Biosimilars: A Value Proposition  Abstract Biosimilars are biological agents that effectively replicate original reference products. The main driver of their development is the promise of bringing competition into the marketplace, and consequently contributing to the sustainability of healthcare systems. By reducing financial barriers to biological therapies, biosimilars play a part in budgetary redistribution and, hence, in increasing patients’ access to treatment. They also foster innovation and deliver other non-price-driven advantages. However, the market is such that harmonization of pricing of reference biologics and biosimilars may dissuade physicians from prescribing biosimilars and often creates an unfavorable market environment for the launch of biosimilars. Such dynamics result in a high cost by denying patients the full benefits and added value inherent in biosimilar agents. A more equitable offering of established original biologics and biosimilars is needed to ensure the viability of current healthcare services.

Budget Impact of Switching to Biosimilar Trastuzumab (CT-P6) for the Treatment of Breast Cancer and Gastric Cancer in 28 European Countries Abstract Background As the economic burden of treating cancer patients has been soaring in European countries, performing a budget impact analysis is becoming one of the requirements for payers’ application dossiers. Objective The objective of this study was to estimate the budgetary impact of introducing the biosimilar trastuzumab (CT-P6) from the payer’s perspective and to determine the number of additional patients who could be treated with resulting savings in 28 European countries. Methods A budget impact model was developed to analyze the financial impact of switching from originator trastuzumab to biosimilar CT-P6 in the treatment of early and metastatic breast cancer and metastatic gastric cancer with a time horizon of 1–5 years. Budgetary savings and the number of patients potentially affected were measured based on epidemiological and sales volume data. The base-case analysis assumed that the price of CT-P6 is 70% of the originator price, the switching rate of originator to CT-P6 in the first year is 20%, and the annual growth in the switching rate for each subsequent year is 5%. Results For analyses using the base-case scenario following CT-P6 introduction, the total estimated budgetary savings over a 5-year period (depending on the scenario) ranged from €1.13 billion to €2.27 billion based on epidemiological data, or from €0.91 billion to €1.82 billion based on sales volume data. In the first year only, the projected budgetary savings ranged from €58 million to €136 million, and the number of additional patients who could be treated using the savings ranged from 3503 to 7078 by sensitivity analysis. Conclusions The conducted budget impact analysis assessing a switch from originator trastuzumab to biosimilar CT-P6 in 28 European countries indicates that budget savings could be between €0.91 billion and €2.27 billion over the next 5 years. These savings could be used to help improve patient access to local biologics in their respective countries while simultaneously strengthening the overall public health landscape across the European Union.

Bimekizumab: The First Dual Inhibitor of Interleukin (IL)-17A and IL-17F for the Treatment of Psoriatic Disease and Ankylosing Spondylitis Abstract Psoriasis is a chronic inflammatory skin disease with significant psychological and physical impact. Over the last few decades, several highly effective target therapies have been developed, leading to a major paradigm shift in the way psoriatic disease is managed. Despite this, a proportion of patients still do not respond or lose response over time. Bispecific antibodies target two different cytokines simultaneously, potentially offering a better disease control. Interleukin (IL)-17A and IL-17F share structural homology and have similar biologic function. IL-17A is classically considered to be the most biologically active, but recent studies have shown that IL-17F is also increased in psoriatic skin and synovial cell in psoriatic arthritis, supporting the rationale for targeting both IL-17A and IL-17F in psoriatic disease. Bimekizumab is the first-in-class monoclonal antibody designed to simultaneously target IL-17A and IL-17F. Bimekizumab is currently in clinical development for psoriasis, psoriatic arthritis, and ankylosing spondylitis, with promising results. In early clinical trials, bimekizumab demonstrated a rapid onset of action, good safety profile, and high tolerability by treated study participants. Long-term results and head-to-head trials comparing bimekizumab with other agents will be crucial to define the role of bimekizumab in the treatment of psoriatic disease.

Analysis of Pharmacokinetic and Pharmacodynamic Parameters in EU- Versus US-Licensed Reference Biological Products: Are In Vivo Bridging Studies Justified for Biosimilar Development? Abstract Background Bridging studies are mandatory in the EU and USA if the reference biological product used in the biosimilar comparability exercise is foreign sourced. However, it has been argued that the duplication of bridging studies may limit biosimilar development. Objective The aim of the study was to explore whether it is necessary to conduct pharmacokinetic (PK)/pharmacodynamic (PD) bridging studies for biosimilars. This study examines similarities and differences between EU- and US-licensed reference biological products, based on literature-reported PK and/or PD data. Methods We searched PubMed, Drugs@FDA, and European Medicines Agency (EMA) databases to identify biosimilar bridging studies designed to evaluate similarities between EU- and US-licensed reference biological products. PK and/or PD parameters were retrieved; the ratio of the parameter value of the EU-licensed product to that of the US-licensed product and its corresponding 90% confidence intervals (CIs) were calculated. Similarity was declared if the 90% CIs for the ratios of the PK or PD parameters were within the range of 80–125%. Results Thirty-one bridging studies were identified for 11 biosimilars, including adalimumab (n = 10), bevacizumab (n = 4), epoetin alfa (n = 1), etanercept (n = 2), filgrastim (n = 1), infliximab (n = 3), insulin glargine (n = 1), insulin lispro (n = 1), PEGfilgrastim (n = 2), rituximab (n = 2), and trastuzumab (n = 4). Most studies showed PK and/or PD similarities between the EU- and US-licensed reference biological products. However, among the 31 studies, only three studies (accounting for two biologics, PEGfilgrastim and adalimumab) showed dissimilarity between the EU and US reference products. Although one bridging study on PEGfilgrastim (Sandoz) indicated dissimilar PKs (maximum observed plasma concentration [Cmax] and area under the concentration–time curve [AUC]) between the reference products, the other study (Mylan) demonstrated similar PK. Moreover, two of ten studies involving adalimumab failed to demonstrate similarities between the reference products. However, for both cases, PK similarities were later confirmed in the follow-up bridging studies with larger sample sizes. Conclusion Our analysis reveals that, in most cases, the reference biological products originated from the EU and those from the USA are almost indistinguishable in terms of PK/PD properties. Additional in vivo bridging studies between reference products from different global regions may not be required if similar physicochemical and structural properties are evident in vitro.

Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: Review of Current Status Abstract Three prospective controlled clinical trials and numerous small series and case reports have confirmed that durable, drug-free remission in systemic sclerosis is possible via an autologous hematopoietic stem cell transplantation. Similar results have been seen in other autoimmune diseases. The exact mechanism by which this immune “reset” was achieved in some but not all cases remains elusive, but includes major reduction of autoreactive immune competent cells, re-establishment of T- and B cell regulatory networks and normalization of tissue niche function, particularly vascular. Some aspects regarding mobilization, conditioning and graft manipulation still remain open, but clearly a significant toxicity is associated with all effective regimens at present, and therefore patient selection remains a key issue. In the hematology/oncology arena, major efforts are being made to reduce genotoxic and other collateral toxicity induced by current mobilization and conditioning protocols, which may also translate to autoimmune disease. These include developments in rapid mobilization and antibody drug conjugate conditioning technology. If effective, such low-toxicity regimens might be applied to autoimmune disease at an earlier stage before chronicity of autoimmunity has been established, thus changing the therapeutic paradigm.

Biological Characterization of SB3, a Trastuzumab Biosimilar, and the Influence of Changes in Reference Product Characteristics on the Similarity Assessment Abstract Background SB3 has been developed as a trastuzumab biosimilar, a therapeutic monoclonal antibody targeted to human epidermal growth factor receptor 2 (HER2), and approved by the European Commission and United States (US) Food and Drug Administration (FDA). During the developmental period of a biosimilar, setting an appropriate quality target is critical for assessing the similarity of the biosimilar product to the reference product. A stepwise approach should be taken to assessing similarity, beginning with extensive characterization of the reference product to establish the quality target. Objective In this study, we evaluated the similarity of SB3 to the reference product and the impact of changes in the biological profile of the reference product on similarity assessment. Methods Analytical similarity was assessed with defined test procedures in terms of critical quality attributes (CQAs) that could affect efficacy, potency, and safety, as well as for the non-CQAs that are related to process consistency. The quality target was established using up to 154 lots of European Union (EU)- and US-sourced Herceptin® (reference product), analyzed during the developmental period of SB3. Results Trends of the EU- and US-sourced reference product showed that the biological profile exhibited two marked changes for Fc-related attributes, and then recovered to pre-change quality level. Since the similarity range set by pre-change lots was considered most relevant, the changed lots were excluded from establishing the similarity range, which resulted in tightened acceptance criteria. As shown in the results of similarity assessment using the stringent quality target ranges, SB3 exhibits highly similar functional activities compared to the reference product in terms of both CQAs and non-CQAs. Conclusion SB3 has been developed as a trastuzumab biosimilar approved in the EU and USA, and its manufacturing process is deemed to be robust and well-controlled within stringent quality target ranges.

Efficacy and Safety of Anti-cancer Biosimilars Compared to Reference Biologics in Oncology: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Abstract Background Many biosimilars of monoclonal antibodies (mAbs) are becoming increasingly available as anticancer therapies, such as the rituximab, bevacizumab, and trastuzumab biosimilars. However, no comprehensive summary of their efficacy and safety is available. Objective This study synthesized current evidence on the efficacy and safety of mAb biosimilars relative to their reference biologics among cancer patients. Methods We searched PubMed, Embase, the Cochrane library, ClinicalTrials.gov, the ISI Web of Science, and several Chinese databases from their inception dates to December 31, 2018, for randomized controlled trials (RCTs) or comparative observational studies that compared the efficacy and safety of biosimilars with reference biologics used in oncology. The binary outcomes were pooled using risk ratio (RR) with 95% confidence intervals (CIs), continuous outcomes using weighted mean difference (WMD) with 95% CIs, and time-to-event outcomes using hazard ratios (HRs). Subgroup and sensitivity analyses were conducted following this. We used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to rate the quality of the evidence. Results We did not find any comparative observational studies that fit the criteria. Twenty-three RCTs were identified for biosimilars of three mAbs, of which eight RCTs examined rituximab biosimilars (total N = 1534), six RCTs were for bevacizumab biosimilars (total N = 1897), and nine were for trastuzumab biosimilars (total N = 4953), respectively. The quality of the GRADE evidence for efficacy and safety outcomes was moderate or low. The findings were robust for all pre-specified subgroup and sensitivity analyses. Conclusion The existing evidence suggests highly comparable efficacy and safety profiles between mAb biosimilars and their reference biologics in oncological drugs.

Challenges in Post-marketing Studies of Biological Drugs in the Era of Biosimilars: A Report of the International Society for Pharmacoepidemiology 2019 Mid-Year Meeting in Rome, Italy Abstract Several controversial issues related to challenges in the post-marketing studies of biological drugs, including biosimilars, were discussed at the International Society for Pharmacoepidemiology (ISPE) 2019 Mid-Year Meeting in Rome (Italy) in April. In recent years, the marketing of biosimilars has been growing, thus offering opportunities for wider access by patients to high-cost biological drugs as well as ensuring the economic sustainability of national healthcare systems. Through the comparability exercise required for marketing approval, the similarity of biosimilars to the reference products in terms of efficacy, safety and quality has to be demonstrated in pre-marketing studies. In Europe, the 15 years of experience of marketing of biosimilars has allowed the accumulation of a significant amount of scientific evidence confirming the comparability of the benefit–risk profile of biosimilars and originators. However, some aspects remain to be addressed both from a scientific and regulatory perspective, such as interchangeability and the automatic substitution of originators and biosimilars. The (long-term) monitoring of all biological drugs, including biosimilars, in real-world settings is warranted, with the ultimate goal of integrating pre- and post-marketing evidence relating to the aforementioned open questions. This conference report describes priorities, data sources and methodological strategies for the post-marketing surveillance of biological drugs in the era of biosimilars.

Efficacy and Safety of Supportive Care Biosimilars Among Cancer Patients: A Systematic Review and Meta-Analysis Abstract Background Biologics are widely used to manage the side effects of cancer treatment (e.g., epoetin alfa is used to treat chemotherapy-induced anemia [CIA] and granulocyte colony-stimulating factors [G-CSFs] are used to treat chemotherapy-induced neutropenia [CIN]). As several patents for biologics used in cancer treatment have expired, a number of companies have developed supportive care biosimilars (e.g., epoetin alfa biosimilar, filgrastim biosimilar, pegfilgrastim biosimilar). Objective The objective of this study was to synthesize current evidence on the efficacy and safety of supportive care biosimilars compared with their reference biologics in oncology. Methods We searched PubMed, Embase, the Cochrane library, ClinicalTrials.gov, ISI Web of Science and several Chinese databases from their inception dates to December 31, 2018 for randomized controlled trials (RCTs) or comparative observational studies that compared the efficacy and safety of supportive care biosimilars and their reference biologics in oncology. We pooled results separately for RCTs and observational studies, as such studies involve different patient populations and are designed differently. We pooled binary outcomes using risk ratios (RR) with confidence intervals (CIs) and continuous outcomes using weighted mean differences (WMD) with 95% CIs, then conducted subgroup and sensitivity analyses. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the quality of evidence. Results We identified 29 studies that compared biosimilars of G-CSF or epoetin alfa: one RCT and five cohort studies (total N = 2816) of epoetin alfa biosimilars, and 13 RCTs and 10 cohort studies (total N = 23,561) of G-CSF biosimilars. Despite involving different populations, RCTs and observational studies comparing biosimilars and reference biologics indicated similar efficacy and safety results. Overall, there was no statistically significant difference in any efficacy or safety outcomes between any biosimilars and their corresponding original biologics (all p > 0.05). The quality of GRADE evidence of efficacy and safety outcomes was moderate or low. Findings were robust for all prespecified subgroup and sensitivity analyses. Conclusion Existing evidence suggests highly comparable efficacy and safety profiles for supportive care biosimilars and their reference biologics in oncology.

PF-06439535 (a Bevacizumab Biosimilar) Compared with Reference Bevacizumab (Avastin ® ), Both Plus Paclitaxel and Carboplatin, as First-Line Treatment for Advanced Non-Squamous Non-Small-Cell Lung Cancer: A Randomized, Double-Blind Study Abstract Background PF-06439535 is a bevacizumab biosimilar. We aimed to compare the efficacy and safety of PF-06439535 with that of reference bevacizumab (Avastin®) sourced from the EU (bevacizumab-EU), each with paclitaxel and carboplatin, in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC). Methods In this double-blind, parallel-group study, we recruited patients from 159 centers in 27 countries. Participants were randomized 1:1 to receive PF-06439535 plus paclitaxel and carboplatin or bevacizumab-EU plus paclitaxel and carboplatin on day 1 of each 21-day cycle for 4–6 cycles, followed by blinded monotherapy with PF-06439535 or bevacizumab-EU until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study. Randomization was stratified by region, sex, and smoking history. The primary endpoint was objective response rate (ORR) in accordance with RECIST 1.1, based on responses achieved by week 19 and confirmed by week 25. Results Between 21 May 2015 and 14 November 2016, 719 patients were randomized to the PF-06439535 group (n = 358) or the bevacizumab-EU group (n = 361). As of data cutoff for analysis of the primary endpoint (8 May 2017), 45.3% (95% confidence interval [CI] 40.01–50.57) of patients in the PF-06439535 group and 44.6% (95% CI 39.40–49.89) of patients in the bevacizumab-EU group achieved an objective response by week 19 that was confirmed by week 25. The unstratified ORR risk ratio was 1.015 (95% CI 0.863–1.193; 90% CI 0.886–1.163), and the unstratified ORR risk difference was 0.653% (95% CI − 6.608 to 7.908); all three CIs fell within pre-specified equivalence margins. Using final data after study completion (22 December 2017), no notable differences in progression-free survival or overall survival were observed between the groups. The most frequently reported grade 3 or higher treatment-emergent adverse events were hypertension, neutropenia, and anemia. There were no clinically meaningful differences in safety, pharmacokinetics, or immunogenicity across treatment groups. Conclusion Among patients with advanced non-squamous NSCLC, PF-06439535 demonstrated similarity to bevacizumab-EU in terms of efficacy. Safety profiles for the two treatments were comparable. Trial Registration ClinicalTrials.gov, NCT02364999. Funding Pfizer.