is defined, and the corresponding test procedures are developed based on asymptotic theory. The Type I error rates and powers are investigated theoretically and empirically. Supplementary materials for this article are available online.

Abstract P5-05-08: Comparative evaluation of a trastuzumab biosimilar or originator trastuzumab in association with pertuzumab: Binding and biological activities in cell culture-based assays

Abstract Background: trastuzumab (TZB) is approved for the treatment of HER2-positive (HER2+) breast cancer in different indications and schemes. The association of pertuzumab (PTZ) in some regimens has shown to improve the clinical benefit. Recently, biosimilars (BS) of trastuzumab were approved after extensive exercises of comparison with the originator, proving that these new biologicals are highly similar in structure and biological activity, and inherent microheterogeneity is not clinically relevant, since efficacy, safety and immunogenicity were found to be equivalent in pivotal phase 3 trials. In this study, we aimed to compare binding and biological activities of biosimilar trastuzumab (BS-TZB) or trastuzumab originator in association with PTZ in cell culture-based assays. Methods: two cancer cell lines were used to perform all the tests: BT474 (HER2+/ progesterone (PR) and estrogen receptor (ER)- positive) and HCC1954 (HER2+/PR and ER-negative); fluorescent labeling of trastuzumab originator (Herceptin®- Produtos Roche Químicos e Farmacêuticos S.A.) with Alexa 488, biosimilar of trastuzumab (trastuzumab-dkst, Biocon Limited/ Zedora- Libbs Farmacêutica Ltda.) with Alexa 488 and pertuzumab (Perjeta®- Produtos Roche Químicos e Farmacêuticos S.A.) with Alexa 647; FACS-based antigen binding evaluations and live cell imaging were performed (TZB or BS-TZB, and PTZ at concentrations of: 0; 10; 100; 1,000 ng/mL in every combinations. Predefined acceptance criteria for ligand-binding assay (LBA) was ±20% (25% at lower limit of quantification - LLOQ). Proliferation and CDC (complement-dependent cytotoxicity) assays: TZB or BS-TZB were tested at concentrations of: 0.01; 0.03; 0.1; 0.3; 1; 3; 10; 30; 100 μg/mL combined with PTZ at concentrations 1; 10; 100 μg/mL; the number of viable cells were estimated by quantitation of the ATP present using the CellTiter-Glo® kit. Equivalence was stablished with 95% confidence if 90% confidence interval (CI) of difference between means (DBM) lies within the zone of indifference (±20%). Results: tests were done using different concentrations and combinations of antibodies. For LBA, results are shown with concentrations in which the effect was neither minimal nor maximal (for both cell lines: 100 ng/mL for PTZ; 1,000 ng/mL for TZB or BS-TZB) (Table 1). For proliferation and CDC analysis, results at concentrations 100 μg/mL for PTZ, and TZB or BS-TZB (for both cell lines) are shown as a ratio to control. Table 1: Ligand-binding, proliferation and CDC assays. SD: standard deviation.Cell lineAnti-bodiesLBA (% cells) mean ± SDDBM 90% CIProliferation (ratio) mean ±SDDBM 90% CICDC (% cells) mean ± SDDBM 90% CIBT474BS-TZB + PTZ69.6 ±0.3-4.5 to -3.465.3 ±2.5-7.2 to -0.358.2 ±0.1-5.8 to -3.2TZB + PTZ73.5 ±0.369.6 ±1.262.8 ±1.1HCC1954BS-TZB + PTZ94.2 ±0.35.8 to 6.480.5 ±1.9-14.3 to -0.349.8 ±0.1-4.3 to -1.9TZB + PTZ88.1 ±0.187.8 ±5.452.9 ±1.0 Conclusions: trastuzumab and pertuzumab bind to HER2 receptor at different subdomains acting synergistically and, ultimately, improving the clinical benefit. In this study we comparatively evaluated the ligand and biological activities of the biosimilar BS-TZB and the TZB originator in the presence of PTZ. In addition to the previous findings of highly similar structure and biological activities of biosimilar to its originator, this study showed that not only PTZ binding to HER2 domain II but also biological activity showed the same pattern in the presence of BS-TZB as well as in the presence of TZB. Herein, in evaluated mechanisms, we have showed that the combination of BS-TZB and PTZ are highly similar to the combination of TZB and PTZ. Citation Format: Franklin F Pimentel, Juliano S Toledo, João Gonçalves, Leandro L Alves, Mayara I de Paula, Jurandyr M de Andrade, Daniel G Tiezzi, Roger Chammas. Comparative evaluation of a trastuzumab biosimilar or originator trastuzumab in association with pertuzumab: Binding and biological activities in cell culture-based assays [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-08.

Availability of anticancer biosimilars in 40 countries.

Availability of anticancer biosimilars in 40 countries.

Statistical tests for biosimilarity based on relative distance between follow-on biologics for ordinal endpoints

Investigations of biosimilarity between reference drugs and test drugs required statistical tests; in addition, statistical tests to evaluate biosimilarity have been recently proposed. Ordinal outcome data has been observed in research; however, appropriate statistical tests to deal with ordinal endpoints for biosimilar have not yet been proposed. This paper extends existing design for ordinal endpoints. Using measure of nominal-ordinal association and relative distances between drugs are defined so that testing procedures are developed. Through simulation studies, we investigate type I error rate and power to show the performance of our suggested method. Furthermore, a comparison between the statistical tests and other designs is proviede to show significance of ordinal endpoints.

New drugs, biosimilar, indication, formulation, generics

New drugs, biosimilar, indication, formulation, generics

Biologicals and Biosimilars in Hematology: The Case of Rituximab.

Biologicals and Biosimilars in Hematology: The Case of Rituximab.

Adalimumab and the Challenges for Biosimilars

Adalimumab and the Challenges for Biosimilars

A brief overview of biosimilars and factors limiting their uptake.

A brief overview of biosimilars and factors limiting their uptake.

Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri®

Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri®