Outcomes of a 12-month course of early and late rituximab BCD020 biosimilar administration in juvenile systemic lupus erythematosus:A retrospective study

BACKGROUND Juvenile systemic lupus erythematosus(SLE)is a severe,life-threatening disease.However,the role of rituximab in managing juvenile SLE remains undefined,although early biological intervention may improve disease outcomes.AIM To assess the differences in the outcomes of different types of rituximab administration(early and late).METHODS In this retrospective cohort study,the information of 36 children with SLE with administration(LRA)was analyzed.We compared initial disease characteristics at onset,at baseline(start of rituximab),and at the end of the study(EOS)at 12 months,as well as outcomes and treatment characteristics.RESULTS The main differences at baseline were a higher daily median dose of corticosteroids,increased MAS frequency,and a higher Systemic Lupus Erythematosus Disease Activity Index(SLEDAI)in the ERA group.No differences in the main SLE outcomes between groups at the EOS were observed.The part of lupus nephritis patients who achieved remission changed from 44%to 31%in ERA and 32%to 11%in the LRA group.Patients with ERA had a shorter time to achieve low daily corticosteroid dose(≤0.2 mg/kg)at 1.2(0.9;1.4)years compared to 2.8(2.3;4.0)years(P=0.000001)and higher probability to achieve this low dose[hazard ratio(HR)=57.8(95%confidence interval(CI):7.2-463.2),P=0.00001 and remission(SLEDAI=0);HR=37.6(95%CI:4.45-333.3),P=0.00001].No differences in adverse events,including severe adverse events,were observed.CONCLUSION ERA demonstrated a better steroid-sparing effect and a possibility of earlier remission or low disease activity,except for lupus nephritis.Further investigations are required.

Analytical Method Development and Validation of Some Biosimilar Drugs by High Performance Thin Layer Chromatography

A simple and rapid HPTLC analytical method has been developed and validated for the determination of Etanercept and Filgrastim in pure form and in marketed formulation. Both the drugs were chromatographed on silica gel 60 F254s HPTLC plates, as stationary phase. The mobile phase optimized for Filgrastim and Etanercept was Water: n-butanol (7.5:2.5 v/v) and Isopropyl alcohol: water (6.5:4.5 v/v), respectively. The chromatogram obtained was scanned at 225 nm and 222 nm for filgrastim and etanercept which resulted in a retention factor of 0.45 ± 0.07 and 0.32 ± 0.03, respectively. The method was validated for parameters like linearity, accuracy, precision, specificity and robustness. Recovery studies were performed at three concentration levels, to demonstrate suitability, accuracy and precision of proposed method. Statistical analysis proved that the proposed method is accurate and reproducible with linearity in the range of 500 to 3000 ng/band for filgrastim and 200 to 1200 ng/band for etanercept. The limit of detection and limit of quantification for filgrastim was found to be 63.418 ng/band and 192.177 ng/band. For etanercept, LOD and LOQ were found to be 33.381 ng/band and 101.153 ng/band, respectively. The proposed method can be employed for the routine analysis of selected biosimilars.

抗肿瘤生物类似药临床互换用药有效性与安全性的系统评价

目的系统评价抗肿瘤生物类似药临床互换用药的有效性、安全性与免疫原性,为促进其临床合理应用提供循证医学证据。方法系统检索PubMed、Embase、Cochrane Library、中国知网(CNKI)、万方数据库(WANFANG)、中国生物医学文献数据库(SinoMed)等数据库中有关抗肿瘤生物类似药互换用药的临床研究,检索时间为建库至2022年6月。对符合纳入标准的文献进行资料提取,并根据纳入研究类型选择相应的质量评价工具进行质量评价,采用描述性分析方法对纳入研究进行定性评价。结果共纳入5项研究,包括2项随机对照试验(randomized controlled trial,RCT)、2项队列研究与1项病例系列研究,总体研究质量较好。对于血液肿瘤患者,3项研究结果表明,利妥昔单抗生物类似药与参照药的单次互换用药治疗未对有效性、安全性与免疫原性产生显著影响。1项队列研究结果提示,2种利妥昔单抗生物类似药的单次互换未增加治疗安全性风险。对于HER-2阳性乳腺癌患者,1项RCT结果提示,曲妥珠单抗生物类似药与参照药的单次互换未对有效性、安全性与免疫原性产生显著影响。尚无研究评价贝伐珠单抗生物类似药的临床互换用药。结论利妥昔单抗与曲妥珠单抗生物类似药与参照药的单次互换用药未对患者治疗结局造成影响,贝伐珠单抗生物类似药临床互换用药的证据仍缺乏。鉴于当前证据有限,本结论仍需开展高质量、大样本临床研究进行验证。

利益相关者视角下生物类似药互换使用国际经验借鉴与启示

选取美国和欧盟生物类似药监管历程作为研究对象,搭建利益相关者框架分析美国和欧盟在生物类似药互换使用管理过程中的职责分配与激励机制。美国和欧盟药品管理部门均建立了推动生物类似药可互换使用体系,并将可互换决定权限下放。美国食品药品监督管理局(FDA)/欧洲药品管理局(EMA)、卫生系统/支付方、医生和患者协会是推动生物类似药可互换使用的重要利益相关者。美国通过调整报销支付方式以及与患者的有效沟通实现激励;欧盟则综合运用了利益分配机制、配额和跨利益相关者的患者沟通实现生物类似药使用和互换使用激励。与美国将生物类似药可互换进行严格的政策规制相比,欧盟更倾向于将其作为一个科学和医学问题,在促进生物类似药使用和互换使用方面激励机制也更加多元化。推动我国生物类似药互换使用需要建立和完善药物警戒系统、医生培训和患者教育等配套政策体系,明确各利益相关方职责,建立基于按病种分值付费(DIP)的财务激励、基于医生教育的非财务激励机制。

Phase 1 studies comparing safety, tolerability, pharmacokinetics and pharmacodynamics of HLX01(a rituximab biosimilar) to reference rituximab in Chinese patients with CD20-positive B-cell lymphoma

Objective: This study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01(a rituximab biosimilar) and reference rituximab sourced from China(Mab Thera?;rituximab-CN).Methods: Here we report the results of two phase 1 studies. In the phase 1 a, open-label, dose-escalation study(NCT03218072, CTR20140400), eligible patients received 250, 375 and 500 mg/m^(2) HLX01 sequentially at 7-day intervals, after confirming no dose-limiting toxicity(DLT). In the phase 1 b, double-blind study(NCT02584920,CTR20140764), eligible patients were given a single dose of 375 mg/m^(2) HLX01 or rituximab-CN. The primary endpoints included safety and tolerability parameters for the phase 1 a and the area under the plasma concentrationtime curve from time zero to day 91(AUC0-91 d) for the phase 1 b study. Equivalence was concluded if 90%confidence interval(90% CI) for the geometric least squares mean ratio(GLSMR) fell in the pre-specified equivalence criteria(80%-125%).Results: Between June 20, 2014 and January 5, 2015, 12 patients were enrolled in the phase 1 a study. The pharmacokinetics of HLX01 showed dose proportionality and accumulation to steady state. HLX01 was well tolerated, with no serious adverse events(AEs), discontinuations or DLTs. Between November 8, 2014 and August13, 2015, 87 eligible patients were enrolled in the phase 1 b study, including 43 who received HLX01 and 44 who were treated with rituximab-CN. The equivalence endpoint was met with GLSMR for AUC0-91 d being 89.6%(90% CI: 80.4%-99.8%). AEs, anti-drug antibodies, and CD19+ and CD20+ B lymphocyte counts were similar between the HLX01 and rituximab-CN treatment groups.Conclusions: Treatment with HLX01 was safe and well tolerated in Chinese patients with B-cell lymphoma.HLX01 and rituximab-CN have similar pharmacokinetic, pharmacodynamic and safety profiles.

Equivalent efficacy study of QL1101 and bevacizumab on untreated advanced non-squamous non-small cell lung cancer patients: a phase 3 randomized, double-blind clinical trial

Objective:This phase 3 study aimed to test equivalence in efficacy and safety for QL1101,a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer(NSCLC).Methods:Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab,15 mg/kg every 3-week for 6 cycles.This was followed by maintenance treatment with single agent QL1101 every 3-week.The primary end-point was objective response rate(ORR),with secondary end-points being progression-free survival(PFS),overall survival(OS),disease control rate(DCR),and adverse events(AEs).Results:Of 675 patients,535 eligible patients were randomized to the QL1101 group(n=269)and bevacizumab group(n=266).ORRs were 52.8%and 56.8%,respectively,for the QL1101 and bevacizumab groups,with an ORR hazard ratio 0.93(95%confidence interval:0.8-0131.1).The PFS,OS,DCR,and AEs were comparable between the 2 groups,which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history.Conclusions:QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

Insights on the use of biosimilars in the treatment of inflammatory bowel disease

Biologic therapy, such as those that target tumor necrosis factor(TNF) signaling, has proven to be an efficacious method of treatment for patients with inflammatory bowel disease(IBD) with regards to symptom management and mucosal healing. However, the rising prevalence of IBD worldwide and the everincreasing burden of biologic pharmaceuticals in the health care industry is alarming for insurance companies, clinicians, and patients. The impending patent expiry and the relatively high costs of biologics, particularly anti-TNF agents, have paved the way for biosimilar development for IBD. The United States Food and Drug Administration defines a biosimilar as a biological product that is highly similar to its reference medicinal product, with no clinically meaningful differences in terms of safety, purity, and potency. The hope with biosimilars is that their entry into the market will be able to drive competition between pharmaceutical companies to reduce prices like that of the generic market, and that access to appropriate biologic treatments for IBD patients is increased in the long-term. Yet, there are challenging issues such as indication extrapolation and interchangeability that are still being debated in the field of IBD and must be addressed in future issued guidance. This review will discuss the issues and implications concerning the use of biosimilar therapy for IBD.

Equivalent efficacy assessment of QL1101 and bevacizumab in nonsquamous non-small cell lung cancer patients:A two-year follow-up data update

Objective: Anti-vascular endothelial growth factor(VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer(NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data.Methods: In total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate(ORR);equivalence was confirmed if the two-sided 90% confidence interval(90% CI) of the relative risk was within the range of 0.75-1.33. The secondary endpoints were progression-free survival(PFS) and overall survival(OS).Results: The two-year updated data showed similar ORR(QL1101 vs. bevacizumab: 53.1% vs. 54.3%;relative risk=0.977;90% CI: 0.838-1.144), PFS(235 d vs. 254 d, log-rank P=0.311), and OS(577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group(22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group(n=157) and the bevacizumab group(n=148)(PFS: 253 d vs. 272 d, log-rank P=0.387;OS: 673 d vs. 790 d, log-rank P=0.101;mean tumor shrinkage rate: 26.6% vs. 27.5%).Conclusions: This study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.

Biosimilars:Review of current applications,obstacles,and their future in medicine

Biosimilars are a growing drug class designed to be used interchangeably with biologics.Biologics are cr-eated in living cells and are typically large,complex pr-oteins that may have a variety of uses.Within the field of gastroenterology alone,biologics are used to treat inflammatory bowel diseases,cancers,and endocrine disorders.While biologics have proven to be effective in treating or managing many diseases,patient acce-ss is often limited by high costs.The development of biosimilars is an attempt to reduce treatment costs.Biosimilars must be nearly identical to their reference biologics in terms of efficacy,side effect risk profile,and immunogenicity.Although the manufacturing process still involves production within living cells,biosimilars undergo fewer clinical trials than do their reference biologics.This ultimately reduces the cost of production and the cost of the biosimilar drug compared to its reference biologic.Currently,seven biosimilars have been approved by the United States Food and Drug Administration(FDA)for use in Crohn’s disease,ulcerative colitis,and colorectal cancer.There are other biologics involved in treating gastroenterologic diseases for which there are no FDA approved biosimilars.Although biosimilars have the po-tential to reduce healthcare costs in chronic disease management,they face challenges in establishing a sig-nificant market share.Physician comfort in prescribing reference biologics instead of biosimilars and patient reluctance to switch from a biologic to a biosimilar are two common contributing factors to biosimilars’slow in-crease in use.More time will be needed for biosimilars to establish a larger and more consistent market share compared to their reference biologics.Additional da-ta confirming the safety and efficacy of biosimilars,increased number of available biosimilars,and further cost reduction of biosimilars will all be necessary to im-prove physician confidence in biosimilars and patient comfort with biosimilars.

德国生物类似药参考价格组形成机制

采用案例分析法分析德国已分组生物类似药的《决议》《决议理由》《决议摘要》,总结其分组原则、分组契机、关键问题。德国已上市的19种生物类似药中,3种按通用名分组管理,6种按药理学及疗效可比分组管理,10种药品未进行分组。分组主要关注生物类似药与原研药差异、药理学可比性、临床疗效、儿童用药等方面。分组过程中各利益相关方参与程度较高,分组根据市场情况适时调整。建议我国在生物类似药价格管理过程中提高利益相关方参与程度,关注儿童用药情况,探索建立精细长效的分组方式。

Biosimilars in Brazil: The Beginning of an Era of Broader Access

Cancer is a major public health issue worldwide, especially in the developing world where 70% of the cancer-related deaths occur. During the last three decades, with the advent of targeted therapies using monoclonal antibodies, patients’ survival and quality of life have dramatically improved. Unfortunately, these great accomplishments came at the expense of high financial costs which most of the population living in low-and middle-income countries cannot afford. Biosimilars (biotherapeutic products that are similar to an already licensed reference biotherapeutic product in terms of quality, safety and efficacy) have been successfully used in Europe and in US with a substantial reduction in price of around 30%. Brazil is about to have trastuzumab as the first biosimilar available to treat cancer patients in the country. Based on strict regulatory legislations, biosimilars are expected to deliver affordable yet effective and safe treatment options all over the world, expanding the access to cancer treatment and reducing inequalities.

国内外生物类似药发展的立法比较与启示

概述美国、欧盟、日本、韩国、中国等国家和地区在生物类似药物发展的立法现状,运用比较分析的方法,对比上述国家和地区在生物类似药发展的关键环节中的立法共性和差异,初步论证我国生物类似药发展的立法必要性,探讨国内生物类似药立法可行性的法律启示与建议。

Analytical Method Development and Validation of Filgrastim by UV and RP-UFLC Methods

The research work was carried out for establishing a new Ultra Violet (UV)— Visible spectroscopy and Reverse phase-Ultra Fast Liquid Chromatography (RP-UFLC) method for the analysis and quantification of a biosimilar drug, Filgrastim. Filgrastim or recombinant methionyl granulocyte colony stimulating factor (rGCSF) is a glycoprotein. It has a biological action essential for proliferation and differentiation of hematopoetic and progenitor cells. The UV and RP-UFLC work was carried on a Shimadzu UV1800 Spectrophotometer and Shimadzu Prominence LC-20AD UFLC systems, respectively. The λmax of filgrastim was found to be 215 nm. The correlation coefficient by UV spectroscopy was found to be 0.9994 for the concentration range of 1 to 3 μg/ml in double distilled water. The Reverse phase UFLC was done by using Phenomenex C4 (25 cm × 0.46 cm internal diameter) 15 μ, 300 A° analytical column. The optimized mobile phase for binary elution was Acetonitrile and double distilled water (80:20) with a flow rate of 1 ml/min. The retention time of drug was at 3.2 min. It was observed that the response of the detector was linear in the range of 5 - 15 μg/ml with correlation coefficient value of 0.999. After developing the methods, it was assured for the intended use by validation of the analytical parameters like linearity, accuracy, precision, limit of detection, limit of quantitation, ruggedness and robustness. The results of all the parameters for both the methods were found to be within the acceptance criteria as per the International Council for Harmonisation (ICH) guidelines.

Biosimilars in inflammatory bowel disease:A review of post-marketing experience

Biologic compounds are obtained from living organisms or cell cultures by means of biotechnology methods. A similar biologic drug, commonly called biosimilar, is a product copied by a native approved biologic drug whose license has expired. Biosimilar drugs usually are marketed at a lower price and provide important financial savings for public healthcare systems. Some differences between biosimilars and original biologic drugs might exist but they are acceptable if they fall within defined “boundaries of tolerance”: differences in some features between the two molecules are considered important only if clinical relevant. Considering that the efficacy of the innovator biologic drug has already been established, the clinical studies required for approval of a biosimilar could be reduced compared with those required for the approval of the originator. In this review, real life data available in inflammatory bowel disease patients treated with biosimilars are reported, documenting in general satisfactory outcomes, sustained efficacy and no sign of increased immunogenicity, although, further controlled data are awaited.

Biosimilars in paediatric inflammatory bowel disease

The introduction of biological treatments has changed disease outcomes for patients with inflammatory bowel disease. Biologicals have high efficacy, and can induce and maintain remission after failed responses to conventional immunosuppressive and/or steroid therapy. The increasing occurrence of severe disease at diagnosis has resulted in infliximab being more often introduced as the firstline treatment in a "top-down" approach. Besides their favourable efficacy and safety profile, biologicals have one significant disadvantage, which is their high cost. This results in many patients stopping therapy prematurely, with the maintenance phase being too short. This often leads to disease exacerbation shortly after treatment cessation. Every newly started course of biological therapy can induce production of anti-drug antibodies, which can result in treatment failure and possible allergic/anaphylactic reactions. The introduction of biological biosimilars was intended to greatly reduce therapy costs thus increasing the availability of these agents to more patients. It was also anticipated that biosimilars would prevent premature termination of therapy. Analyses of paediatric data suggest that biosimilar infliximabs are equally effective as the reference infliximab. Safety patterns also seem to be similar. Paediatric experience places costtherapy reductions at around 10%-30%.

What do oncologists need to know about biosimilar products?

Many biologic products have improved the outcomes of cancer patients,but the costs can substantially burden healthcare systems.Biosimilar products can potentially reduce drug costs and increase patient access to beneficial treatments.Approval of a biosimilar product relies on the demonstration of "comparability" or "no clinically meaningful differences" as compared to its reference biologic product.Biosimilar products for erythropoietin,granulocyte colonystimulating factor,trastuzumab,and rituximab are already available,and the regulatory processes in various countries are constantly evolving.It is important that oncologists be familiar with the potential issues surrounding the clinical use of biosimilar products.In this review article,we provide background information about biosimilar products and their regulatory approval processes,followed by a discussion of individual biosimilar drugs.

Biosimilars: A novel perspective in diabetes therapy

Diabetes mellitus, an endocrine disorder, has a wider reach among most of the world population. The incidence of diabetes is high not only among adults but wider-age groups are also becoming susceptible to this disease because of modified food habits and lifestyle changes that are alien to the physiological system. The control of blood glucose level would be the prime focus of all the therapeutic targets, which is achieved through drugs, modified lifestyle, and paleo-based diets. To find a solution to these problems, earlier humans have revolutionized the science with the discovery of insulin from the porcine pancreatic crude extract. Later, developments have been made with artificial recombinant insulin and even insulin analogs that would mimic the physiological basal insulin in controlling the blood sugar levels. Various factors such as cost and logistics for quality delivery to the end-user at various corners of the world have impeded the reach of the original product. Hence, biosimilar insulins that are original insulin analogs were designed to execute similar physiological functions. In the current situation, the use of biosimilars has been approved in various clinical conditions that are very promising in its functions. In the present review, the various developmental phases of biosimilar preparations and the regulations enforced ensuring a quality product in the market through the Food and Drug Administration and the European Medicines Agency have been discussed.

Challenges of modern day transition care in inflammatory bowel disease: From inflammatory bowel disease to biosimilars

In this article we discuss the challenges of delivering a high quality Transition care. A good understanding of the adolescent needs with good communication between Transition care physicians and the patient is essential for good continuity of care. Despite availability of several guidelines, one model doesn't fit all and any transition service development should be determined by the local need and available healthcare facilities.

Loss of efficacy and safety of the switch from infliximab original to infliximab biosimilar(CT-P13)in patients with inflammatory bowel disease

BACKGROUND Infliximab original has changed the natural history of inflammatory bowel diseases(IBD) over the past two decades. However, the recent expiration of its patent has allowed the entry of the first Infliximab biosimilar into the European and Spanish markets. Currently switching drugs data in IBD are limited. AIM To compare the efficacy of infliximab biosimilar, CT-P13, against infliximab original, analyzing the loss of response of both at the 12 mo follow-up in patients with IBD.METHODS An observational study of two cohorts has been conducted. One retrospective cohort that included patients with IBD treated with Infliximab original, and a prospective cohort of patients who were switching from infliximab original to infliximab biosimilar(CT-P13). We had analyzed the overall efficacy and loss of efficacy in patients in remission at the end of one year after treatment with the original drug compared to the results of the year of treatment with the biosimilar.RESULTS98 patients(CD 67, CU 31) were included in both cohorts. The overall efficacy for infliximab original per year of treatment was 71% vs 68.2% for infliximab biosimilar(P = 0.80). The loss of overall efficacy at 12 mo for infliximab original was 6.6% vs 14.5% for infliximab biosimilar(P = 0.806). The loss of efficacy in patients who were in basal remission was 16.3% for infliximab original vs 27.1% for infliximab biosimilar. Adverse events were 9.2% for infliximab original vs 11.2% for infliximab biosimilar. CONCLUSION The overall efficacy and loss of treatment response with infliximab biosimilar(CT-P13) is similar to that observed with infliximab original in patients who were switching at the 12 mo follow-up. There is no difference in the rate of adverse events.

Emerging role of biosimilars in the clinical care of inflammatory bowel disease patients

The increasing incidence of inflammatory bowel disease(IBD)globally has redirected the healthcare system's focus towards safe and affordable pharmacological interventions.The inception of anti-tumor necrosis factor-α(TNF-α)had resulted in a trend shift from surgical interventions.However,as the patents of approved anti-TNF-αdrugs expire,biological copies of the many approved products are in the pipeline.The most commonly used biosimilar for IBD has been infliximab,followed by Adalimumab biosimilars which have been approved in major countries across the world.Although biosimilars are approved on the basis of similarity of their reference product,the lack of real-world evidence of its safety in ulcerative colitis and Crohn’s disease patients has contributed to physicians’hesitancy.However,biosimilars are expected to reduce treatment costs and provide economic benefits.