Evaluating the economic impact of eculizumab biosimilars in Germany

Evaluating the economic impact of eculizumab biosimilars in Germany | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluating the economic impact of eculizumab biosimilars in Germany Isabell Kaufhold, Daniel Lewkowicz, Danila Seidel, Paul Thomas Brinkkoetter, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9140376/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Eculizumab, a humanized monoclonal antibody, inhibits activation of complement component C5. For patients with atypical hemolytic uremic syndrome, the introduction of eculizumab has markedly improved survival, restoring life expectancy close to that of the general population. The long-acting C5 complement inhibitor (CI) ravulizumab has since expanded treatment options, offering extended dosing intervals. In 2023, the first eculizumab biosimilars received market authorization. This study aims to evaluate the short-term economic impact of CIs from a German healthcare payer perspective. Methods An economic model with weekly cycles was developed to assess treatment costs for eculizumab originator, eculizumab biosimilars, and ravulizumab. The analysis included direct drug acquisition costs calculated on a milligram basis, obtained from publicly available German price databases and outpatient reimbursement regulations, as well as preparation costs for infusions. Treatment costs were analyzed up to 52 weeks to reflect short-term and annual treatment periods. All costs are presented in euros (2025), and no discounting was performed. Results Milligram-based prices were estimated at €12.92 for eculizumab biosimilar, €17.87 for eculizumab originator, and €13.63 for ravulizumab. After 13 weeks, cumulative costs were €124,941 (biosimilar), €172,466 (originator), and €127,062 (ravulizumab). After 52 weeks, costs reached €421,439, €581,836, and €352,463, respectively. Conclusions At treatment initiation, the eculizumab biosimilar appears to be the most cost-efficient option among CIs in Germany, offering cost savings relative to both the originator and the long-acting agent. Sequential use of different CIs may therefore represent a relevant therapeutic and cost-efficient option. atypical hemolytic uremic syndrome biosimilars cost-minimization analysis eculizumab ravulizumab Figures Figure 1 Background Atypical hemolytic-uremic syndrome (aHUS) is a rare, complement-mediated thrombotic microangiopathy associated with high morbidity, mortality, and healthcare burden due to expensive drug treatments and hospitalizations 1,2 . Genetic or acquired defects in complement-regulating proteins found in 60–70% of patients, most commonly complement factors H, I, and B, or membrane cofactor protein (MCP), lead to uncontrolled activation of the alternative pathway, causing microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal impairment 3–5 . Patients face a lifelong risk of multi-organ involvement, including neurological, cardiovascular, and gastrointestinal complications 3,6 . The global annual incidence of aHUS is estimated between 0.23 and 1.9 per million population, with a prevalence at approximately 4.9 per million and with 35–42% occurring in patients under the age of 18 1,7 . In Germany, the CESAR study identified 142 incident aHUS patients between 2014 and 2017, corresponding in 47 patients per year and an annual incidence of 0.57 per million population, based on German total population amounting to 82,792,351 as of December 2017 8,9 . Extrapolated to the 2025 German SHI population, this translates into approximately 42 incident cases per year and 365 statutory health insurance (SHI) patients nationwide 10 . Despite its rarity, aHUS imposes a disproportionate economic burden due to the high cost of potential lifelong administered complement inhibitors and frequent hospitalizations, thus, optimizing treatment duration and improving affordability have become major clinical and policy priorities 2,11 . Before the introduction of complement inhibitors, prognosis was poor; despite plasma exchange or infusion, up to 70% of patients progressed to end-stage renal disease or died within one year of diagnosis 3 . The introduction of eculizumab, a humanized monoclonal antibody targeting complement component C5 approved in 2011, fundamentally changed the prognosis for aHUS. In pivotal phase II and registry studies, use of eculizumab resulted into rapid control of complement-mediated hemolysis and thrombotic microangiopathy, leading to marked reductions in transfusion need and thromboembolic events and sustained improvements in renal function, survival, and quality of life 3,6,12–14 . Ravulizumab, a second-generation C5 inhibitor with an extend dosing interval of eight weeks, demonstrated non-inferior efficacy and safety compared with eculizumab and provides per-patient cost reductions of approximately 30–35% due to less frequent administration 15–17 . However, there are recommendations suggesting that treatment duration should be individualized according to the patient’s clinical profile and disease course. The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference further emphasizes this point by expressing concerns about the use of long-acting complement inhibitors during the acute phase of the disease 4,18,19 . Recent trials demonstrated that time-limited eculizumab therapy with structured continuous monitoring can be safe and economically superior for selected patients 20 . In the Dutch CUREiHUS study, withdrawal after a median of 13 weeks reduced total medical costs to 30% of the expected lifetime expenses while maintaining renal function 11 . Similarly, the UK SETS aHUS trial found that eculizumab withdrawal with structured monitoring did not increase the risk of harm and compared with continuous treatment 21 . Orozco-Leal et al. projected potential lifetime savings of £ 4.2 million per patient for a withdrawal-and-monitoring strategy versus lifelong eculizumab dosing, with negligible loss in life years and potential quality of life gains 2 . These findings underscore the need for economically sustainable treatment strategies in aHUS. Following the expiration of Soliris® patents, the first eculizumab biosimilars Epysqli® (Samsung Bioepis) and Bekemv® (Amgen) received European Medicines Agency (EMA) authorization in 2023, including the indication for aHUS 22,23 . The EMA concluded biosimilarity and established therapeutic equivalence to the reference product across all approved indications 22,23 . While the EMA establishes biosimilarity on a scientific basis, the decisions on interchangeability and substitution are made by individual EU Member States. In Germany, automatic substitution for selected biosimilars at pharmacy level was introduced in 2024 24 . From a health-economic perspective, biosimilars play a crucial role in balancing therapeutic innovation with sustainable access to high-cost orphan therapies. By increasing price competition and reducing budgetary pressure, they enable payers to reallocate resources to other areas of unmet need and support the long-term affordability of specialized care. The introduction of biosimilar complement inhibitors offers an opportunity to restore affordability and thus access to life-saving therapy in rare diseases such as aHUS 25 . European analyses indicate that biosimilar C5 inhibitors may reduce per-patient costs by 30–50% and alleviate national expenditures substantially 25,26 . Such savings can be reinvested to expand patient access and support innovation. Across the EU, biosimilar competition has consistently reduced list prices of biologics by 20–70%, demonstrating its system-wide impact on cost containment and equity 25,27 . Robust quantification of the budgetary implications of biosimilar complement inhibitors is required to inform German reimbursement policy and rare-disease budget planning. This study evaluates the health-economic impact of introducing the eculizumab biosimilar Epysqli® for the treatment of aHUS into the healthcare system, compared to the reference eculizumab and the long-acting follow-on ravulizumab, with a disaggregated time horizon from the German healthcare payer perspective. Methods The analysis aimed to estimate and compare short-term per-patient treatment costs associated with complement inhibitors for patients with aHUS. A cost-minimization framework was applied from SHI payer perspective, assuming clinical equivalence of all comparators based on published evidence demonstrating therapeutic equivalence between eculizumab and ravulizumab 22 . Model structure An economic model was developed in Microsoft Excel 365 (Version 2510, Microsoft Corporation, Redmond, WA, USA) to simulate drug acquisition cost over a one-year time horizon. Weekly cycles were selected to reflect the actual administration patterns of complement inhibitors. For each weekly cycle, treatment costs were calculated separately for each drug and subsequently aggregated to obtain cumulative treatment costs over time. To reflect time-limited, acute-phase and switching to follow-on treatment, costs were reported at 13, 26, and 52 weeks to capture short-term and annual treatment periods. All costs are expressed in 2025 euros. Due to the limited analytical time horizon, no discounting was applied. The perspective of the German SHI was applied. Input parameters Dosing and administration Dosing information was obtained from the official product information, published by the European Medicines Agency 17,28,29 . The reference adult patient weight of 77.7 kg was derived from the mean body weight of adult patients reported in German population statistics 30 . Table 1 summarizes the dosing regimens used in the model. Table 1 Dosing information (dose, cycle length and cycles) for eculizumab and ravulizumab Treatment phase Dose (mg) Cycle length (weeks) Cycles Eculizumab Induction 900 1 4 Maintenance 1,200 2 Ongoing Ravulizumab Induction 2,700 2 1 Maintenance 3,300 8 Ongoing Patients ≥ 40 kg. mg = milligram, kg = kilogram. Drug acquisition cost As patients with aHUS are commonly treated in specialized outpatient hospital centres, acquisition costs were determined in accordance with the contractual framework for outpatient drug reimbursement at hospitals (§ 129a Sozialgesetzbuch V), and the current agreement on pricing for substances and preparations containing substances (Hilfstaxe) 31,32 . Ex-factory price data were obtained from the official German pharmacy pricing database Lauertaxe as of November 1, 2025 33 . Drug acquisition costs for the eculizumab biosimilars, the eculizumab originator, and ravulizumab were calculated on a milligram basis. All substances are administered parenterally; therefore, preparation costs were added for each administration. In line with German reimbursement regulations for parenteral preparations, vial wastage was not included in the base case analysis 32 . For the eculizumab biosimilar, a fixed milligram price was used 32 . For the eculizumab originator and ravulizumab, negotiated ex-factory prices were applied 32 . For all products, statutory value-added tax (19%) was added and the mandatory manufacturers rebate (7%) deducted from the ex-factory price, consistent with German SHI regulations 31–34 . The resulting prices per milligram are summarized in Table 2 . Table 2 Drug acquisition cost (mg-based) for eculizumab biosimilar, eculizumab originator and ravulizumab Price basis Eculizumab biosimilars (in Euro) Eculizumab originator (in Euro) Ravulizumab (in Euro) Fixed mg price Ex-factory price Ex-factory price Price per mg 11.75 15.96 12.17 + VAT tax (19%) + 2.23 + 3.03 + 2.31 - Legal manufacturer’s rebate (7%) -1.06 -1.12 -0.85 Price per mg for SHI 12.92 17.87 13.63 VAT: value added tax, mg: milligram, SHI: statutory health Sensitivity analysis (dup: abstract ?) To ensure the robustness and stability of the model outcomes, deterministic one-way sensitivity analyses were performed. In these analyses, the unit prices of all complement inhibitors were systematically varied by − 5%, − 10%, and − 20% relative to their respective base-case values. Each parameter was varied individually while holding all others constant to isolate its specific impact on total treatment costs. This approach aimed to capture potential price fluctuations and expected market dynamics, particularly the anticipated price erosion following the market entry and diffusion of eculizumab biosimilars. The resulting changes in cumulative per-patient treatment costs at 13, 26, and 52 weeks were recorded and compared to the base-case estimates. Results Based on the model assumptions, the per-dose acquisition cost for eculizumab 900 mg (induction) and 1200 mg (maintenance) were estimated at € 11,279 and € 15,605 for the biosimilar, and € 16,184 and € 21,546 for the originator, respectively. For ravulizumab corresponding costs were € 36,902 (2,700 mg induction) and € 45,080 (3,300 mg maintenance). Table 3 Results treatment costs per patient at 13, 26 and 52 weeks Time horizon Eculizumab biosimilar (in Euro) Eculizumab originator (in Euro) Ravulizumab (in Euro) 13 weeks 124,941 172,466 127,062 26 weeks 218,572 301,741 172,142 52 weeks 421,439 581,836 352,463 Bold: lowest-cost option at each time point At 13 weeks, cumulative treatment costs per patient were € 124,941 for the eculizumab biosimilar, € 172,466 for the originator, and € 127,063 for ravulizumab (Table 3 ). This translates into cost savings of € 47,525 for the eculizumab biosimilar compared to its originator and € 2,121 compared to ravulizumab, respectively. Similar relative cost savings were observed at weeks 26 and 52, for eculizumab biosimilar vs. originator, amounting to € 83,168 and € 160,397 per patient, respectively. At 13 weeks, the eculizumab biosimilar yielded the lowest cumulative cost; at 26 and 52 weeks, ravulizumab represented the most cost-efficient option, while the eculizumab originator remained consistently the highest-cost alternative. Detailed results including week-by-week costs for each complement inhibitor and cumulative totals over time are provided in Supplementary Table S1 . Sensitivity analysis The sensitivity analysis confirmed the robustness of the base-case findings, with ravulizumab becoming the lowest-cost treatment option at week 26 whereas the eculizumab originator remains the highest-cost option at all time points (Table 4 and Fig. 1 ). At week 13, varying the acquisition price of ravulizumab by 5% led to this complement inhibitor becoming the lowest-cost treatment option overall compared to eculizumab biosimilar and originator. When varying eculizumab biosimilar, it remained the lowest-cost option until week 13, thereby widening the cost difference between itself and ravulizumab. Detailed results are provided in Supplementary Tables S2, S3 and S4. Table 4 Sensitivity analysis of cumulative per-patient treatment costs of complement inhibitors for aHUS at 13, 26, and 52 weeks. Time horizon Price variation Eculizumab biosimilar (in Euro) Eculizumab originator (in Euro) Ravulizumab (in Euro) 13 weeks 124,941 172,466 127,062 -5% 118,739 163,888 120,724 -10% 112,537 155,309 114,386 − 20% 100,133 138,153 101,710 26 weeks 218,572 301,741 172,142 − 5% 207,718 286,729 163,555 − 10% 196,865 271,717 154,968 − 20% 175,158 241,693 137,794 52 weeks 421,439 581,836 352,463 − 5% 400,507 552,884 334,880 -10% 379,575 523,932 317,297 − 20% 337,711 466,028 282,130 Bold: time horizon and lowest-cost option at each time point At week 26, cost rankings remained stable across all price variation scenarios. At week 52, the overall results also remained consistent. However, when the eculizumab biosimilar price was reduced by 20%, cumulative treatment costs fell below those of ravulizumab. The sensitivity analysis yielded robust results for eculizumab originator, which was identified as the costliest option across all variations and time horizons. Discussion This analysis estimated weekly per-patient treatment cost of complement inhibitors for the treatment of aHUS from the German statutory health insurance perspective. By applying a disaggregated time horizon, the study provides a differentiated assessment on cost dynamics during treatment initiation and longer-term maintenance therapy. This approach allows a nuanced understanding of economic implications in a disease where the need for rapid therapeutic action and the uncertainty of early diagnostic information play a central role. In terms of short-term treatment over 13 weeks, eculizumab biosimilars resulted in measurable cost savings compared with both the originator and ravulizumab. The economic relevance of this early phase is amplified by the clinical challenge posed by diagnostic uncertainties due to incomplete diagnostic information during the initial days of treatment, as prompt initiation of therapy is required to achieve optimal therapeutic outcomes and mitigate the risk of enduring end-organ damage 35,36 . This highlights that short-term treatment periods are not only of medical but also economic relevance regarding the induction phase of temporary complement inhibition, where the rapid onset of action and lower upfront costs of eculizumab biosimilars may offer an advantage 4,22,29 . Based on the calculated incidence from CESAR study by Schönermarck et al., the potential annual cost-savings are estimated to range between € 0.09 million and € 1.99 million, if incident patients are treated with an eculizumab biosimilar during the first thirteen weeks of treatment instead of ravulizumab or the eculizumab originator, respectively. However, these savings diminish over longer treatment horizons as the less frequent administration of ravulizumab offsets its higher price 17,33 . For selected patients requiring continuous, long-term therapy, the extended dosing interval of ravulizumab could result into comparable or even lower overall treatment costs 16,17,37 . In a scenario where all incident patients transition to long-term ravulizumab after initial treatment, annual savings of €2.90 million to €9.63 million could be realized compared with continued therapy with a biosimilar or the originator. Our findings suggest that a treatment sequence initiating with an eculizumab biosimilar for 13 weeks in cases of thrombotic microangiopathy (TMA) where atypical hemolytic uremic syndrome (aHUS) is the most probable clinical diagnosis, followed by transition to long-acting ravulizumab in patients with a sustained medical requirement for treatment, may offer an economically efficient and medically appropriate strategy within the German SHI context 38 . Several economic evaluations have examined treatment strategies for aHUS, yet the findings remain heterogeneous across settings 8,16,37,39,40 . Orozco-Leal et al. found that disease monitoring is cost-effective compared to lifelong eculizumab 2 . Jang et al. assessed the regulatory pathways in Europe and development of eculizumab biosimilars and emphasized the importance of biosimilars in reducing costs and enhancing patients access 40 . In addition, Levy et al. demonstrated reduced productivity loss for ravulizumab compared with eculizumab across Germany, Italy, the UK and the US, while Wang et al. conducted a cost-minimization-analysis from a US payer perspective showing cost reductions of 32–35% with ravulizumab 16,37 . Divergent pricing structures, reimbursement regulations, and healthcare utilization patterns across countries likely contribute to observed differences. To the best of our knowledge, this is the first study providing economic evidence based on treatment costs for complement inhibitors in the German setting. Our results partly contrast the existing evidence, primarily due to the disaggregated time horizon applied in our analysis. The results from this analytical approach highlight the importance of evaluating short-term time horizons in respective diseases like aHUS, where acute or temporary treatment is highly relevant. Long-term cost assumptions may overestimate the actual economic burden. From the perspective of the German SHI, both complement inhibitors impose substantial annual drug acquisition cost, underscoring the need for biosimilar introduction and uptake in rare diseases like aHUS. Biosimilars offer the potential to generate meaningful cost savings while maintaining equivalent clinical efficacy and safety, thereby contributing to the financial relief of the healthcare system 41 . Beyond direct cost savings, the adoption of biosimilars may generate additional reinvestment effects, as the released budget could be allocated to other innovative therapies or healthcare interventions. Our analysis is subject to several limitations. First, the model applied a short-term time horizon of up to 52 weeks and therefore does not account for long-term treatment continuation and deviant treatment patterns. Potential cost differences related to long-term efficacy, treatment persistence, or safety profiles were not considered. Second, dosing was based on the official product information and a standard bodyweight, therefore dosing adjustments and patient weight variability were not considered. Third, drug acquisition costs were derived from official German pricing databases but are subject to confidential rebate contracts. Therefore, actual costs may vary and depend on the specific SHI. Conclusions While short-term treatment scenarios particularly favor eculizumab biosimilars, the longer dosing interval of ravulizumab may reduce the cost gap over extended treatment horizons. Overall, the results highlight the importance of biosimilar uptake as a key mechanism to enhance cost efficiency and patient access within the German healthcare system. Future research incorporating real-world utilization data and confidential pricing agreements will be valuable to confirm these findings and further inform payer decision-making. These findings underline the budget impact potential of biosimilar adoption in rare diseases such as aHUS, where high-cost therapies represent a considerable burden to the healthcare system. From the perspective of the German SHI, this cost-minimization analysis demonstrated that eculizumab biosimilars offer substantial cost savings compared with the eculizumab originator and short-term economic advantages compared with ravulizumab. Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Not applicable Availability of data and materials: All data generated or analysed during this study are included in this published article and its supplementary information files. Competing interests: I Kaufhold, D Lewkowicz, D Seidel and F Kron are employees of the VITIS Healthcare Group, which was sponsored by Samsung Bioepis in connection with the development of this manuscript. P Brinkkoetter received speaker honoraria and consultant fees from AstraZeneca, Alexion, Bayer, Boehringer-Ingelheim, Novartis, Roche, Sanofi-Genzyme, Travere, Vifor CSL and participated in advisory boards for Alexion, Samsung Bioepis, Sanofi-Genzyme, Novartis, TaregED Biopharmaceuticals, Travere, Takeda, Vifor CSL and Bayer. He declares research funding from the German Research Foundation BR-2955/8 and Sanofi-Genzyme. Funding: This study was sponsored by Samsung Bioepis. Authors' contributions: IK: Conceptualization, Methodology, Validation, Formal analysis, investigation, Writing – Original Draft, Writing – Review & Editing, Visualization, Project administration; DL: Methodology, Validation, Writing – Review & Editing; DS: Validation, Writing – Original Draft; Visualization PTB: Validation, Writing - Review & Editing; FK: Supervision, Writing – Review & Editing, Funding acquisition. 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Additional Declarations Competing interest reported. I Kaufhold, D Lewkowicz, D Seidel and F Kron are employees of the VITIS Healthcare Group, which was sponsored by Samsung Bioepis in connection with the development of this manuscript. P Brinkkoetter received speaker honoraria and consultant fees from AstraZeneca, Alexion, Bayer, Boehringer-Ingelheim, Novartis, Roche, Sanofi-Genzyme, Travere, Vifor CSL and participated in advisory boards for Alexion, Samsung Bioepis, Sanofi-Genzyme, Novartis, TaregED Biopharmaceuticals, Travere, Takeda, Vifor CSL and Bayer. He declares research funding from the German Research Foundation BR-2955/8 and Sanofi-Genzyme. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9140376","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620470687,"identity":"fd8dabd2-577c-4bc3-9bed-1c80aa117909","order_by":0,"name":"Isabell Kaufhold","email":"","orcid":"","institution":"VITIS Healthcare Group","correspondingAuthor":false,"prefix":"","firstName":"Isabell","middleName":"","lastName":"Kaufhold","suffix":""},{"id":620470688,"identity":"8888cd68-282a-4781-82b7-036c8476e403","order_by":1,"name":"Daniel Lewkowicz","email":"","orcid":"","institution":"VITIS Healthcare Group","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Lewkowicz","suffix":""},{"id":620470689,"identity":"3f4f1e6c-82cf-403f-b273-eabc74129690","order_by":2,"name":"Danila Seidel","email":"","orcid":"","institution":"VITIS Healthcare Group","correspondingAuthor":false,"prefix":"","firstName":"Danila","middleName":"","lastName":"Seidel","suffix":""},{"id":620470690,"identity":"f044f9b8-be0c-456d-a7c8-bbf1b6642714","order_by":3,"name":"Paul Thomas Brinkkoetter","email":"","orcid":"","institution":"University Hospital of Cologne, University of Cologne","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"Thomas","lastName":"Brinkkoetter","suffix":""},{"id":620470691,"identity":"5cb1c983-82f5-4d05-8fdd-306d1dfb16b0","order_by":4,"name":"Florian Kron","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBAC9nYgkQDEEiDeBxsGKBcP4DmMpIVxRhqxWhigWph5iNLCzHzsw4OaOwySsw8fe2yTYBPNwJ58gIAWtuQZCceeMUjzpaUb5ySk5TbwPMNvjT0zjzFDAtthBjkeHjPp3B+HcxskcgwI2ALS8g+qxSIBpCX/A2EtiW2HGaRBWhjAWnLw6gD7hSGx7zCPZA9bmmQP0C9tPM8IOIy9+TDjj2+H5STOMB+T+JFgk9vPnvwAvzUwrXAWG1HqR8EoGAWjYBTgBQDmbzqIEE70EwAAAABJRU5ErkJggg==","orcid":"","institution":"VITIS Healthcare Group","correspondingAuthor":true,"prefix":"","firstName":"Florian","middleName":"","lastName":"Kron","suffix":""}],"badges":[],"createdAt":"2026-03-16 16:39:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9140376/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9140376/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106944975,"identity":"713e9f2e-4562-4908-94c2-eb571a8992c9","added_by":"auto","created_at":"2026-04-15 06:27:21","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":263201,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis. Solid line: base case, dotted lines from top to bottom: -5 %, - 10%, -20%.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9140376/v1/602c0b0c5aef62e46473029d.jpg"},{"id":106945009,"identity":"bed16d35-d586-4fc8-ae41-4be9e0deb3f7","added_by":"auto","created_at":"2026-04-15 06:27:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":975649,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9140376/v1/714c6ca3-8cac-4224-abeb-4bd75abceb8e.pdf"},{"id":106944861,"identity":"418ca5fd-e8ea-4dac-bec6-7ca90f5965b2","added_by":"auto","created_at":"2026-04-15 06:26:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":191329,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9140376/v1/a50b5afb1dae6b884ef56e0f.pdf"}],"financialInterests":"Competing interest reported. I Kaufhold, D Lewkowicz, D Seidel and F Kron are employees of the VITIS Healthcare Group, which was sponsored by Samsung Bioepis in connection with the development of this manuscript. P Brinkkoetter received speaker honoraria and consultant fees from AstraZeneca, Alexion, Bayer, Boehringer-Ingelheim, Novartis, Roche, Sanofi-Genzyme, Travere, Vifor CSL and participated in advisory boards for Alexion, Samsung Bioepis, Sanofi-Genzyme, Novartis, TaregED Biopharmaceuticals, Travere, Takeda, Vifor CSL and Bayer. He declares research funding from the German Research Foundation BR-2955/8 and Sanofi-Genzyme.","formattedTitle":"Evaluating the economic impact of eculizumab biosimilars in Germany","fulltext":[{"header":"Background","content":"\u003cp\u003eAtypical hemolytic-uremic syndrome (aHUS) is a rare, complement-mediated thrombotic microangiopathy associated with high morbidity, mortality, and healthcare burden due to expensive drug treatments and hospitalizations \u003csup\u003e1,2\u003c/sup\u003e. Genetic or acquired defects in complement-regulating proteins found in 60\u0026ndash;70% of patients, most commonly complement factors H, I, and B, or membrane cofactor protein (MCP), lead to uncontrolled activation of the alternative pathway, causing microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal impairment \u003csup\u003e3\u0026ndash;5\u003c/sup\u003e. Patients face a lifelong risk of multi-organ involvement, including neurological, cardiovascular, and gastrointestinal complications \u003csup\u003e3,6\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe global annual incidence of aHUS is estimated between 0.23 and 1.9 per million population, with a prevalence at approximately 4.9 per million and with 35\u0026ndash;42% occurring in patients under the age of 18 \u003csup\u003e1,7\u003c/sup\u003e. In Germany, the CESAR study identified 142 incident aHUS patients between 2014 and 2017, corresponding in 47 patients per year and an annual incidence of 0.57 per million population, based on German total population amounting to 82,792,351 as of December 2017 \u003csup\u003e8,9\u003c/sup\u003e. Extrapolated to the 2025 German SHI population, this translates into approximately 42 incident cases per year and 365 statutory health insurance (SHI) patients nationwide \u003csup\u003e10\u003c/sup\u003e. Despite its rarity, aHUS imposes a disproportionate economic burden due to the high cost of potential lifelong administered complement inhibitors and frequent hospitalizations, thus, optimizing treatment duration and improving affordability have become major clinical and policy priorities \u003csup\u003e2,11\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBefore the introduction of complement inhibitors, prognosis was poor; despite plasma exchange or infusion, up to 70% of patients progressed to end-stage renal disease or died within one year of diagnosis \u003csup\u003e3\u003c/sup\u003e. The introduction of eculizumab, a humanized monoclonal antibody targeting complement component C5 approved in 2011, fundamentally changed the prognosis for aHUS. In pivotal phase II and registry studies, use of eculizumab resulted into rapid control of complement-mediated hemolysis and thrombotic microangiopathy, leading to marked reductions in transfusion need and thromboembolic events and sustained improvements in renal function, survival, and quality of life \u003csup\u003e3,6,12\u0026ndash;14\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRavulizumab, a second-generation C5 inhibitor with an extend dosing interval of eight weeks, demonstrated non-inferior efficacy and safety compared with eculizumab and provides per-patient cost reductions of approximately 30\u0026ndash;35% due to less frequent administration \u003csup\u003e15\u0026ndash;17\u003c/sup\u003e. However, there are recommendations suggesting that treatment duration should be individualized according to the patient\u0026rsquo;s clinical profile and disease course. The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference further emphasizes this point by expressing concerns about the use of long-acting complement inhibitors during the acute phase of the disease \u003csup\u003e4,18,19\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRecent trials demonstrated that time-limited eculizumab therapy with structured continuous monitoring can be safe and economically superior for selected patients \u003csup\u003e20\u003c/sup\u003e. In the Dutch CUREiHUS study, withdrawal after a median of 13 weeks reduced total medical costs to 30% of the expected lifetime expenses while maintaining renal function \u003csup\u003e11\u003c/sup\u003e. Similarly, the UK SETS aHUS trial found that eculizumab withdrawal with structured monitoring did not increase the risk of harm and compared with continuous treatment \u003csup\u003e21\u003c/sup\u003e. Orozco-Leal et al. projected potential lifetime savings of \u0026pound; 4.2\u0026nbsp;million per patient for a withdrawal-and-monitoring strategy versus lifelong eculizumab dosing, with negligible loss in life years and potential quality of life gains \u003csup\u003e2\u003c/sup\u003e. These findings underscore the need for economically sustainable treatment strategies in aHUS.\u003c/p\u003e \u003cp\u003eFollowing the expiration of Soliris\u0026reg; patents, the first eculizumab biosimilars Epysqli\u0026reg; (Samsung Bioepis) and Bekemv\u0026reg; (Amgen) received European Medicines Agency (EMA) authorization in 2023, including the indication for aHUS \u003csup\u003e22,23\u003c/sup\u003e. The EMA concluded biosimilarity and established therapeutic equivalence to the reference product across all approved indications \u003csup\u003e22,23\u003c/sup\u003e. While the EMA establishes biosimilarity on a scientific basis, the decisions on interchangeability and substitution are made by individual EU Member States. In Germany, automatic substitution for selected biosimilars at pharmacy level was introduced in 2024 \u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFrom a health-economic perspective, biosimilars play a crucial role in balancing therapeutic innovation with sustainable access to high-cost orphan therapies. By increasing price competition and reducing budgetary pressure, they enable payers to reallocate resources to other areas of unmet need and support the long-term affordability of specialized care. The introduction of biosimilar complement inhibitors offers an opportunity to restore affordability and thus access to life-saving therapy in rare diseases such as aHUS \u003csup\u003e25\u003c/sup\u003e. European analyses indicate that biosimilar C5 inhibitors may reduce per-patient costs by 30\u0026ndash;50% and alleviate national expenditures substantially \u003csup\u003e25,26\u003c/sup\u003e. Such savings can be reinvested to expand patient access and support innovation. Across the EU, biosimilar competition has consistently reduced list prices of biologics by 20\u0026ndash;70%, demonstrating its system-wide impact on cost containment and equity \u003csup\u003e25,27\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRobust quantification of the budgetary implications of biosimilar complement inhibitors is required to inform German reimbursement policy and rare-disease budget planning. This study evaluates the health-economic impact of introducing the eculizumab biosimilar Epysqli\u0026reg; for the treatment of aHUS into the healthcare system, compared to the reference eculizumab and the long-acting follow-on ravulizumab, with a disaggregated time horizon from the German healthcare payer perspective.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe analysis aimed to estimate and compare short-term per-patient treatment costs associated with complement inhibitors for patients with aHUS. A cost-minimization framework was applied from SHI payer perspective, assuming clinical equivalence of all comparators based on published evidence demonstrating therapeutic equivalence between eculizumab and ravulizumab \u003csup\u003e22\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eModel structure\u003c/h2\u003e \u003cp\u003eAn economic model was developed in Microsoft Excel 365 (Version 2510, Microsoft Corporation, Redmond, WA, USA) to simulate drug acquisition cost over a one-year time horizon. Weekly cycles were selected to reflect the actual administration patterns of complement inhibitors. For each weekly cycle, treatment costs were calculated separately for each drug and subsequently aggregated to obtain cumulative treatment costs over time. To reflect time-limited, acute-phase and switching to follow-on treatment, costs were reported at 13, 26, and 52 weeks to capture short-term and annual treatment periods. All costs are expressed in 2025 euros. Due to the limited analytical time horizon, no discounting was applied. The perspective of the German SHI was applied.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInput parameters\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDosing and administration\u003c/h2\u003e \u003cp\u003eDosing information was obtained from the official product information, published by the European Medicines Agency \u003csup\u003e17,28,29\u003c/sup\u003e. The reference adult patient weight of 77.7 kg was derived from the mean body weight of adult patients reported in German population statistics \u003csup\u003e30\u003c/sup\u003e. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the dosing regimens used in the model.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDosing information (dose, cycle length and cycles) for eculizumab and ravulizumab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment phase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDose (mg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCycle length (weeks)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCycles\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eEculizumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e900\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaintenance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOngoing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eRavulizumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaintenance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOngoing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatients\u0026thinsp;\u0026ge;\u0026thinsp;40 kg. mg\u0026thinsp;=\u0026thinsp;milligram, kg\u0026thinsp;=\u0026thinsp;kilogram.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDrug acquisition cost\u003c/h3\u003e\n\u003cp\u003eAs patients with aHUS are commonly treated in specialized outpatient hospital centres, acquisition costs were determined in accordance with the contractual framework for outpatient drug reimbursement at hospitals (\u0026sect;\u0026nbsp;129a Sozialgesetzbuch V), and the current agreement on pricing for substances and preparations containing substances (Hilfstaxe) \u003csup\u003e31,32\u003c/sup\u003e. Ex-factory price data were obtained from the official German pharmacy pricing database Lauertaxe as of November 1, 2025 \u003csup\u003e33\u003c/sup\u003e. Drug acquisition costs for the eculizumab biosimilars, the eculizumab originator, and ravulizumab were calculated on a milligram basis. All substances are administered parenterally; therefore, preparation costs were added for each administration. In line with German reimbursement regulations for parenteral preparations, vial wastage was not included in the base case analysis \u003csup\u003e32\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor the eculizumab biosimilar, a fixed milligram price was used \u003csup\u003e32\u003c/sup\u003e. For the eculizumab originator and ravulizumab, negotiated ex-factory prices were applied \u003csup\u003e32\u003c/sup\u003e. For all products, statutory value-added tax (19%) was added and the mandatory manufacturers rebate (7%) deducted from the ex-factory price, consistent with German SHI regulations \u003csup\u003e31\u0026ndash;34\u003c/sup\u003e. The resulting prices per milligram are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDrug acquisition cost (mg-based) for eculizumab biosimilar, eculizumab originator and ravulizumab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePrice basis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEculizumab biosimilars\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEculizumab originator\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRavulizumab (in Euro)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFixed mg price\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEx-factory price\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEx-factory price\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrice per mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e+ VAT tax (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;3.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;2.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Legal manufacturer\u0026rsquo;s rebate (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrice per mg for SHI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e12.92\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e17.87\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e13.63\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eVAT: value added tax, mg: milligram, SHI: statutory health\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSensitivity analysis (dup: abstract ?)\u003c/h3\u003e\n\u003cp\u003eTo ensure the robustness and stability of the model outcomes, deterministic one-way sensitivity analyses were performed. In these analyses, the unit prices of all complement inhibitors were systematically varied by \u0026minus;\u0026thinsp;5%, \u0026minus;\u0026thinsp;10%, and \u0026minus;\u0026thinsp;20% relative to their respective base-case values. Each parameter was varied individually while holding all others constant to isolate its specific impact on total treatment costs. This approach aimed to capture potential price fluctuations and expected market dynamics, particularly the anticipated price erosion following the market entry and diffusion of eculizumab biosimilars. The resulting changes in cumulative per-patient treatment costs at 13, 26, and 52 weeks were recorded and compared to the base-case estimates.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBased on the model assumptions, the per-dose acquisition cost for eculizumab 900 mg (induction) and 1200 mg (maintenance) were estimated at \u0026euro; 11,279 and \u0026euro; 15,605 for the biosimilar, and \u0026euro; 16,184 and \u0026euro; 21,546 for the originator, respectively. For ravulizumab corresponding costs were \u0026euro; 36,902 (2,700 mg induction) and \u0026euro; 45,080 (3,300 mg maintenance).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults treatment costs per patient at 13, 26 and 52 weeks\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime horizon\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEculizumab biosimilar\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEculizumab originator\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRavulizumab\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e124,941\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e172,466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e127,062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e218,572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e301,741\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e172,142\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e52 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e421,439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e581,836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e352,463\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eBold: lowest-cost option at each time point\u003c/h3\u003e\n\u003cp\u003eAt 13 weeks, cumulative treatment costs per patient were \u0026euro; 124,941 for the eculizumab biosimilar, \u0026euro; 172,466 for the originator, and \u0026euro; 127,063 for ravulizumab (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This translates into cost savings of \u0026euro; 47,525 for the eculizumab biosimilar compared to its originator and \u0026euro; 2,121 compared to ravulizumab, respectively. Similar relative cost savings were observed at weeks 26 and 52, for eculizumab biosimilar vs. originator, amounting to \u0026euro; 83,168 and \u0026euro; 160,397 per patient, respectively. At 13 weeks, the eculizumab biosimilar yielded the lowest cumulative cost; at 26 and 52 weeks, ravulizumab represented the most cost-efficient option, while the eculizumab originator remained consistently the highest-cost alternative. Detailed results including week-by-week costs for each complement inhibitor and cumulative totals over time are provided in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eSensitivity analysis\u003c/h3\u003e\n\u003cp\u003eThe sensitivity analysis confirmed the robustness of the base-case findings, with ravulizumab becoming the lowest-cost treatment option at week 26 whereas the eculizumab originator remains the highest-cost option at all time points (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At week 13, varying the acquisition price of ravulizumab by 5% led to this complement inhibitor becoming the lowest-cost treatment option overall compared to eculizumab biosimilar and originator. When varying eculizumab biosimilar, it remained the lowest-cost option until week 13, thereby widening the cost difference between itself and ravulizumab. Detailed results are provided in Supplementary Tables S2, S3 and S4.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analysis of cumulative per-patient treatment costs of complement inhibitors for aHUS at 13, 26, and 52 weeks.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime horizon\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrice variation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEculizumab biosimilar\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEculizumab originator\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRavulizumab\u003c/p\u003e \u003cp\u003e(in Euro)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e13 weeks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e124,941\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e172,466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e127,062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e118,739\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e163,888\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e120,724\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e112,537\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e155,309\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e114,386\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100,133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e138,153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e101,710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e26 weeks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e218,572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e301,741\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e172,142\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e207,718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e286,729\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e163,555\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e196,865\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e271,717\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e154,968\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e175,158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e241,693\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e137,794\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e52 weeks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e421,439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e581,836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e352,463\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e400,507\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e552,884\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e334,880\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e379,575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e523,932\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e317,297\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e337,711\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e466,028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e282,130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eBold: time horizon and lowest-cost option at each time point\u003c/h2\u003e \u003cp\u003eAt week 26, cost rankings remained stable across all price variation scenarios. At week 52, the overall results also remained consistent. However, when the eculizumab biosimilar price was reduced by 20%, cumulative treatment costs fell below those of ravulizumab.\u003c/p\u003e \u003cp\u003eThe sensitivity analysis yielded robust results for eculizumab originator, which was identified as the costliest option across all variations and time horizons.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis analysis estimated weekly per-patient treatment cost of complement inhibitors for the treatment of aHUS from the German statutory health insurance perspective. By applying a disaggregated time horizon, the study provides a differentiated assessment on cost dynamics during treatment initiation and longer-term maintenance therapy. This approach allows a nuanced understanding of economic implications in a disease where the need for rapid therapeutic action and the uncertainty of early diagnostic information play a central role.\u003c/p\u003e \u003cp\u003eIn terms of short-term treatment over 13 weeks, eculizumab biosimilars resulted in measurable cost savings compared with both the originator and ravulizumab. The economic relevance of this early phase is amplified by the clinical challenge posed by diagnostic uncertainties due to incomplete diagnostic information during the initial days of treatment, as prompt initiation of therapy is required to achieve optimal therapeutic outcomes and mitigate the risk of enduring end-organ damage \u003csup\u003e35,36\u003c/sup\u003e. This highlights that short-term treatment periods are not only of medical but also economic relevance regarding the induction phase of temporary complement inhibition, where the rapid onset of action and lower upfront costs of eculizumab biosimilars may offer an advantage \u003csup\u003e4,22,29\u003c/sup\u003e. Based on the calculated incidence from CESAR study by Sch\u0026ouml;nermarck et al., the potential annual cost-savings are estimated to range between \u0026euro; 0.09\u0026nbsp;million and \u0026euro; 1.99\u0026nbsp;million, if incident patients are treated with an eculizumab biosimilar during the first thirteen weeks of treatment instead of ravulizumab or the eculizumab originator, respectively.\u003c/p\u003e \u003cp\u003eHowever, these savings diminish over longer treatment horizons as the less frequent administration of ravulizumab offsets its higher price \u003csup\u003e17,33\u003c/sup\u003e. For selected patients requiring continuous, long-term therapy, the extended dosing interval of ravulizumab could result into comparable or even lower overall treatment costs \u003csup\u003e16,17,37\u003c/sup\u003e. In a scenario where all incident patients transition to long-term ravulizumab after initial treatment, annual savings of \u0026euro;2.90\u0026nbsp;million to \u0026euro;9.63\u0026nbsp;million could be realized compared with continued therapy with a biosimilar or the originator. Our findings suggest that a treatment sequence initiating with an eculizumab biosimilar for 13 weeks in cases of thrombotic microangiopathy (TMA) where atypical hemolytic uremic syndrome (aHUS) is the most probable clinical diagnosis, followed by transition to long-acting ravulizumab in patients with a sustained medical requirement for treatment, may offer an economically efficient and medically appropriate strategy within the German SHI context \u003csup\u003e38\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral economic evaluations have examined treatment strategies for aHUS, yet the findings remain heterogeneous across settings \u003csup\u003e8,16,37,39,40\u003c/sup\u003e. Orozco-Leal et al. found that disease monitoring is cost-effective compared to lifelong eculizumab \u003csup\u003e2\u003c/sup\u003e. Jang et al. assessed the regulatory pathways in Europe and development of eculizumab biosimilars and emphasized the importance of biosimilars in reducing costs and enhancing patients access \u003csup\u003e40\u003c/sup\u003e. In addition, Levy et al. demonstrated reduced productivity loss for ravulizumab compared with eculizumab across Germany, Italy, the UK and the US, while Wang et al. conducted a cost-minimization-analysis from a US payer perspective showing cost reductions of 32\u0026ndash;35% with ravulizumab \u003csup\u003e16,37\u003c/sup\u003e. Divergent pricing structures, reimbursement regulations, and healthcare utilization patterns across countries likely contribute to observed differences.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first study providing economic evidence based on treatment costs for complement inhibitors in the German setting. Our results partly contrast the existing evidence, primarily due to the disaggregated time horizon applied in our analysis. The results from this analytical approach highlight the importance of evaluating short-term time horizons in respective diseases like aHUS, where acute or temporary treatment is highly relevant. Long-term cost assumptions may overestimate the actual economic burden.\u003c/p\u003e \u003cp\u003eFrom the perspective of the German SHI, both complement inhibitors impose substantial annual drug acquisition cost, underscoring the need for biosimilar introduction and uptake in rare diseases like aHUS. Biosimilars offer the potential to generate meaningful cost savings while maintaining equivalent clinical efficacy and safety, thereby contributing to the financial relief of the healthcare system \u003csup\u003e41\u003c/sup\u003e. Beyond direct cost savings, the adoption of biosimilars may generate additional reinvestment effects, as the released budget could be allocated to other innovative therapies or healthcare interventions.\u003c/p\u003e \u003cp\u003eOur analysis is subject to several limitations. First, the model applied a short-term time horizon of up to 52 weeks and therefore does not account for long-term treatment continuation and deviant treatment patterns. Potential cost differences related to long-term efficacy, treatment persistence, or safety profiles were not considered. Second, dosing was based on the official product information and a standard bodyweight, therefore dosing adjustments and patient weight variability were not considered. Third, drug acquisition costs were derived from official German pricing databases but are subject to confidential rebate contracts. Therefore, actual costs may vary and depend on the specific SHI.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWhile short-term treatment scenarios particularly favor eculizumab biosimilars, the longer dosing interval of ravulizumab may reduce the cost gap over extended treatment horizons. Overall, the results highlight the importance of biosimilar uptake as a key mechanism to enhance cost efficiency and patient access within the German healthcare system. Future research incorporating real-world utilization data and confidential pricing agreements will be valuable to confirm these findings and further inform payer decision-making. These findings underline the budget impact potential of biosimilar adoption in rare diseases such as aHUS, where high-cost therapies represent a considerable burden to the healthcare system. From the perspective of the German SHI, this cost-minimization analysis demonstrated that eculizumab biosimilars offer substantial cost savings compared with the eculizumab originator and short-term economic advantages compared with ravulizumab.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: Not applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: All data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003eCompeting interests: I Kaufhold, D Lewkowicz, D Seidel and F Kron are employees of the VITIS Healthcare Group, which was sponsored by Samsung Bioepis in connection with the development of this manuscript. P Brinkkoetter received speaker honoraria and consultant fees from AstraZeneca, Alexion, Bayer, Boehringer-Ingelheim, Novartis, Roche, Sanofi-Genzyme, Travere, Vifor CSL and participated in advisory boards for Alexion, Samsung Bioepis, Sanofi-Genzyme, Novartis, TaregED Biopharmaceuticals, Travere, Takeda, Vifor CSL and Bayer. He declares research funding from the German Research Foundation BR-2955/8 and Sanofi-Genzyme.\u003c/p\u003e\n\u003cp\u003eFunding: This study was sponsored by Samsung Bioepis.\u003c/p\u003e\n\u003cp\u003eAuthors' contributions: IK: Conceptualization, Methodology, Validation, Formal analysis, investigation, Writing – Original Draft, Writing – Review \u0026amp; Editing, Visualization, Project administration; DL: Methodology, Validation, Writing – Review \u0026amp; Editing; DS: Validation, Writing – Original Draft; Visualization PTB: Validation, Writing - Review \u0026amp; Editing; FK: Supervision, Writing – Review \u0026amp; Editing, Funding acquisition.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable\u003c/p\u003e\n\u003cp\u003eAuthors' information (optional): Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaim\u0026eacute; F, Dragon-Durey M-A, Ngo S, et al. 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Kidney Int. 2024;106:369\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eNoris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood. 2014;124:1715\u0026ndash;26.\u003c/li\u003e\n\u003cli\u003eGreenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89:701\u0026ndash;11.\u003c/li\u003e\n\u003cli\u003eYan K, Desai K, Gullapalli L, Druyts E, Balijepalli C. Epidemiology of Atypical Hemolytic Uremic Syndrome: A Systematic Literature Review. Clin Epidemiol. 2020;12:295\u0026ndash;305.\u003c/li\u003e\n\u003cli\u003eSch\u0026ouml;nermarck U, Ries W, Schr\u0026ouml;ppel B, Pape L, Dunaj-Kazmierowska M, Burst V, et al. 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Kidney Int Rep. 2023;8:91\u0026ndash;102.\u003c/li\u003e\n\u003cli\u003eLicht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015;87:1061\u0026ndash;73.\u003c/li\u003e\n\u003cli\u003eFakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, et al. Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial. Am J Kidney Dis Off J Natl Kidney Found. 2016;68:84\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eRondeau E, Cataland SR, Al-Dakkak I, Miller B, Webb NJA, Landau D. Eculizumab Safety: Five-Year Experience From the Global Atypical Hemolytic Uremic Syndrome Registry. Kidney Int Rep. 2019;4:1568\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eRondeau E, Scully M, Ariceta G, Barbour T, Cataland S, Heyne N, et al. The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome na\u0026iuml;ve to complement inhibitor treatment. Kidney Int. 2020;97:1287\u0026ndash;96.\u003c/li\u003e\n\u003cli\u003eWang Y, Johnston K, Popoff E, Myren K-J, Cheung A, Faria C, et al. A US cost-minimization model comparing ravulizumab versus eculizumab for the treatment of atypical hemolytic uremic syndrome. J Med Econ. 2020;23:1503\u0026ndash;15.\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency. Ultomiris : EPAR - Product information. 2025.\u003c/li\u003e\n\u003cli\u003e\u0026Aacute;vila A, Cao M, Espinosa M, Manrique J, Morales E. Recommendations for the individualised management of atypical hemolytic uremic syndrome in adults. Front Med. 2023;10:1264310.\u003c/li\u003e\n\u003cli\u003eHaas CS, Nitschke M, Menne J, Guthoff M, G\u0026auml;ckler A, Bruck H, et al. 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LAUER-TAXE\u0026copy; Online 4.0. 2025. Available at https://lto.cgmlauer.cgm.com/LTO40.160101/taxe Accessed March 31, 2025.\u003c/li\u003e\n\u003cli\u003eUmsatzsteuergesetz in der Fassung der Bekanntmachung vom 21. Februar 2005 (BGBl. I S. 386), das zuletzt durch Artikel 27 des Gesetzes vom 2. Dezember 2024 (BGBl. 2024 I Nr. 387) ge\u0026auml;ndert worden ist. 2025.\u003c/li\u003e\n\u003cli\u003eBrocklebank V, Wood KM, Kavanagh D. Thrombotic Microangiopathy and the Kidney. Clin J Am Soc Nephrol CJASN. 2018;13:300\u0026ndash;17.\u003c/li\u003e\n\u003cli\u003eFakhouri F, Schwotzer N, Fr\u0026eacute;meaux-Bacchi V. How I diagnose and treat atypical hemolytic uremic syndrome. Blood. 2023;141:984\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eLevy AR, Chen P, Johnston K, Wang Y, Popoff E, Tomazos I. Quantifying the economic effects of ravulizumab versus eculizumab treatment in patients with atypical hemolytic uremic syndrome. J Med Econ. 2022;25:249\u0026ndash;59.\u003c/li\u003e\n\u003cli\u003eShen Y-M. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14:19.\u003c/li\u003e\n\u003cli\u003eDecision No 1295/1999/EC of the European Parliament and of the Council of 29 April 1999 adopting a programme of Community action on rare diseases within the framework for action in the field of public health (1999 to 2003). OPOCE; 1999.\u003c/li\u003e\n\u003cli\u003eJang JH, Han B, Jung J, Russo P, Kulasekararaj AG. The Path to Accessible Care: Development and Impact of Eculizumab Biosimilars for Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome. BioDrugs. 2025;39:281\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency. Guideline on similar biological medicinal products.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"atypical hemolytic uremic syndrome, biosimilars, cost-minimization analysis, eculizumab, ravulizumab","lastPublishedDoi":"10.21203/rs.3.rs-9140376/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9140376/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEculizumab, a humanized monoclonal antibody, inhibits activation of complement component C5. For patients with atypical hemolytic uremic syndrome, the introduction of eculizumab has markedly improved survival, restoring life expectancy close to that of the general population. The long-acting C5 complement inhibitor (CI) ravulizumab has since expanded treatment options, offering extended dosing intervals. In 2023, the first eculizumab biosimilars received market authorization. This study aims to evaluate the short-term economic impact of CIs from a German healthcare payer perspective.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAn economic model with weekly cycles was developed to assess treatment costs for eculizumab originator, eculizumab biosimilars, and ravulizumab. The analysis included direct drug acquisition costs calculated on a milligram basis, obtained from publicly available German price databases and outpatient reimbursement regulations, as well as preparation costs for infusions. Treatment costs were analyzed up to 52 weeks to reflect short-term and annual treatment periods. All costs are presented in euros (2025), and no discounting was performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMilligram-based prices were estimated at \u0026euro;12.92 for eculizumab biosimilar, \u0026euro;17.87 for eculizumab originator, and \u0026euro;13.63 for ravulizumab. After 13 weeks, cumulative costs were \u0026euro;124,941 (biosimilar), \u0026euro;172,466 (originator), and \u0026euro;127,062 (ravulizumab). After 52 weeks, costs reached \u0026euro;421,439, \u0026euro;581,836, and \u0026euro;352,463, respectively.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAt treatment initiation, the eculizumab biosimilar appears to be the most cost-efficient option among CIs in Germany, offering cost savings relative to both the originator and the long-acting agent. Sequential use of different CIs may therefore represent a relevant therapeutic and cost-efficient option.\u003c/p\u003e","manuscriptTitle":"Evaluating the economic impact of eculizumab biosimilars in Germany","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-15 06:24:54","doi":"10.21203/rs.3.rs-9140376/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-27T08:00:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-26T07:46:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T20:59:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T15:46:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"234315236617806548699467554544438856480","date":"2026-04-08T07:07:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"152222601697130998732552570002408785153","date":"2026-04-07T20:45:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128495006678706345640055839873517479768","date":"2026-04-07T07:16:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-04T14:58:18+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-26T16:02:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-17T08:51:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-17T08:51:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2026-03-16T16:31:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"27c9edbf-7a29-42af-8012-36841161e99e","owner":[],"postedDate":"April 15th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T20:53:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-15 06:24:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9140376","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9140376","identity":"rs-9140376","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}