Expert Opinion on Biological Therapy ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iebt20 Expert opinion paper on the treatment of hemophilia B with albutrepenonacog alfa María Teresa Álvarez Román, Olga Benítez, Maria Isabel Canaro, María Fernanda López Fernández, Francisco J. López Jaime, José Mateo Arranz, Ramiro Núñez, Manuel Rodríguez López, Cristina Sierra Aisa & Victor Jiménez-Yuste To cite this article: María Teresa Álvarez Román, Olga Benítez, Maria Isabel Canaro, María Fernanda López Fernández, Francisco J. López Jaime, José Mateo Arranz, Ramiro Núñez, Manuel Rodríguez López, Cristina Sierra Aisa & Victor Jiménez-Yuste (2021) Expert opinion paper on the treatment of hemophilia B with albutrepenonacog alfa, Expert Opinion on Biological Therapy, 21:9, 1165-1171, DOI: 10.1080/14712598.2021.1932811 To link to this article: https://doi.org/10.1080/14712598.2021.1932811 © 2021 The Author(s). Published by Informa Published online: 06 Jul 2021. UK Limited, trading as Taylor & Francis Group. Submit your article to this journal Article views: 2186 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iebt20 EXPERT OPINION ON BIOLOGICAL THERAPY 2021, VOL. 21, NO. 9, 1165–1171 https://doi.org/10.1080/14712598.2021.1932811 REVIEW Expert opinion paper on the treatment of hemophilia B with albutrepenonacog alfa María Teresa Álvarez Román a, Olga Benítezb, Maria Isabel Canaroc, María Fernanda López Fernándezd, Francisco J. López Jaimee, José Mateo Arranzf, Ramiro Núñezg, Manuel Rodríguez Lópezh, Cristina Sierra Aisai and Victor Jiménez-Yuste j a Haemophilia Unit, Hematology Department, Hospital Universitario La Paz -idipaz, Madrid, Spain; bHemophilia Unit, Hematology Department, Hospital Vall d’Hebron, Barcelona, Spain; cHematology Service, Hospital Universitario Son Espases, Palma de Mallorca, Spain; dHematology and Hemotherapy Service, Hospital Materno Infantil INIBIC-CHUAC, A Coruña, Spain; eHematology Department, Hospital Universitario Regional de Málaga, Spain; fThrombosis and Hemostasis Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; gHematology Service, Hospital Universitario Virgen del Rocío, Sevilla, Spain; hHematology and Hemotherapy Service, Hospital Alvaro Cunqueiro, Vigo, Spain; iHemostasis and Thrombosis Section, Hematology and Hemotherapy Service, Hospital Universitario Cruces, Barakaldo, Spain; jHematololy Department, Hospital Universitario La Paz-IdiPaz, Madrid, Spain ABSTRACT ARTICLE HISTORY Introduction: Current guidelines recommend prophylactic treatment of hemophilia B with the missing Received 8 February 2021 coagulation factor IX, either with standard half-life or extended half-life products. Extended half-life Accepted 17 May 2021 products have half-lives three to six times longer than the former, allowing a reduction in the number KEYWORDS of weekly injections and therefore, potentially impacting on treatment adherence and quality of life. Albutrepenonacog alfa; Albutrepenonacog alfa is an extended half-life fusion protein of coagulation factor IX with recombinant blood coagulation factors; human albumin, indicated for both on-demand and prophylactic treatment for bleeding in patients factor IX; hemophilia B; with hemophilia B of all ages. qualitative research Areas covered: The authors review the clinical and pharmacokinetic characteristics of albutrepenona­ cog alfa, as well as the available information regarding trough levels and real-world evidence. Given the availability of other factor IX products in the market, indirect comparisons of clinical and pharmacoki­ netic characteristics are presented. Expert opinion: The authors exhibit their expert opinion on which patient profiles are candidates for prophylactic treatment with albutrepenonacog alfa, and on the management of patients in terms of dosing, regimens of administration and protocols for switching the treatment. 1. Introduction products (Table 1). SHL-FIX products typically need to be administered two or three times per week. On the other Hemophilia B is a congenital bleeding disorder caused by hand, EHL-FIX have half-lives three to six times longer than a deficiency of coagulation factor IX (FIX), manifested by either SHL-FIX, and therefore entail less injections and a potential spontaneous bleeding or bleeding after trauma or surgery improvement in adherence [1,2,9,10]. [1,2]. According to the World Federation of Hemophilia, hemo­ The clinical development program of albutrepenonacog philia B affects approximately 3.75 per 100,000 males, and alfa (recombinant fusion protein linking FIX with albumin -rIX- rates vary considerably between different countries [3,4]. The FP-), initiated in 2010, has provided promising clinical data and severity of hemophilia depends on the blood levels of clotting has brought up new prophylactic regimens for patients with factor – levels of 5–40% have been correlated with mild dis­ hemophilia B. ease; 1–5%, with moderate disease; and less than 1%, with The authors of this publication held a virtual meeting to severe disease [5]. review the available evidence and provide expert opinion on According to current guidelines, prophylaxis with FIX con­ the new scenario of prophylaxis of bleeding in patients with centrates should be the goal of therapy to preserve normal hemophilia B treated with rIX-FP. musculoskeletal function, since it prevents bleeding and joint destruction, and it is a cost-effective intervention. Both plasma- derived (pd-FIX) and recombinant FIX (rFIX) concentrates are 2. Characteristics of albutrepenonacog alfa recommended options for replacement therapy [2]. However, (recombinant fusion protein linking FIX with rFIX concentrates are the preferred choice in some countries, albumin, rIX-FP) due to a negligible risk of pathogen contamination [6–8]. The rIX-FP molecule was designed to improve the biological Current prophylactic treatment options include either stan­ characteristics of rFIX in vivo. To that purpose, rFIX was geneti­ dard half-life FIX (SHL-FIX) or extended half-life FIX (EHL-FIX) cally fused to albumin via a peptide linker that undergoes CONTACT María Teresa Álvarez Román talvarezroman@gmail.com Haemophilia Unit, Hematology Department, Hospital Universitario La Paz -idipaz, Paseo de la Castellana 261, Madrid 28046, Spain. This article has been republished with minor changes. These changes do not impact the academic content of the article. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 1166 M. T. ÁLVAREZ ROMÁN ET AL. terminal half-life of rIX-FP was 4.3 times longer, and the clear­ Article highlights ance was 6.4 times slower [19]. ● Albutrepenonacog alfa is a fusion protein of recombinant FIX with human albumin, which extends the product circulation time. ● Albutrepenonacog alfa is an effective and safe option for the pro­ 4. Trough levels phylactic treatment of patients with hemophilia B of all ages. ● Optimal dosing of FIX products relies on accurately monitoring In patients with hemophilia B, maintaining appropriate trough plasma factor levels. High trough levels can be achieved with the levels of the clotting factor helps to reduce the incidence of administration of albutrepenonacog alfa, regardless of the adminis­ bleeds, and consequently, to reduce joint disease and improve tration regimen (7-, 10-, 14- or 21-day regimens), which represents an advantage for patients with bleeding episodes, arthropathies, high quality of life and life expectancy [2,20]. However, due to physical activity, and those undergoing surgery or invasive phenotype variability among patients, current recommenda­ procedures. tions tend to individualized prophylaxis approaches, rather This box summarizes key points contained in the article. than considering specific trough levels for all patients. Besides, the time that a patient remains above certain levels can be as important as the trough level itself [20,21]. Achieving high trough levels is particularly important in patients with bleeding episodes, with arthropathies, with cleavage in parallel with FIX activation. Therefore, the mole­ high physical activity, and those undergoing surgery or inva­ cule remains intact until activation and cleavage of albumin, sive procedures [21]. which makes the circulation time of the product longer than Trough levels higher than 5 IU/dL can be maintained 7 days that of SHL-FIX [11,12]. Albumin is a convenient fusion protein, after the administration of 25 IU/kg of rIX-FP, or 14 days after since its half-life is around 20 days, it lacks enzymatic and 50 IU/kg in adults [17], and 10 days after 50 IU/kg in children immune activity, it is a natural carrier of other proteins and [19]. In contrast, the mean FIX activity is around 5 IU/dL peptides, it is already abundant in plasma, and it is a very 48 hours after the administration of 50 IU/kg of either rFIX or stable molecule [13]. Besides, albumin recycles via the neona­ pd-FIX, both in adults and pediatrics [17,19]. For the adult and tal Fc receptor pathway, which is an additional mechanism adolescent population, the mean steady-state trough FIX responsible for prolonging the half-life of rIX-FP in vivo [14]. activity level was 20.9% when receiving 35-50 IU/kg every rIX-FP is approved for long-term prophylaxis to prevent 7 days, and 12.76% when receiving 50-75 IU/kg every bleeding in patients with severe hemophilia B, at a weekly 14 days. In pediatrics treated with 35-50 IU/kg every 7 days, dose of 35–50 IU/kg of body weight. Adult patients who are it was 12.8% [22]. In the extension study that evaluated the well-controlled on a once-weekly regimen might be treated efficacy of rIX-FP in adult patients previously enrolled in the with up to 75 IU/kg on an interval of 10 or 14 days. When phase III study or who initiated prophylaxis following surgery, control is also achieved with these regimens, further extension mean steady-state trough FIX activity was 22.0%, 19.8%, of the treatment interval to 21 day with a dose of 100 IU/kg 13.6%, and 7.6% with 7-, 10-, 14-, and 21-day regimens, may be considered in some adult patients [15]. respectively [23]. 3. Pharmacokinetics 5. Clinical efficacy of rIX-FP rIX-FP was first studied in a phase I, multicenter, dose- A phase III study evaluated the efficacy and safety of rIX-FP in escalation trial that assessed pharmacokinetics (PK) and safety 63 previously treated adolescent and adult patients with of the molecule in 25 adult patients with hemophilia B. rIX-FP severe hemophilia B. The median annualized spontaneous produced an increase of FIX activity levels, compared to the bleeding rate (AsBR) was reduced from 15.43 to 0.00 after same dose of rFIX or pd-FIX. The mean terminal half-life and switching from on-demand to weekly prophylaxis treatment the mean area under the curve (AUC) were higher with rIX-FP (p < 0.0001). Median AsBR was also 0.00 on 10- and 14-day than with rFIX – 5.3- and 7-fold increase, respectively. Other PK regimens. The annualized bleeding rate (ABR) was 0.00 in parameters, such as incremental recovery and clearance, were patients on 7- and 10-day regimens, and 1.08 in patients also improved with rIX-FP [16,17]. In the phase III study, a 14- with 14-day regimens. The annualized joint bleeding rate day PK evaluation was also performed, and rIX-FP displayed (AjBR) was 0.00 on all prophylaxis regimens [18]. In the exten­ a better PK profile when compared to SHL-FIX products; the sion study, median AsBR was 0.00, 0.28, 0.37 and 0.00 for the mean terminal half-life was 4.3 times longer than with the 7-, 10-, 14- and 21-day regimens, respectively [23], meaning previous FIX treatment [18]. In the pediatric population, that 14- and 21-day regimens have comparable efficacy to the when compared to the previous FIX treatment, the mean 7-day regimen. Table 1. Current recombinant prophylactic treatment options for hemophilia B approved by the EMA. Classification according to half-life Product Fussion protein Brand Manufacturer Standard rFIX (nonacog alfa) BeneFIX® Pfizer BAX 326 (nonacog gamma) ® Rixubis Baxalta Innovations GmbH Extended rIX-FP (albutrepenonacog alfa) Albumin ® Idelvion CSL Behring rFIX-Fc (eftrenonacog alfa) Fragment crystallizable ® Alprolix Biogen Inc N9-GP (nonacog beta pegol) Polietilenglicol ® Refixia Novo Nordisk EXPERT OPINION ON BIOLOGICAL THERAPY 1167 In children under 12 who were treated with rIX-FP on the median ABR was 0.50, the median AsBR was 0.25, and a prophylaxis weekly regimen, median AsBR turned out to patients reported good quality of life [34]. A case report of be 0.00 [19]. The extension study for the pediatric population a patient with severe hemophilia B treated with rFIX from the showed a very low median AsBR on any regimen: 0.00 for the age of 15 months to 7 years with poor venous access and 7- and 10-day regimens, and 1.10 for the 14-day regimen [24]. repetition infections, using rFIX and then switching to rIX-FP, showed a reduction of 64.8% in FIX consumption, and no hospitalizations were observed after 6 months with rIX-FP 6. Comparison to other EHL-FIX [35]. Another patient, a 3-year-old with moderate hemophilia A systematic review conducted by Davis and collaborators B, was switched from rFIX to rIX-FP due to difficult venous compared, through indirect statistical comparison, the efficacy access and mobility reasons (health emergency secondary to of rIX-FP to that of other SHL-FIX and EHL-FIX for prophylaxis COVID-19): the efficacy was maintained, the reported quality treatment of adult patients [9]. On a 7-day regimen, the mean of life was improved, and the number of injections adminis­ ABR was significantly lower with 35–50 IU/kg of rIX-FP than tered was reduced [36]. A recent case series has described the with 50 IU/kg of rFIX-Fc (1.2 [1.8] vs 3.1 [2.9], p < 0.001). Mean efficacy and safety of rIX-FP in two previously untreated pedia­ AsBR and AjBR values were not provided in the rFIX-Fc pivotal tric patients in Italy [37]. study, so an indirect comparison was not possible. However, A few recent reported real world experiences have asso­ and although data come from different studies, the median ciated prophylaxis with rIX-FP with spontaneous bleeding and AsBR and AjBR values were lower with rIX-FP than with rFIX-Fc poor response [38–41]. In a single center case series, the (median AsBR was 0.00 with all regimens of rIX-FP vs 1.0 for recommendations of the European Summary of Product weekly and 0.9 for individualized administration of rFIX-Fc; the Characteristics (SmPC) to perform the switches to rIX-FP were median AjBR was 0.00 with all regimens of rIX-FP vs 1.1 for not followed in none of the three patients reported with poor weekly and 0.4 for individualized administration of rFIX-Fc) bleed control. All of them started with a 2-week regimen, [18,25]. No indirect comparison has been performed in pedia­ without ensuring well-control in the previous weekly regimen, tric patients, since mean bleeding rates were not reported in as recommended in the SmPC, which may explain the clinical the pivotal study of rFIX-Fc [26]. outcome in these three patients [38]. On the other hand, the An indirect comparison with N9-GP was neither possible, authors reported that 25 other patients had been switched to since mean ABR, AsBR, and AjBR were not provided in the rIX-FP since its licensure, with similar dosing to the three pivotal study [27]; however, rIX-FP achieved a lower median reported cases and had positive outcomes. In another report, ABR than N9-GP, on 7-day regimen (0.00 vs 1.04). rIX-FP also key information was missing: no data on the dose or dose achieved lower mean ABR values than the SHL-FIX products regimens were provided, neither, for example, regarding the encompassed in the systematic review [9,28,29]. patients’ baseline bleeding rate, physical activity levels and joint health. Furthermore, patients ranged in age from a few months to 23 years. The mean or median ages of patients on 7. Real-world evidence using rIX-FP each product were not provided and, as children typically A retrospective study collected data from preexisting medical have higher bleeding rates than adults, this could have had records of patients treated with rIX-FP for 8 weeks or more in an impact on the findings [39,40]. The authors thereof specu­ Germany, and compared its efficacy with the patient’s prior lated that a poor distribution of rIX-FP to the extravascular FIX product. The mean ABR decreased from 2.6 (2.9) with the space could be the key contributor for these results, although prior product to 0.3 (0.6) with rIX-FP, and the proportion of it has been published that extravascular distribution of rIX-FP patients with zero bleeds increased from 24% to 81%. The is comparable to that of natural FIX [42,43]. Moreover, evi­ mean factor consumption was nearly half with rIX-FP than dence to ensure that biodistribution of FIX is related to bleed­ with prior prophylaxis (44.2 vs 82.3 IU/kg/week) [30]. ing rates is still lacking, and clinical efficacy is still the most A similar study was performed with patients from Italy, relevant outcome to assess treatment success [44,45]. In Belgium and the United Kingdom. Mean ABR reductions after a third report, 3 out of the 7 patients treated with rIX-FP the switch ranged from 67.7% to 94.3%, depending on the reported unexpected bleeding episodes. However, mean doses administered in each country. The administration of rIX- doses used were lower than those currently recommended FP increased the proportion of patients experiencing zero in the product label [41]. spontaneous bleeds from 41% to 88%. Dosing and frequency of administration were also reduced after the switch [31]. 8. Safety In the United States, 145 patients treated with rIX-FP were included in a study to evaluate utilization and bleeding rates. rIX-FP was well tolerated by adult and pediatric patients The mean ABR changed from 8.9 to 0.7 when switching from included in the clinical trials of the development program. Of rFIX-Fc to rIX-FP, and from 4.5 to 1.5 when switching from rFIX the reported adverse events (AEs), most were mild or moder­ to rIX-FP. Mean and median consumption was also diminished ate in severity [16,18,19,46]. As described in the SmPC, the with rIX-FP, when compared to previous FIX, and specifically common (≥1/100 to <1/10) mild/moderate AEs are headache, to rFIX or rIX-Fc [32,33]. dizziness and injections site reactions. Other adverse reactions Some case series and case reports from patients receiving as rash, hypersensitivity or eczema are uncommon (uncom­ prophylactic treatment with rIX-FP in Spain have been recently mon (≥1/1,000 to <1/100) [15]. In the pivotal study, the most presented. In a case series of six patients treated for two years, frequently reported treatment-emergent AEs were 1168 M. T. ÁLVAREZ ROMÁN ET AL. nasopharyngitis, headache, arthralgia, and influenza; only two poor venous access or a high level of physical activity can patients experienced serious AEs (SAEs), and were classified as obtain an extra benefit from rIX-FP administration. not related to rIX-FP treatment [18]. In the extension study, the Adult patients who require a high number of infusions or majority of treatment-emergent AEs were also mild to moder­ those poorly controlled with the former treatment can also ate. About 17% of adults experienced SAEs, and only one was especially benefit from rIX-FP, since the reduction in the num­ considered to be related to the treatment: arterial thrombosis ber of injections can entail an even larger increase in quality of after undergoing knee replacement surgery, followed by per­ life, and it could be a cost-effective option. Actually, a recent sistent postoperative complications, although the patient’s pharmacoeconomic model assessed the budget impact of history was also considered a contributing factor. 29.1% of treating severe hemophilia B with reimbursed rIX-FP over pediatric patients experienced SAEs, but none was related to 3 years in Italy, concluding that rIX-FP is expected to decrease treatment [23,24]. The safety profile of the 21-day regimen pharmaceutical costs [50]. A recent real world study found was similar to that of the 14-day regimen [23]. No inhibitors or that the cost per success (defined as patients experiencing antibodies were detected in any patient participating in these no spontaneous bleeding) in patients switching from nonacog studies. However, an isolated case of a young patient with alfa to rIX-FP was reduced by 29% in Italy, 55% in Belgium, and hemophiliac arthropathy, mainly due to a delay in the initia­ 50% in the United Kingdom. The reduction continued to be tion of an adequate prophylactic treatment, treated with pro­ true even when the price of nonacog alfa or when the efficacy phylactic rIX-FP and developing a low-titer inhibitor has been of rIX-FP were reduced by 20% [31]. Patients with complica­ reported [47]. This patient started with an off-label prophylac­ tions, such as arthropathies, severe muscle hematomas, and tic regimen (50 IU/kg every 14 days). life-threatening hemorrhages, or those who are to undergo surgery, are also good candidates for prophylaxis with rIX-FP (Figure 1). 9. Conclusions •Optimal dosing of FIX products relies on accurately mon­ rIX-FP has an excellent efficacy in the prophylactic treatment itoring plasma factor levels [51]. The authors agreed that of patients with hemophilia B, with very low median values of trough levels need to be individualized according to each ABR, AsBR and AjBR, which can positively impact joint protec­ patient’s characteristics. Higher trough levels should be con­ tion, preservation of physical activity and quality of life, as sidered in patients with joint concerns, uncontrolled patients, observed in real-world data. Clinical trials have also demon­ patients undergoing surgery or on secondary prophylaxis after strated that over 95% of treated patients can achieve a steady- muscle hematomas or life-threatening hemorrhages. Likewise, state FIX activity trough level higher than 5%, and a good children and adolescents with a high clearance and high bleeding control under 7-, 14- and even 21-day regimens; all physical activity would also be candidates for higher trough this data translates in a decrease in the burden of treatment levels. Current recommendations include factor target levels of administration, less factor consumption and higher adherence 5–15% for children and adults performing high-risk activity, rates. 15–30% for patients performing intensive sport activity, and In summary, rIX-FP is an excellent choice for the prophy­ 50–80% for patients performing very high impact physical lactic treatment of any patient with hemophilia B, providing activity [21]. Schedules involving weekly dosing or dosing benefits in terms of efficacy, adherence and quality of life. every two weeks are feasible with rIX-FP, and it is a good option for patients requiring high trough levels. As stated in the summary of product characteristics, the 10. Expert opinion usual dose of rIX-FP for long-term prophylaxis to prevent According to the authors’ opinion, and based on its clinical bleeding is 35–50 IU/kg once a week, and well-controlled efficacy, rIX-FP is a convenient option for prophylactic treat­ adolescent and adult patients on a once-weekly regimen ment of hemophilia B in all patients, in any age group. Its PK can receive up to 75 IU/kg dose every 10 or 14 days. In 18- profile allows an extension of the dosing interval up to 14 or year-old or older patients, a greater extension of the treat­ even 21 days, and a reduction in the number of intravenous ment interval can be considered [15]. In order to help injections, which may have a positive impact on patient’s practitioners to switch patients from other FIX products to quality of life. In fact, substantial improvements have been rIX-FP, the authors designed an algorithm, where decisions observed in the quality of life of pediatric patients, as well as are prompted by hemostatic efficacy after a period under in the satisfaction of their caregivers [48]. Extended dosing a specific regimen (Figure 2). According to the opinion of intervals can also have a positive impact on adherence, which the experts, and based on recent recommendations [20,52], in turn can lead to improved clinical outcomes. Excellent a PK assessment can be done before switching to estimate adherence rates have been observed in both clinical trials the dose and frequency of infusion for maintaining appro­ and clinical practice with rIX-FP [49]. priate trough levels; and/or two weeks after switching, to Specifically, rIX-FP can be a good option in pediatric and assess whether the dose and frequency of infusion are teenage patients, since they usually have higher physical adequate. The Web Accessible Population Pharmacokinetic activity, more difficult venous access, higher number of trau­ Service for Hemophilia (WAPPS-Hemo) is a free tool to make matic bleeds and higher FIX clearance. Additionally, the fact of PK evaluations easier [53]. The authors also suggest to receiving intravenous injections can be more unpleasant and assess trough levels at the discretion of the treating clin­ burdensome in pediatric and young patients, so reducing their ician, and perform further PK studies when changes in frequency may be advisable. Likewise, adult patients who have trough levels are identified. The one-stage (OS) assay is EXPERT OPINION ON BIOLOGICAL THERAPY 1169 Figure 1. Characteristics of patients who may especially benefit from prophylactic treatment with rIX-FP and potential advantages. Figure 2. Algorithm for switching patients from FIX products to rIX-FP. PK, Pharmacokinetics*PK assessment to be performed before switching, to estimate the dose and frequency of infusion for maintaining appropriate trough levels; or two weeks after switching, to assess whether the dose and frequency of infusion are adequate.** At the discretion of the clinician. useful and reliable to confirm that adequate rIX-FP levels Acknowledgments have been achieved and maintained. However, it should be The authors want to thank Ampersand Consulting and CSL Behring, considered that some activated partial thromboplastin time respectively, for organizing and supporting the virtual meeting to review (aPTT) reagents, such as actin FS or kaolin-based aPTT the available evidence. reagents could lead to an underestimation of the activity of up to 50% [15,54]. Therefore, FIX activity was measured Reviewer disclosures in clinical trials evaluating rFIX-FP with silica activator aPTT Peer reviewers on this manuscript have no relevant financial relationships reagent [55,56]. or otherwise to disclose. 1170 M. T. ÁLVAREZ ROMÁN ET AL. Declaration of interest 12. Metzner HJ, Weimer T, Kronthaler U, et al. Genetic fusion to albu­ min improves the pharmacokinetic properties of factor IX. Thromb María Teresa Álvarez Román has participated as speaker, in advisory boards Haemost. 2009;102(10):634–644. and sponsored symposia with Novo Nordisk, Bayer, Takeda, Roche, Pfizer, 13. Lyseng-Williamson KA. Coagulation Factor IX (Recombinant), Octapharma, Amgen, Novartis, CSL Behring and Sobi. Olga Benítez has participated as consultant, speaker or has received medical grants from Albumin Fusion Protein (Albutrepenonacog Alfa; Idelvion ): ® a review of its use in haemophilia B. Drugs. 2017;77(1):97–106. Bayer, CSL Behring, Pfizer, Sobi, Roche and Takeda. Francisco J. López Jaime 14. Chia J, Louber J, Glauser I, et al. Half-life– extended recombinant has participated as consultant or speaker for CSL Behring, Novo Nordisk, coagulation factor IX–albumin fusion protein is recycled via the Roche, Sobi and Takeda. José Mateo Arranz has participated as speaker or FcRn-mediated pathway. J Biol Chem. 2018;293(17):6363–6373. consultant for CSL-Behring, Bayer-AG, Sobi, Roche, Octapharma, Grifols, 15. Idelivon, Summary of product characteristics [Internet]. [cited 2021 Takeda, Novo Nordisk. Ramiro Núñez has received fees from Novo Nordisk, Apr 21]. Available from: https://www.ema.europa.eu/en/documents/ Takeda, Grifols, Roche, Pfizer, Octapharma, CSL Behring and Sobi. Victor product-information/idelvion-epar-product-information_en.pdf Jiménez Yuste has received grants, travel or research support from Pfizer, 16. Santagostino E. PROLONG-9FP clinical development Grifols, Shire, Novo Nordisk, Sobi and Octapharma, and has participated in program-phase i results of recombinant fusion protein linking scientific advisory boards for CSL Behring, Sobi, Octapharma, Grifols, Pfizer, coagulation factor IX with recombinant albumin (rIX-FP). Thromb Shire, Novo Nordisk, Roche, Biomarin and Sanofi. The authors have no other Res. 2013;131:S7. relevant affiliations or financial involvement with any organization or entity 17. Santagostino E, Negrier C, Klamroth R, et al. Safety and pharmaco­ with a financial interest in or financial conflict with the subject matter or kinetics of a novel recombinant fusion protein linking coagulation materials discussed in the manuscript apart from those disclosed. factor IX with albumin (rIX-FP) in hemophilia B patients. Blood. 2012;120(12):2405–2411. •• Phase 1 safety and pharmacokinetics results of albutrepeno­ ORCID nacog alfa. 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