The Path to Accessible Care: Development and Impact of Eculizumab Biosimilars for Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome

Abstract

Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thrombosis in paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy in atypical hemolytic uremic syndrome, respectively. Nevertheless, many patients still have difficulty accessing eculizumab treatment because of its high costs. Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs. Clinical use of biosimilars in Europe in the last 15 years has demonstrated that they are as safe and effective as their reference products, and can also drive cost reductions and increase patients’ access to treatment. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general and the concept of extrapolation in particular.

Key Points

SB12 and ABP 959 are two biosimilars of reference eculizumab, a humanized monoclonal antibody developed for complement-mediated diseases.

Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs.

Introduction

Eculizumab is a biological medicine consisting of a humanized monoclonal antibody that targets the complement protein C5 and inhibits its activation to prevent or reduce hemolysis [1]. Eculizumab is the first drug approved for the treatment of complement-mediated diseases and is indicated to treat patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis, and neuromyelitis optica spectrum disorder [2, 3].

Paroxysmal nocturnal hemoglobinuria is a rare form of acquired hemolytic anemia associated with high mortality and morbidity [4]. It has an estimated prevalence of approximately 16 per million people, onset in young adulthood, and usual age of diagnosis in the early 30s [4, 5]. Paroxysmal nocturnal hemoglobinuria is characterized by hemolysis, bone marrow failure, and thrombosis caused by high sensitivity of PNH erythrocytes to complement-mediated lysis [6], a process in which the patient’s erythrocytes are recognized as foreign and destroyed by their immune system’s complement proteins. Prior to the advent of eculizumab, patients with PNH had a median survival of between 10 and 22 years [7] and the incidence of thrombosis was 29–44%, accounting for up to 65% of deaths [8]. Eculizumab has revolutionized the treatment of patients with PNH, near normalizing their life expectancy and improving their quality of life by reducing the risk of thrombosis by approximately 85%, reducing the requirements of blood transfusions by approximately 75%, and avoiding the need for stem cell transplantation [5, 7–9].

The life-threatening disease aHUS is a rare and severe form of thrombotic microangiopathy with an estimated incidence of 2 cases per million people in the USA [10]. It can occur at any age [11], is caused by inherited or acquired complement abnormalities, and is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure [12]. Atypical hemolytic uremic syndrome is associated with high mortality [13] and poor prognosis, with approximately 50% of patients requiring dialysis, experiencing permanent kidney damage, or dying within 1 year of the first occurrence despite plasma therapy [14]. Complement-targeting therapy with eculizumab has changed the prognosis of aHUS, with thrombotic microangiopathies event-free status reported in up to 94% of patients, improved quality of life in more than 70% of patients, and up to 100% of patients achieving hematological recovery [10, 15–18].

While eculizumab has revolutionized the treatment of PNH and aHUS, many patients throughout the world have still no access to eculizumab treatment because of its high costs [7, 10, 15, 19]. Biosimilars have abbreviated approval processes and lower development costs relative to reference products, eventually leading to reduced costs for the healthcare system [20–26]. This generally introduces price competition with more affordable prices, and expands patient access to treatment by increasing the number of available treatment options. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with PNH or aHUS based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general.

Biosimilar Definition and Regulatory Pathway

Biosimilars

Biosimilars are biological medicines (biologics) that are highly similar and clinically equivalent to other already approved biologics, called “reference products” [27, 28]. Biologics are medicines originating from living cells and organisms, and most of those in current clinical use contain proteins such as monoclonal antibodies as the active principle. Because of the high inherent variability of the biological source and the complex manufacturing process, biologics exhibit microheterogeneity—minor variations in structure or composition—both within or between batches of the same biologic, as well as between biosimilars and their reference products. This makes the production of identical copies (generics) of biologics impossible [29]. Accordingly, rigorous regulatory frameworks have been implemented in order to ensure that, despite this inherent microheterogeneity, a biosimilar and its reference product have no clinically meaningful differences in terms of biological activity, efficacy, pharmacokinetics, pharmacodynamics, and safety, including immunogenicity [28, 30].

Stringent Regulatory Pathway Required by the European Medicines Agency and the US Food and Drug Administration

A rigorous dedicated regulatory framework for approval of biosimilars was implemented first in the European Union (EU) in 2004 and then in the USA in 2010 [29, 31, 32]. Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) established regulatory frameworks that are based on the same scientific rationale [33–36]. Overall, the regulatory paths for approval of biosimilars rely heavily on “comparability studies,” consisting of comprehensive analytical, non-clinical, and clinical head-to-head comparisons of the biosimilar candidate with the reference product. The aim of the comparability studies is to generate the “totality-of-the-evidence,” demonstrating that the proposed biosimilar is highly similar and clinically equivalent to the reference product [32, 36]. Comparability studies are based on well-established scientific principles that have been used before to evaluate changes in the manufacturing process of widely used biologics and evaluate whether such changes affect the medicine’s quality, safety, and efficacy [37–39].

Comparability Studies: The Steps Towards Biosimilar Approval

Assessment of biosimilarity is a stepwise process where each step is designed based on the level of evidence obtained in the preceding step(s) (Fig. 1) [29, 32].

Fig. 1.

Stepwise comparative studies for biosimilar development

The foundation of biosimilarity lies in extensive analytical characterization (Step 1), which aims to demonstrate a high similarity between the biosimilar and its reference product. Using sensitive state-of-the-art analytical techniques, these studies thoroughly evaluate key attributes such as primary and higher order structures, post-translational modifications, impurities, stability, and biological activity. These analyses are pivotal as they establish the biosimilar’s physicochemical and functional properties, forming the cornerstone of biosimilarity. Analytical characterization is designed to detect even minor clinically relevant differences, ensuring that the biosimilar mirrors the reference product in all critical aspects.

Comparative non-clinical studies (Step 2) are performed to evaluate properties that cannot be fully elucidated by analytical characterization alone, such as certain pharmacodynamic and toxicological parameters. For instance, an assessment of animal toxicity is required by the US FDA as part of the demonstration of biosimilarity [40]. However, if the biosimilar comparability exercise encompassing physicochemical and biological characteristics as well as analytical in vitro studies (step 1) is deemed satisfactory, and no concerns are identified in step 2 that would preclude direct human testing, further in vivo animal studies are generally not required [34, 41, 42]. Therefore, non-clinical in vivo animal studies are conducted only if necessary to further evaluate pharmacokinetic, pharmacodynamic, or safety parameters.

Comparative clinical studies (Step 3) are conducted to confirm biosimilarity, address any remaining uncertainties, and exclude clinically meaningful differences between the proposed biosimilar and the reference product. These studies typically begin with pharmacokinetic, and where appropriate, pharmacodynamic studies, which are critical to assessing bioavailability and functional similarity. Clinical efficacy studies that are designed to evaluate efficacy, safety, and immunogenicity are only required if residual uncertainties remain unresolved after comprehensive analytical pharmacokinetic/pharmacodynamic studies. It is important to note that clinical efficacy studies are confirmatory rather than exploratory and are tailored to ensure sensitivity in detecting potential differences in clinically relevant outcomes.

The key objective of comparative studies in biosimilar development is to assess the equivalence of a biosimilar candidate and its reference product and exclude clinically meaningful differences between them. This is different to non-inferiority studies where a test treatment must not be inferior but is allowed to be superior to a comparator treatment (Fig. 2). Accordingly, the confidence interval (CI) of the difference or ratio between the primary endpoint(s) of a biosimilar candidate and its reference product must be within a pre-defined equivalence interval.

Fig. 2.

Equivalence versus superiority versus non-inferiority. For equivalence studies to meet their objective, the confidence interval of the primary endpoint has to be within pre-defined equivalence margins. For a non-inferiority study, the confidence interval of the primary endpoint can take any range above the lower equivalence margin to meet its objective

By this approach to demonstrating biosimilarity, the biosimilar can rely on the safety and efficacy knowledge gained over several years of clinical use of the reference product. In fact, in comparison to the regulatory approval process of the reference product, fewer clinical data are needed and therefore, biosimilar development costs are lower than those of the reference product, potentially resulting in lower treatment expenses [41, 43]. However, it is fundamental in biosimilar clinical trials that the study endpoints, the sample size, and the study population recruited are most sensitive to detect any potential differences between the biosimilar and the reference product [30, 40].

Challenges in Phase III Clinical Trials for Orphan Biosimilars

Comparative phase III clinical trials between a biosimilar and its reference product are confirmatory studies designed to address residual uncertainties regarding biosimilarity and verify that the similarity demonstrated through analytical and functional characterization is reflected at the clinical level. While these trials can be required to confirm biosimilarity, they are not universally necessary and are only mandated when earlier studies, such as analytical, functional, or pharmacokinetic studies, leave unresolved questions. Thus, their inclusion in the biosimilar development pathway must be guided by the specific context of each biosimilar program.

Conducting clinical efficacy studies presents significant challenges in the context of rare diseases, such as those targeted by orphan drugs such as eculizumab. These challenges include feasibility in recruiting sufficient participants for large, adequately powered clinical trials owing to small patient populations. The heterogeneity in disease subtypes and stages can also affect the consistency and reliability of clinical outcomes. Additionally, a substantial number of patients with rare diseases are already receiving existing treatments and may be reluctant to switch to a trial setting, further complicating recruitment efforts [44]. In such cases, phase III trials may yield wide CIs that limit the statistical robustness of the results [45], thereby reducing the added value of these studies in confirming biosimilarity. Furthermore, conducting these trials can impose significant logistical burdens because patient populations with rare diseases are geographically dispersed and may have limited access to clinical sites.

From an ethical perspective, avoiding unnecessary clinical studies is paramount to ensure resources are not expended on trials that offer limited value while exposing patients to unnecessary risks. For orphan biosimilars, regulatory agencies increasingly prioritize robust analytical comparability exercises complemented by pharmacokinetic/pharmacodynamic data from phase I trials to establish biosimilarity (Fig. 1). This approach is supported by a recent study that analyzed marketing authorization applications for 33 biosimilar monoclonal antibodies and three biosimilar fusion proteins and found that sufficient evidence for biosimilarity can be obtained from a combination of analytical and functional testing and pharmacokinetic studies, calling into question the usefulness of comparative efficacy studies for regulatory decision making [46]. Similarly, another report covering 12 biosimilars found that clinical efficacy data played a limited role in addressing quality concerns, encouraging a regulatory shift towards reliance on robust analytical and pharmacokinetic data [47].

As biosimilar development expands into the orphan drug space, it is crucial to balance the need for clinical confirmation with practical trial feasibility [48]. Streamlined regulatory approaches focusing on comprehensive analytical characterization and pharmacokinetic/pharmacodynamic studies may be sufficient for demonstrating biosimilarity, thereby simplifying the approval process and facilitating patient access.

Extrapolation

The biosimilar concept relies on the ‘totality-of-the-evidence’ as much as the concept of extrapolation of biosimilarity, the latter being described by Weise et al. as a logical consequence of the biosimilar concept [49]. In general, comparability clinical studies focus on one of the therapeutic indications approved for the reference product. However, “extrapolation” from the studied indication to all indications approved for the reference product is allowed by both the EMA and FDA, provided there is a sound scientific justification that the molecular mechanism of action of the reference product does not differ across the approved indications [30, 49, 50]. This means that although clinical trials assessing biosimilarity can be conducted in a single indication, the product can be approved for all indications licensed for the reference product by extrapolation without the need for clinical trials in all indications. In addition to a shared clinically relevant mode of action across indications, extrapolation requires sensitivity and relevance of the studied population for the other (extrapolated) indications.

Since the first biosimilar approval in Europe, more than 15 years of experience and data have been gathered from thousands of patients treated with biosimilars in clinical trials as well as real-world clinical practice, and no new issues relating to efficacy and safety have been reported in comparison to the reference product, neither in originally tested nor in extrapolated indications [51–53]. For example, biosimilars of reference adalimumab (an anti-tumor necrosis factor-α biologic), such as Amgevita^®, ABP 501 (Amgen), Hyrimoz^®, GP2017 (Sandoz), and Imraldi^®, SB5 (Samsung Bioepis) have demonstrated equivalence in clinical trials conducted in one indication (rheumatoid arthritis) [54–56]. On the basis of extrapolation, they have been licensed for all indications approved for the reference adalimumab in Europe, including rheumatoid arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis, pediatric plaque psoriasis, hidradenitis suppurativa, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, pediatric ulcerative colitis, non-infectious uveitis, and pediatric non-infectious uveitis.

Several real-world studies have supported the effectiveness and safety of adalimumab biosimilars in extrapolated indications [57]. For instance, a recent retrospective case series evaluated the efficacy of SB5 in non-infectious uveitis [58], a leading cause of preventable blindness in developed countries. The study showed notable effectiveness of SB5 in the management of non-infectious uveitis with a safety profile in line with that of the reference product. Uveitis relapses decreased from 121 relapses/100 patients/year in the 12 months before SB5 initiation to 4 relapses/100 patients/year during the first 12 months of treatment (P = 0.0004), drastically reduced the occurrence of retinal vasculitis (P < 0.0001), and improved visual acuity (mean best-corrected visual acuity increased from 7.7 ± 3.41 at baseline to 8.9 ± 2.46 at the last follow-up [P = 0.0045]) [58]. In another extrapolated indication, a study in a real-life cohort of patients with inflammatory bowel disease treated with SB5, an analysis of 12-month follow-up data showed that SB5 was effective (60.4% and 74.5% of the overall remission rate at 12 months in adalimumab-naïve and switched patients, respectively) and safe (three [2.1%] severe adverse events leading to drug discontinuation) in line with its reference product profile as well as comparable to real-life studies conducted with the adalimumab reference product [59]. Similar results that were obtained in several other studies and indications were recently summarized in a review by Gisbert and colleagues [60]. Overall, the review showed that currently available data in inflammatory bowel disease and other extrapolated immune-mediated diseases in dermatology (plaque psoriasis and hidradenitis suppurativa) do not suggest clinically meaningful differences between SB5 and the adalimumab reference product, neither in patients who received SB5 as initial adalimumab nor patients who switched from another adalimumab product to SB5. Taken together, these results with adalimumab biosimilars confirm the feasibility of the rigorous science-based regulatory pathways in evaluating the totality of evidence generated for biosimilar approval and for granting extrapolation to other indications and can boost healthcare providers’ confidence in prescribing biosimilars in clinical practice, both in tested and extrapolated indications.

Switching

As a general definition, switching is when the treating physician as prescriber decides to exchange one medicine for another medicine with the same therapeutic intent [61]. As applicable to biosimilars, switching is the act by the treating physician to switch patients from a reference product to a biosimilar (or vice versa) or between biosimilars. Switching should not be confused with substitution (automatic), which is the practice of dispensing one medicine instead of another equivalent medicine at the pharmacy level, which implies not consulting the prescriber. For example, the EMA provides guidance but does not regulate interchangeability, switching, and substitution of a reference medicine by its biosimilar, as these fall within the remit of European Member States [61]. As the market for biosimilars continues to expand, the likelihood of patients undergoing switching is increasing [62, 63]. A recent systematic overview summarized 178 studies, with approximately 21,000 patients that switched from the reference product to a biosimilar, covering randomized controlled trials, real-world evidence studies, and different molecules (adalimumab, etanercept, infliximab, rituximab, and trastuzumab) across different therapeutic areas. The available switching data were reviewed to assess whether switching affected efficacy, safety, or immunogenicity outcomes, and support that switching from a reference product to a biosimilar is not associated with any major efficacy, safety, or immunogenicity issues, corroborating that it is possible to switch from the reference product to the biosimilar with no new concerns [63]. Similarly, another systematic review examined 23 real-world evidence studies and 3657 patients who underwent switching between biosimilars of the same reference product. Results showed no unanticipated effectiveness or safety data in biosimilar-to-biosimilar switching studies, thus suggesting that these switches are safe and effective and may become routine clinical practice [64]. Since completion of this review, an updated analysis by Cohen and Bodenmueller has expanded the evidence base to include 31 studies with 6081 patients, further supporting the safety and efficacy of biosimilar-to-biosimilar switching studies across broader patient populations and indications [65]. Overall, the evidence gathered with clinical studies as well as real-world data do not indicate any additional risks or particular safety concerns associated with switching from the reference product to a biosimilar or between biosimilars that underwent a stringent and comprehensive regulatory review [64–67].

Biosimilars of Reference Eculizumab: Development Status

Approval and market entry of biosimilars of reference eculizumab can be expected to address the need of patients without access to eculizumab treatment because of its high costs. As demonstrated by more than 15 years of experience with biosimilars, the increased number of treatment options creates market competition and eventually leads to a reduction in treatment costs [20–23]. Currently, Epysqli^®, SB12 (Samsung Bioepis), and Bekemv^®, ABP 959 (Amgen) are the only eculizumab biosimilars approved by the EMA (May 2023 and April 2023, respectively) [68, 69], FDA (July 2024, and May 2024, respectively) [70, 71] and by the UK’s Medicines and Healthcare products Regulatory Agency (October 2023 and October 2022, respectively) [72, 73]. SB12 has also been granted marketing authorization by the Korean Ministry of Food and Drug Safety (January 2024) [74]. Another biosimilar, Elizaria^® (Generium), has received Russian marketing approval (April 2019) [75].

Eculizumab targets the complement component C5, inhibiting its cleavage into C5a and C5b, thereby preventing the formation of the membrane attack complex and subsequent complement-mediated hemolysis. This mechanism of action underlines the importance of specific functional assays in the biosimilarity assessment. The development and approval of SB12, ABP 959, and Elizaria involved comprehensive analytical and functional characterizations demonstrating similarity to the reference eculizumab product. This approach aligns with EMA and FDA requirements for the totality of evidence [30, 34, 40], which necessitate that analytical similarity be established as the foundation of biosimilarity.

The analytical comparability program for SB12, ABP 959, and Elizaria included structural, physicochemical, biophysical, and functional evaluations (Table 1), and demonstrated high similarity to the reference eculizumab products [76–78]. For certain quality attributes, such as the primary structure, the biosimilars were shown to be identical to the reference product. Specifically, for SB12, the peptide chromatograms of trypsin-digested SB12 and reference eculizumab demonstrated a highly similar peak profile, with no missing or additional peaks and comparative retention times. The amino acid sequences were confirmed to be 100% identical with complete sequence coverage, and the molecular weights of SB12 and reference eculizumab were found to be identical [76]. Similarly, ABP 959 and Elizaria were shown to have identical primary structures to their respective reference products [77, 78].

Table 1.

Comparative analytical studies of eculizumab biosimilars

Category	SB12 [76]	ABP 959 [77]	Elizaria [78]
Study drugs	SB12, EU-ECU, US-ECU	ABP 959, EU-ECU, US-ECU	Elizaria, EU-ECU
Primary structure	Identical	Identical	Identical
High-order structure	Highly similar	Highly similar	Highly similar
Purity and impurity	Highly similar	Highly similar	Highly similar
Charge distribution	Highly similar	Highly similar	Elizaria: subtle differences in the abundance of charged variants
Glycan profile	SB12: absence of α-gal/NGNA glycans	ABP 959: absence of α-gal/NGNA glycans	Elizaria: absence of α-gal/NGNA glycans
Hydrophobicity	Highly similar	Highly similar	Highly similar
Post-translational modification	Highly similar	Highly similar	Highly similar
Quantity	Highly similar	Highly similar	Highly similar
C5 binding affinity	Highly similar	Highly similar	Highly similar
C5 inhibition	Highly similar	Highly similar	Not tested
Hemolysis inhibition	Highly similar	Highly similar	Highly similar

α-gal galactose-α-1,3-galactose, C5 C5 complement protein, ECU reference eculizumab, EU-ECU European Union-sourced ECU, NGNA N-glycolylneuraminic acid, US-ECU USA-sourced ECU

For other attributes, such as higher order structure, charge distribution, and hydrophobicity, the biosimilars exhibited highly similar characteristics, with minor variations that fell within acceptable limits and were not expected to impact clinical performance. Differences in glycan composition such as the absence of α-gal/NGNA-attached glycans in the biosimilars are linked to their production in Chinese hamster ovary cell lines versus the NS0 murine cell lines used for the reference products. These variations have been fully characterized and are expected to have no impact on the safety, efficacy, or quality of the biosimilars.

Functional characterization of SB12, ABP 959, and Elizaria involved the evaluation of critical eculizumab quality attributes such as C5 inhibition, anti-hemolytic activity, and C5 binding studies. As the hybrid human IgG2-IgG4 heavy-chain constant regions of eculizumab are unable to activate complement-dependent cytotoxicity (CDC) or bind to Fc-γ receptors [79], the Fc domain does not play a significant role in the mechanism of action of eculizumab. The biological activities of SB12, ABP 959, and Elizaria were found to be highly similar to eculizumab in key assays (Table 1), confirming that the biological function of these biosimilars closely matches the reference product.

The clinical results of all biosimilars approved to date are summarized in Table 2. As part of the clinical studies for demonstrating biosimilarity, a phase I study of SB12 compared to reference eculizumab in healthy subjects showed comparable pharmacokinetics, pharmacodynamics, treatment-emergent adverse events, and incidence of anti-drug antibodies (no neutralizing antibodies were detected), confirming high similarity between the two drugs [80]. Moreover, a randomized, double-blind, multi-center, multi-national, phase III clinical study compared SB12 and reference eculizumab in patients with PNH not previously treated with complement inhibitor (naïve) and with signs of intravascular hemolysis (≥1.5 upper limit of normal range of lactate dehydrogenase) [81]. The primary efficacy endpoint was hemolysis measured by the LDH level at week 26 and the time-adjusted area of under the effect curve (AUEC) of LDH from week 14 to 26 and week 40 to 52. The least-squares (LS) mean difference between the SB12 group and the reference eculizumab group and the 95% CI in LDH at week 26 versus baseline was 34.48 U/L (− 47.66, 116.62 U/L) and the ratio of geometric LS mean in time-adjusted AUEC of LDH was 1.08 (0.95, 1.23). The CIs fell within the pre-defined equivalence margins. A sensitivity analysis on the primary efficacy endpoints showed consistent results and validated robustness of the primary analysis [82]. Overall, the phase III study demonstrated the clinical equivalence in efficacy of SB12 and reference eculizumab, and the comparability of pharmacokinetics, safety, and immunogenicity in patients with PNH, which support its biosimilarity [81]. A post-hoc subgroup efficacy analysis by Asian and non-Asian (by race) showed comparable efficacy results between SB12 and reference eculizumab, similar to the overall population [83].

Table 2.

Comparative clinical studies of eculizumab biosimilars

NCT number (reference)	Study design	Study drugs	Condition	Number of patients	Summary of results
SB12
NCT03722329 [80]	Phase I, randomized, double-blind, three-arm, parallel group, single-dose study to compare PK, PD, safety, and immunogenicity in healthy male and female subjects	SB12, EU-ECU, US-ECU	Healthy	240	PK and PD Pharmacokinetic parameters were within the pre-defined bioequivalence margin (0.80–0.25). Pharmacodynamic measurements were comparable between the three groups Safety and immunogenicity Incidence of TEAEs were comparable between treatment groups. Incidence of ADAs were also comparable between the three groups (2.5%, 1.3%, and 0.0% of subjects in the SB12, EU-ECU, and US-UCU treatment groups, respectively); no NAbs were detected
NCT04058158 [81]	Phase III, randomized, double-blind, multi-center, multi-national study to compare efficacy, safety, PK, PD, and immunogenicity in adult patients with PNH	SB12, ECU	PNH (naïve)	50	Efficacy (primary), PK, and PD LDH (U/L) of SB12 at week 26 was equivalent to ECU; Time-adjusted AUEC of LDH of SB12 was equivalent to ECU; pharmacokinetic and pharmacodynamic parameters were comparable between the two groups Safety and immunogenicity Incidence of TEAEs and immunogenicity (no patients developed ADAs) were comparable between the two groups
ABP 959
n.a. [84]	Phase I, randomized, double-blind, single-dose, three-arm, parallel- group study to compare PK, PD, safety, and immunogenicity in healthy male subjects	ABP 959, EU-ECU, US-ECU	Healthy	219	PK and PD Pharmacokinetic and pharmacodynamic parameters (within the pre-specified equivalence margin of 0.80–1.25) were comparable between the two groups Safety and immunogenicity Incidences of TEAEs were comparable between the treatment groups. Incidences of ADAs were also comparable between the three groups (9.9%, 9.5%, and 6.9% of subjects in the SB12, EU-ECU, and US-UCU treatment groups, respectively); no NAbs were detected
NCT03818607 [85, 86]	Phase III, randomized, double-blind, active-controlled study to compare efficacy and safety in adult patients with PNH	ABP 959, ECU	PNH (switched)	42	Efficacy (primary), PK, and PD LDH (U/L) of ABP 959 at week 27 was non-inferior to ECU; time-adjusted AUEC of LDH of ABP 959 was non-inferior to ECU; PK and AUC of PD activities such as total complement was comparable between the two groups Safety and immunogenicity Incidence of TEAEs and immunogenicity (no patients developed ADAs) were comparable between the two groups
Elizaria
NCT04463056 [87]	Phase III, randomized, open-label, multi-center, national, non-inferiority study comparing efficacy, safety, PK, PD, and immunogenicity in patients with PNH	Elizaria, EU-ECU	PNH (naïve and switched)	32	Efficacy, PK, and PD LDH concentration–time curve of Elizaria was not inferior to that of the ECU. Pharmacokinetic and pharmacodynamic parameters were deemed comparable between two treatment groups Safety and immunogenicity Adverse drug reactions and immunogenicity profiles were not inferior to those of the ECU. New cases of ADA formation were not registered during the study

ADAs anti-drug antibodies, AUEC area under the effect curve, ECU reference eculizumab, EU-ECU European Union-sourced ECU, LDH lactate dehydrogenase, NAbs neutralizing antibodies, PD pharmacodynamics, PK pharmacokinetics, PNH paroxysmal nocturnal hemoglobinuria, TEAEs treatment-emergent adverse events, US-ECU USA-sourced ECU

Comparative clinical studies of ABP 959 included a randomized, double-blind, phase I study in healthy male subjects [84] and a randomized double-blind, active-controlled, two-period crossover phase III, non-inferiority study to evaluate the safety and efficacy of ABP 959 and reference eculizumab in adult patients with PNH who were stable on eculizumab 900 mg intravenously every 14 ± 2 days [86]. The primary endpoint was LDH at week 27; and clinical similarity was assessed by comparing the one-sided 97.5% upper CI limit for the geometric LS mean ratio between ABP 959 and reference eculizumab. Results from Period 1 showed that the ratio of the geometric LS means of LDH (ABP 959/reference eculizumab) was 1.0628, with a one-sided 97.5% upper CI of 1.1576 contained within the pre-specified non-inferiority margin. Results from the sensitivity analysis were identical with results from the primary efficacy analysis [86]. The crossover comparison endpoint was measured by the time-adjusted AUEC of LDH from weeks 13–27, 39–53, and 65–79. In the crossover comparison, a point estimate of the geometric mean ratio (GMR) of time-adjusted AUEC of LDH (ABP 959 vs reference eculizumab) of 0.9812 with a two-sided 90% CI (0.9403–1.0239) was contained within the pre-specified margin [88].

In summary, the clinical comparability studies for evaluation of SB12 and ABP 959 were conducted in patients with PNH, who were either complement inhibitor naïve with signs of intravascular hemolysis (SB12) or were undergoing treatment with the eculizumab reference product and had stabilized for at least 6 months before enrollment, without signs of breakthrough hemolysis (ABP 959). In both studies, after a pre-defined treatment period with either biosimilar or reference product, patients were switched to the other drug (i.e., from a biosimilar to reference eculizumab and vice versa), in a crossover study design. In the case of SB12 clinical phase III, after completion of the main study, patients who had benefited from study treatment could opt for extended, 2-year, open-label SB12 treatment [81].

Elizaria^®, another eculizumab biosimilar, was approved in the Russian Federation in 2019 based on an open-label randomized non-inferiority study in patients with PNH who were either eculizumab naïve or treated with eculizumab at a maintenance regimen before enrollment [87]. Mean values of the LDH concentration–time curve were similar in both treatment groups without statistically significant differences. However, an equivalence rather than non-inferiority study is usually required to establish that a product is indeed equivalent and neither inferior nor superior to the reference product [30, 35, 36]. Moreover, the study was conducted exclusively in the Russian Federation and not in a multi-national setting, and neither reviewed by the EMA nor the US FDA. Additionally, the biosimilar approval process in non-highly regulated markets such as Russia differs and is generally considered less stringent compared with highly regulated markets such as the EU and USA. Therefore, Elizaria may not be considered a biosimilar meeting the stringent standards established for this class of medicinal products.

The initial EMA’s marketing authorization received by SB12 and ABP 959 was intended for the treatment of adults and children with PNH. At the time when this review was prepared, SB12 and ABP 959 received additionally EMA’s approval of the (extrapolated) indication of aHUS [68, 69].

Biosimilars’ excipients may differ with those of the reference biological without any clinically meaningful impact. Because of ABP 959 containing sorbitol, ABP 959 has an additional specific contraindication in patients with hereditary fructose intolerance, in whom intravenous sorbitol may be life threatening, as well as in all children under 2 years of age, owing to the fact that they may not yet be diagnosed with hereditary fructose intolerance. This is in accordance with the current European medicines legislation [89]. On the contrary, SB12 is sorbitol free, same as the reference eculizumab.

Expectations for Increased Accessibility of Eculizumab after Biosimilar Entry

Currently, eculizumab is unaffordable in many countries, many patients remain untreated, and the high costs often lead to the adjustment or discontinuation of the treatment [90]. A recent study aiming to evaluate the economic burden and treatment patterns of patients with PNH in the USA showed that more than 70% of eculizumab-treated patients were not dosed per label, and two thirds of patients discontinued eculizumab within an average of a 1.5-year timeframe [91]. Discontinuation of eculizumab may be partly attributed to adverse events but the high cost of the therapy is a limiting factor to patient access [7].

Biosimilars have been shown to increase patient access to treatment and support untreated patients in need [23, 51] by increasing the number of treatment options for patients and reducing the therapeutic costs. Biosimilars are generally more affordable (in Europe, their prices have been typically 20–40% lower than those of the reference product) and have been shown to introduce price competition that also leads to lower costs of the reference products [20–22, 26].

Real-world data have demonstrated cost reductions following the uptake of biosimilars up to several years since the introduction of a biosimilar. The uptake of infliximab biosimilars for the treatment of several inflammatory autoimmune diseases led to almost £100 million saved by the UK National Health Service in the financial year 2017/2018 [92]. Among rheumatology specialties in the UK, £38.8 million was saved over 2 years following the introduction of infliximab and etanercept biosimilars because of biosimilar uptake and reductions in prices for the reference products [93]. Since the launch of infliximab biosimilars (Inflectra^® and Remsima^®) and etanercept biosimilar (Benepali^TM) in 2015 and 2016, respectively, the utilization of reference infliximab (Remicade^®) and etanercept (Enbrel^®) gradually decreased and those of their biosimilars achieved 58% and 48% of the infliximab and etanercept market, respectively. Furthermore, the competition between reference infliximab and infliximab biosimilars resulted in price reductions of reference infliximab by 21.17% in the second year after the introduction of infliximab biosimilars. Similarly, the competition between two infliximab biosimilars resulted in further price reductions in comparison with reference infliximab in the second year after their introduction compared to the first (from 42 to 52.18% for one biosimilar and 43.6–59% for the other). This competition and price reduction resulted in increased utilization of the affordable biosimilar and an increased infliximab market share to 29%. Similar competition was evident between reference etanercept and an etanercept biosimilar [93]. In Norway, biosimilar infliximab is used for patients with newly diagnosed inflammatory bowel disease since 2014, and increasingly also to switch patients on maintenance therapy from a reference product to a biosimilar product. Until 2016, this resulted in increased patient access (approximately 800 vs 500 daily doses per 1000 inhabitants) and reduced costs (approximately 230 vs 325 million NOK total expenditure) [53, 94]. In Denmark, any drug assessed by the EMA as a biosimilar can be used in patients including all drug-naïve patients and those switching from another drug product or receiving the reference product since 2014 [95]. From patent expiration of infliximab in February 2015 until July 2015, the defined daily doses of infliximab biosimilar rose to 90.6% of total infliximab doses and accounted for 97.6% in 2016. Despite an increase in daily doses from approximately 200,000 to 350,000 daily doses until 2018, the monthly total costs for infliximab decreased from approximately 30 to 15 million DKK. Similar positive results were achieved for the uptake of the etanercept biosimilar, accounting for 85.4% of total daily etanercept doses in June 2016, 2 months after its first sale to a hospital department. Monthly total etanercept costs decreased from approximately 18 to 10 million DKK.

Based on these benefits following biosimilars approval, patient advocacy groups hope that the approval of affordable biosimilars of eculizumab and other biologics will reduce inequality in access, and claim an increased understanding, recognition, and uptake of biosimilars [90]. Although several years of clinical studies as well as real-world practice data indicate that biosimilars are as effective and safe as their reference products, reduce treatment costs, and increase patient access to therapy, increasing the overall awareness and understanding of biosimilars is fundamental to the acceptance and adoption of this important class of therapeutics. The Danish model for implementation of infliximab and etanercept biosimilars achieved rapid and near-complete adoption through preparation, decisive execution, and clear patient communication [95]. The FDA in its Biosimilars Action Plan recognizes biosimilar education of clinicians, patients, and payors as a key component of promoting their uptake [96]. The role of healthcare professionals is particularly important, as the biosimilars’ market uptake greatly depends on their willingness to use, prescribe, and promote biosimilars in clinical practice [97]. Several studies conducted through 2018 revealed that reference products were preferred to biosimilars, with biosimilars predominantly prescribed to biologic-naïve patients [97, 98]. Affordable price and cost savings from competition were considered the main advantages of biosimilars, while doubts related to the efficacy, safety, and immunogenicity, and a lack of understanding of the concept of extrapolation were limiting their use [97–99]. Although clinician confidence in biosimilars has grown in some markets with increased experience, factors such as national policies and reimbursement frameworks continue to influence prescribing patterns [100]. Biosimilar education is therefore imperative to overcome potential concerns and low prescribing comfort among healthcare professionals, realize the full cost-saving potential of biosimilar medicines, and ultimately increase patients access to treatment to support untreated patients in need.

Conclusions

Over 15 years of experience in biosimilar development and clinical use in Europe have solidified a robust regulatory framework, demonstrating that biosimilars are as safe and efficacious as their reference products. Biosimilars can drive cost reductions and increase patients’ access to treatment by fostering market competition. Although reference eculizumab has significantly improved the management and clinical outcomes of patients with PNH and aHUS, its high costs limit patient access. Biosimilars of reference eculizumab such as SB12 and ABP 959 can expand the number of available treatment options for patients with PNH and aHUS, as well as, in the future, for all other indications of reference eculizumab that could be extrapolated based on each regulatory framework and timeline as applicable. The advanced analytical and functional methods used in biosimilar development ensure their high similarity to reference products and underscore the robustness of the biosimilar development process. Increasing awareness of the safety, efficacy, and regulatory maturity of biosimilars is crucial to fostering their uptake and overcoming unmet patient needs.

Declarations

Funding

This research was supported by a grant of the Korean Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2024-00438476). Funding for the preparation of this article was provided by Samsung Bioepis Co., Ltd. (Incheon, Republic of Korea).

Conflicts of Interest/Competing Interests

Jun Ho Jang and Bing Han have no conflicts of interest that are directly relevant to the content of this article. Austin G. Kulasekararaj reports consultancy fees/honoraria/speaker’s bureau fees from Achillion, Akari, Alexion, AstraZeneca Rare Disease, Amgen, Apellis, Biocryst, Celgene, F. Hoffmann-La Roche, Novartis, Pfizer, NovoNordisk, Samsung, Silence Therapeutics, and Ra Pharma and research funding from Celgene/BMS and Novartis. Jinah Jung and Paola Russo are employees of Samsung Bioepis.

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Authors’ Contributions

JHJ formulated the concept and JJ wrote the draft of the manuscript. All authors participated in editing and revising the final manuscript.