Study population and data collection

Previously treated male patients with severe hemophilia A, who switched from prophylactic treatment with conventional recombinant factor products to rFVIIIFc (efmoroctocog alfa, Swedish Orphan Biovitrum AB) prophylaxis in 2016 or 2017, were retrospectively included in the study. Twentysix patients had a previous prophylaxis with octocog alfa and one patient received simoctocog alfa prophylaxis prior to switching to rFVIIIFC. All data are clinical routine data and were collected at the Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany. Patient characteristics (age, weight, F8 genotype, presence of infectious diseases or arthropathies), data of rFVIII and rFVIIIFc treatment (prescribed injection intervals, dose per injection, and start date of rFVIIIFc treatment) as well as the number of bleeds (overall, spontaneous, traumatic, joint, spontaneous joint) were collected. The initial switch from pre-medication to Elocta was performed according to the SPC label. If necessary during follow-up patients’ treatment was adapted according to individual needs. Data cut-off for rFVIIIFc treatment was on July 31, 2018. Adherence to prophylaxis was evaluated using patient diaries. All surgeries were planned according to localisation, type and complexity and included a substitution plan with the respective factor concentrate as well as the time of injections. For major surgeries the recommendation of the initial dose is 80-100 IU/kg and 50-80 IU/kg in children and adults, respectively. For minor surgeries the recommendation of the initial dose is 50-100 IU/kg and 25-40 IU/kg in children and adults, respectively [20]. To aim for avoidance of wound healing disturbances and post-operative hemorrhages the factor trough level for major surgeries should be in normal range for 7-10 days post-surgery to continuously support the wound healing processes. All patients had a first injection with factor concentrate the evening before surgery (preloading dose). On the day of surgery all patients received a loading dose and dependend of the time to surgery an additional factor concentrate injection immediately before the operation. Follow up injections were based according to the actual factor activity. Total number of injections and factor consumption was calculated peri-operatively for a maximum follow-up time of 10 days post-surgery.

For this retrospective analysis patients data were anonymized and aggregated.

Statistical analysis

For both FVIII and rFVIIIFc treatment, the annualized number of injections was calculated. The percent change in the annualized number of injections after the switch to rFVIIIFc was determined. In analogy, annualized factor consumption and percent change in annualized factor consumption was calculated.

Bleeding rates during FVIII prophylaxis were calculated for a time period of three years and converted to annualized bleeding rates (ABRs). For rFVIIIFc prophylaxis, ABRs were calculated based on the number of bleeds during the follow-up period since start of rFVIIIFc treatment until the date of evaluation. Analogously, ABRs were calculated separately for spontaneous bleeds (AsBR), traumatic bleeds (AtBR), joint bleeds (AjBR), and spontaneous joint bleeds (AsjBR).

Adherence to prophylactic treatment was determined as the percentage of actual injections of prescribed injections.

Descriptive statistics report numbers and percentages for categorical variables and mean and standard deviation (SD) for continuous variables. Wilcoxon signed-rank test was used for paired samples. P<0.05 was considered statistically significant.

Patient characteristics

In total, 27 previously treated patients with severe hemophilia A were included. Demographics and baseline characteristics are presented in Figure 1 Table 1. The cohort comprised 24 adult and adolescent (≥ 12 years) and 3 pediatric patients. All patients were male with a mean age of 37 years. All patients had F8 gene mutations of which 21 patients (77.8%) presented with a genotype which was associated with an increased risk of inhibitor development, i.e. 14 intron 22 inversions, four stop mutations, two splice mutations in a conserved region and one small deletion. The remaining six patients (22,2%) displayed mutations which were associatetd with a low risk of inhibitor development (three missense mutations, one duplication, one splice mutation in a non conserved region and one small deletion in a repetive adenine nucleotide region). Of all 27 patients four had a prior history of inhibitors to FVIII (two patients with an intron 22 inversion, one patient with a stop mutation and one patient with a splice mutation in a conserved region) with two testing positively for high-titer inhibitors (> 5 BU) and two for low-titer inhibitors (< 5 BU), respectively.. Of note, none of them developed a recurrent inhibitor after switching to rFVIIIFc. Nine patients (33.3%) had infectious diseases such as human immunodeficiency virus [HIV], hepatitis C virus [HCV], or both, and 13 patients (48,1%) had at least one joint with arthropathies. Retrospective observational period with conventional rFVIII concentrate was 3 years for all patients. The mean follow-up period after switching to rFVIIIFc treatment was 24.9 months.

Figure 1

Prophylactic regimens and adherence

Switching to rFVIIIFc prophylaxis led to a 33.7% reduction of mean injection frequency compared to prior conventional rFVIII therapy (121 ± 30 vs. 182 ± 71 injections per year) corresponding to a mean reduction from 3.5 to 2.3 injections per week. In total, 22 (81.5%) of the 27 patients were able to extend their injection interval Figure 2 (Table 2). Of those, 12 patients reduced the interval from 3 to 2 injections/week, 6 patients from every other day (3.5 injections/week) to either 2 injections/week (n=3), every 3 (2.3 injections/week) days (n=1), or 3 injections/week (n=2) and one patient from 4 injections/week to every other (3.5 injections/week) day. Three patients with daily injections were able to reduce the injection interval to either every 3 days (n=1) or 3 injections per week (n=2). In five patients, injection intervals did not change, two of those had already a low injection interval during conventional rFVIII therapy (one and two injections per week).

Figure 2

In the patient population of this study (26 of 27 patients with available data for both treatment regimens), mean adherence to rFVIII prophylaxis was 87 ± 16% and after switching to rFVIIIFc, adherence increased to 94 ± 8%.

Factor consumption

The mean annualized factor consumption of rFVIII was 295,461 ± 130,914 IU and was reduced by 18.3% to 241,509 ± 78,644 IU with rFVIIIFc, corresponding to 4,896 ± 2,167 IU/kg BW/year and 3,975 ± 1,382 IU/kg BW/year, respectively. In order to improve bleeding protection, factor reduction did not apply for eight patients. Two patients increased their consumption (156,000 to 286,000 IU/year and 234,000 to 273,000 IU/year, respectively). The mean weekly dose of rFVIIIFc was 76.5 ± 27 IU/kg/wk and the mean weekly dose of rFVIII was 94.1 ± 42 IU/kg/wk.

Intra-patient comparison of weekly factor consumption is shown in Figure 3 Figure 1.

Figure 3

Annualized bleeding rates

The mean ABR and mean joint ABR (AjBR) were 2.5 ± 3.1 and 0.7 ± 1.5 for rFVIII and 1.7 ± 3.7 and 0.3 ± 0.6 for rFVIIIFc, respectively. Mean spontaneous ABR (AsBR) and mean spontaneous joint ABR (AsjBR) were 0.4 ± 0.7 and 0.2 ± 0.4 for conventional rFVIII and 0.2 ± 0.5 and 0.2 ± 0.4 for rFVIIIFc, respectively. Bleeding data prior to, and after initiating treatment with rFVIIIFc are shown in Figure 4 Figure 2.

Figure 4

There were no serious spontaneous bleeding episodes with rFVIIIFc prophylaxis during the follow-up period of this study, which would have required long-term inpatient or outpatient treatment.

Perioperative management

Hemostatic efficacy was rated as excellent during all surgical procedures as defined by Srivastava et al. 20 [20]. Mean consumption in the postoperative setting per patient as well as treatment days are shown in Figure 5 Table 3. In total, eleven surgeries had been conducted in nine patients with severe hemophilia A, after switching to rFVIIIFc. Of five major surgeries, four were orthopaedic. Six interventions were considered minor surgeries. All patients adhered to their prescribed treatment regimen prior to surgery. The evening before surgery, a mean preloading dose of 38 (± 7) and 34 (± 13) IU/kg rFVIIIFc was given in major and minor surgeries, respectively. Prior to surgery, an additional dose of 56 (± 30) IU/kg in major and 49 (± 22) IU/kg in minor surgeries was administered Figure 6 (Table 4).

Figure 5

Figure 6

Successful long-term outcome in PwHA consists of an efficient prophylaxis to reduce the occurrence of bleeding episodes and to maintain joint health. Despite widespread availability of safe and effective replacement therapies, PwHA remain to be exposed to a significant treatment burden of frequent intravenous injections, while still experiencing breakthrough bleedings, and progressive joint disease over a lifetime 9, 21, 22, 23, 24. Novel therapeutic approaches have been developed to overcome these challenges including Efmoroctocog alfa (rFVIIIFc). Attachment to the IgG1 Fc domain permits binding to the FcRn, which is responsible for protection of IgG from lysosomal degradation and facilitates its recycling 12. As a result, rFVIIIFc shows prolonged clearance-related pharmacokinetics with the potential to improve bleed prevention without increasing the overall factor consumption and concurrently to reduce treatment burden with less frequent injections 13, 14, 18.

In the present study, the real-world usage and potential therapeutic benefits of long-acting rFVIIIFc were analyzed in 27 patients with severe hemophilia A previously treated with conventional recombinant factor products. The mean follow-up period after switching to rFVIIIFc was 24.9 months. While randomized clinical trials remain the gold standard to establish efficacy and safety of new therapeutic agents, data from clinical routine produce evidence of therapeutic effectiveness in real-world practice settings. Extensive analyses from clinical trials have been published 13, 14, 15, 16, 17, 25, 26, 27, 28, 29, 30, 31, but uncertainties prevail among physicians despite of a recent uptake in published real-world evidence 32, 33, 34, 35, 36, 37, 38. Especially, the inhibitor risk of patients with a prior history of inhibitors is an issue of debate since those patients are excluded from clinical trials. In our study four patients with a prior history of inhibitors (two with high-titer inhibitors, two with low-titer inhibitors) against FVIII switched to rFVIIIFc and none of those patients developed inhibitors. These data are consistent with an analysis of 36 patients pooled from the phase 4 observational study programs of PREVENT and A-SURE, respectively 39. Furthermore, a recently published Italian single-center study corroborates these findings for the use of rFVIIIFc in clinical routine 37. In our study, overall, the weekly dose of rFVIIIFc was lower compared to that of previous SHL FVIII concentrate. The observed reduction of 18.3% corresponds to 19% reported in a Canadian analysis 40 and 17-26% according to a meta-analysis 41. In the aforementioned single center study conducted in Italy Tagliaferri et al. report a ~12% reduction in weekly dose 37. Importantly, the reduction in factor consumption did not adversely affect bleed protection. Iorio et al. detected significantly lower ABRs on rFVIIIFc compared to standard rFVIII, while ABRs remained stable in our and the Italian study.

The improved prevention of bleeding episodes, especially in joints (70% of patients with zero AjBR within 2 years observation time), might be likely beneficial to long-term joint health.

The reduced clearance of rFVIIIFc allows for a high degree of treatment personalization. PwHA may be enabled to reduce annualized factor consumption and mean dosing frequency to lift the burden of frequent injections. Conversely, an alternative treatment strategy can result in treatment intensification to improve bleed protection and joint health by raising the factor trough levels from 1% to 3-5% or even higher. This assumption is supported by recently published efficacy data on another EHL, rurioctocog alfa pegol, by Klamroth et al. 42. In concordance with this uplift of target trough levels concept PwHA may be switched from SHL to EHL in a 1:1 manner with respect to injection dose and injection frequency 18. Revised treatment strategies as such are increasingly being supported by national and international treatment recommendations and guidelines, that advocate for target trough levels of 1-3% or more recently even 3-5% 20, 43, 44, 45. Observations from clinical practice according to which PwHA dosed to trough levels of 1% still display a considerable risk for developing hemophilic arthropathies are dissatisfactory 21. This and the introduction of EHL factor concentrates such as rFVIIIFc advocate for a more progressive preservation of joint health. Doing so, the otherwise inevitable detrimental triad of recurrent joint bleeds, chronic synovitis and hemophilic arthropathy might be almost prevented.

Adherence to FVIII prophylaxis was generally high in the patient population of this study. However, after switching to rFVIIIFc, adherence further improved significantly from 87% to 94%. The data are in accordance with a review of Ingersoll and Cohen who described that treatment burden and regimen complexity are likely determinants of adherence. Less complex regimens with fewer doses, by contrast, were shown to promote adherence 7. In this regard the benefits of higher trough levels for joint health at equal dosing intervals should be carefully weighed against the possible risk of lower treatment adherence. Hence, the treatment strategy of choice needs to fit the individual needs of the respective patient46.

In addition to bleeding prevention in the daily lives of PwHA, surgical procedures require an optimal therapeutic management for adequate hemostasis. Eleven surgeries were performed with rFVIIIFc within this study. Importantly, rFVIIIFc was shown to be safe and effective in the perioperative setting, and hemostasis management was excellent in both major and minor surgeries.

Limitations of this study are the relatively small number of patients and the single center design. Furthermore, our hemophilia A cohort exclusively consists of patients who had switched to rFVIIIFc from a prior replacement product. Despite the potential limitations of our analyses, however, the results are consistent with published data on rFVIIIFc and add to the body of real-world evidence regarding the therapeutic effectiveness and safety of rFVIIIFc in PwHA previously treated with conventional factor concentrates.

This is the first study to provide real-world evidence on personalized prophylaxis in a German cohort of PwHA being switched from conventional SHL factor concentrates to rFVIIIFc. Data were in line with previously published pivotal rFVIIIFc studies.

Prophylaxis with rFVIIIFc was efficacious in all patients and generally well tolerated. There was no inhibitor development, even in patients with inhibitor history. rFVIIIFc was associated with low overall and joint bleeds as well as significantly improved treatment adherence. Perioperative management was performed according to guidelines and hemostatic efficacy was rated as excellent.

Our findings suggest that rFVIIIFc can improve effectiveness compared to conventional rFVIII concentrates in real-world clinical settings.

Declaration of interest

Johannes Oldenburg: Honoraria; fees for speaking, consulting or symposium/congress attendance; or research funding: Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire Swedish Orphan Biovitrum.

Georg Goldmann: Honoraria; fees for speaking, consulting or symposium/congress attendance; or research funding: Bayer, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Swedish Orphan Biovitrum, Takeda.

Natascha Marquardt: Honoraria; fees for speaking, consulting or symposium/congress attendance; Bayer, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and Swedish Orphan Biovitrum.

Claudia Klein: Not applicable

Silvia Horneff: Honoraria; fees for speaking, consulting or symposium/congress attendance; Roche, Octapharma, Bayer, Novo Nordisk, Swedish Orphan Biovitrum

Thilo Albert: Funds and/or reimbursement for attending symposia, congresses and/or investigator meetings from Baxter/Baxalta/Shire/Takeda, Bayer, Biogen Idec, Biotest, Chugai, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Roche, Swedish Orphan Biovitrum, and Pfizer.

Author contribution

Georg Goldmann: Conceptualization, Methodology, Investigation, Writing- Original draft preparation

Natascha Marquardt: Investigation, Writing- Reviewing and Editing

Silvia Horneff: Data curation, Writing- Reviewing and Editing,

Claudia Klein: Investigation, Writing- Reviewing and Editing

Thilo Albert: Software, Data curation, Validation, Visualization, Project administration

Johannes Oldenburg: Supervision, Writing- Reviewing and Editing

Acknowledgments

The authors would like to acknowledge GKM Gesellschaft für Therapieforschung mbH for assistance in completion of this manuscript.

Highlights

Real-world clinical experience of extended half-life recombinant factor VIII Fc

1.Knobe, K. and E. Berntorp, Haemophilia and joint disease: pathophysiology, evaluation, and management. J Comorb, 2011. 1: p. 51-59. 2.Lobet, S., C. Hermans, and C. Lambert, Optimal management of hemophilic arthropathy and hematomas. J Blood Med, 2014. 5: p. 207-18. 3.Manco-Johnson, M.J., et al., Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med, 2007. 357(6): p. 535-44. Manco-Johnson, M.J., et al., Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost, 2013. 11(6): p. 1119-27. White, G.C., 2nd, et al., Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost, 2001. 85(3): p. 560. Srivastava, A., et al., Guidelines for the management of hemophilia. Haemophilia, 2013. 19(1): p. e1-47. Ingersoll, K.S. and J. Cohen, The impact of medication regimen factors on adherence to chronic treatment: a review of literature. J Behav Med, 2008. 31(3): p. 213-24. Wiley, R.E., et al., From the voices of people with haemophilia A and their caregivers: Challenges with current treatment, their impact on quality of life and desired improvements in future therapies. Haemophilia, 2019. 25(3): p. 433-440. Carcao, M., Changing paradigm of prophylaxis with longer acting factor concentrates. Haemophilia, 2014. 20 Suppl 4: p. 99-105. European Medicines Agency (EMA), Summary of Product Characteristics: Elocta. https://www.ema.europa.eu/en/documents/product-information/elocta-epar-product-information_en.pdf (accessed 19 Aug 2019). Peters, R.T., et al., Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost, 2013. 11(1): p. 132-41. 12.Roopenian, D.C. and S. Akilesh, FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol, 2007. 7(9): p. 715-25. Mahlangu, J., et al., Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood, 2014. 123(3): p. 317-25. Young, G., et al., Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost, 2015. 13(6): p. 967-77. Nolan, B., et al., Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study. Haemophilia, 2020. 26(3): p. 494-502. Powell J S Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients Blood 2012 119 13 3031 3038 Pouplard C Multicentre pharmacokinetic evaluation of rFVIII-Fc (efmoroctocog alfa) in a real life and comparison with non-extended half-life FVIII concentrates Haemophilia 2020 26 2 282 289 Mccue J Manufacturing process used to produce long-acting recombinant factor VIII Fc fusion protein Biologicals 2015 43 4 213 222 Simpson M L Comparing Factor Use and Bleed Rates in U.S. Hemophilia A Patients Receiving Prophylaxis with 3 Different Long-Acting Recombinant Factor VIII Products J Manag Care Spec Pharm 2020 26 4 504 512 Coyle T E Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A J Thromb Haemost 2014 12 4 488 96 Dunn A. L. Ahuja S. P. Mullins E. S. Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A Haemophilia 2018 24 e84 e92 1351-8216 Wiley 10.1111/hae.13403 https://dx.doi.org/10.1111/hae.13403 Tiede A Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A J Thromb Haemost 2013 11 4 670 678 Collins P W Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial Blood 2014 124 26 3880 3886 Giangrande P Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A Thromb Haemost 2017 117 2 252 261 Peyvandi F Real-life experience in switching to new extended half-life products at European haemophilia centres Haemophilia 2019 25 6 946 952 Konkle B A Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015 126 1078 85 Aledort Louis Milligan Scott Watt Maureen Booth Jason A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States Journal of Managed Care & Specialty Pharmacy 2020 26 4 492 503 2376-0540, 2376-1032 10.18553/jmcp.2020.26.4.492 Academy of Managed Care Pharmacy https://dx.doi.org/10.18553/jmcp.2020.26.4.492 Mullins E S Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia 2017 23 238 246 Oldenburg J Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens Blood 2015 125 13 2038 2082 Collins P W Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia Haemophilia 2011 17 1 2 10 Ahnstrom J. Berntorp E. Lindvall K. Bjorkman S. A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia Haemophilia 2004 10 6 689 697 1351-8216, 1365-2516 10.1111/j.1365-2516.2004.01036.x Wiley https://dx.doi.org/10.1111/j.1365-2516.2004.01036.x Berntorp E Dosing regimens, FVIII levels and estimated haemostatic protection with special focus on rFVIIIFc Haemophilia 2016 22 3 389 96 Collins P W Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A J Thromb Haemost 2009 7 3 413 433 Srivastava A WFH Guidelines for the Management of Hemophilia 6 1 158 Oldenburg J Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein Haemophilia 2018 24 1 77 84 Manco-Johnson M J Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART) J Thromb Haemost 2013 11 1119 1146 Aledort Louis Milligan Scott Watt Maureen Booth Jason A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States Journal of Managed Care & Specialty Pharmacy 2020 26 4 492 503 2376-0540, 2376-1032 10.18553/jmcp.2020.26.4.492 Academy of Managed Care Pharmacy https://dx.doi.org/10.18553/jmcp.2020.26.4.492 Berntorp E Dosing regimens, FVIII levels and estimated haemostatic protection with special focus on rFVIIIFc Haemophilia 2016 22 3 389 96 Powell J S Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients Blood 2012 119 13 3031 3038 Peters R T Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein J Thromb Haemost 2013 11 1 132 173 Cross-Sectional Guidelines for Therapy with Blood Products and Plasma Derivates. 5th revised and updated edition 2020 Federal Medical Association 118 146 Coyle T E Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A J Thromb Haemost 2014 12 4 488 96 Iorio A Indirect comparisons of efficacy and weekly factor consumption during continuous prophylaxis with recombinant factor VIII Fc fusion protein and conventional recombinant factor VIII products Haemophilia 2017 23 3 408 416 Holmström M Real-World Usage of rFVIIIFc in Sweden: A Report from the Swedish National Registry for Bleeding Disorders. Presented at the 13th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD 2020 5 7 Young G Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A J Thromb Haemost 2015 13 6 967 77 Collins P W Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial Blood 2014 124 26 3880 3886 Tiede A Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A J Thromb Haemost 2013 11 4 670 678