scholarly journals Population Pharmacokinetic Analysis of Recombinant Factor VIII Fc Fusion Protein in Subjects With Severe Hemophilia A: Expanded to Include Pediatric Subjects

2021 ◽  
Author(s):  
Suresh Katragadda ◽  
Srividya Neelakantan ◽  
Lei Diao ◽  
Nancy Wong
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Hemophilia A ◽  
Population Pharmacokinetic Analysis ◽  
Recombinant Factor Viii ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Severe Hemophilia ◽  
Fc Fusion Protein

scholarly journals A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

2020 ◽  
Vol 120 (05) ◽  
pp. 747-757
Author(s):  
Laura H. Bukkems ◽  
Jessica M. Heijdra ◽  
Mary Mathias ◽  
Peter W. Collins ◽  
Charles R. M. Hay ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Clinical Data ◽  
Hemophilia A ◽  
Clinical Trial Data ◽  
Recombinant Factor Viii ◽  
Percentage Error ◽  
Population Pharmacokinetic ◽  
Population Pk ◽  
Fc Fusion Protein

Abstract Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (–1.0%, 95% CI: –9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children. Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.

scholarly journals Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

Blood ◽  
2014 ◽  
Vol 123 (3) ◽  
pp. 317-325 ◽  
Author(s):  
Johnny Mahlangu ◽  
Jerry S. Powell ◽  
Margaret V. Ragni ◽  
Pratima Chowdary ◽  
Neil C. Josephson ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Phase 3 ◽  
Injection Frequency ◽  
Key Points ◽  
Fc Fusion Protein

Key Points A novel recombinant factor VIII with prolonged half-life, rFVIIIFc, was developed to reduce prophylactic injection frequency. rFVIIIFc was well-tolerated in patients with severe hemophilia A, and resulted in low bleeding rates when dosed 1 to 2 times per week.

scholarly journals Switching toward the use of recombinant factor VIII Fc fusion protein Study among 30 patients with severe hemophilia A

2020 ◽  
Vol 78 (1) ◽  
pp. 35-46
Author(s):  
Laurent Sattler ◽  
Ahlem Raissi ◽  
Damien Fornoff ◽  
Anne-Cécile Gérout ◽  
Olivier Feugeas ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Fc Fusion Protein

scholarly journals Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs

Blood ◽  
2012 ◽  
Vol 119 (13) ◽  
pp. 3024-3030 ◽  
Author(s):  
Jennifer A. Dumont ◽  
Tongyao Liu ◽  
Susan C. Low ◽  
Xin Zhang ◽  
George Kamphaus ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Specific Activity ◽  
Recombinant Factor Viii ◽  
Prophylactic Efficacy ◽  
Reduced Frequency ◽  
Fc Fusion Protein ◽  
Partial Correction

Abstract Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation.

scholarly journals Development of a Pegylated Dimeric Recombinant Factor VIII-Fc Fusion Protein for the Treatment for Hemophilia a Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3783-3783
Author(s):  
Bin Liu ◽  
Xiaoshan Wang ◽  
Xueqin Li ◽  
Haixia Yan ◽  
Shuya Wang ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Treatment Option ◽  
Half Life ◽  
Hemophilia A ◽  
Binding Activity ◽  
Recombinant Factor Viii ◽  
Fc Fusion Protein ◽  
In Vivo Tests

Abstract Hemophilia A is a hereditary bleeding disorder resulting from reduced factor FVIII activity. It occurred in 1/5000 male. Currently, the treatment option is with the factor FVIII replacement therapy. A long-acting recombinant monomeric FVIII-Fc fusion protein product (Eloctate®) has been approved in 2014 by the US FDA, it requires to infuse the drug for every 3 days or twice a week. There is a clinical need to develop longer half-life product to extend the treatment option to once a week infuse for hemophilia A patients. Recently, we have developed a dimeric recombinant factor VIII-Fc (drFVIII-Fc) fusion protein therapeutic candidate, which is entering the clinical development in China. To generate a longer half-life recombinant FVIII product, we have developed a PEGylation method to PEGylated this drFVIII-Fc fusion protein to PEGdrFVIII-Fc. We have analyzed and characterized the fusion protein by various analytic methods, as well as in vivo animal tests. It was shown that PEGdrFVIII-Fc fusion protein has been modified with about five Y type of 40kd PEG; the remaining activity is around 700 IU/mg, and the in vivo tests in cynomolgus monkey demonstrated that the fusion protein has a half-life of about 37 hours. The data also showed that there was no detectable affinity binding activity of vWF to a PEGdrFVIII-Fc fusion protein, as compared with the binding activity of 5.16X10-4M for the molecule of a drFVIII-Fc fusion protein. In conclusion, we are able to generate a PEGylated form of a drFVIII-Fc molecule with the relevant specific activity and has been shown the molecule with the prolonger half-life in the in vivo tests. The further biochemical analysis demonstrated PEGdrFVIII-Fc fusion protein with no detectable vWF binding activity, which might explain why its half-life is longer than vWF's ~15hours half-life in vivo. This molecule is likely to be used as a once-weekly treatment option for hemophilia A patients. Currently, we are in the development stage of an IND filing in China. Disclosures No relevant conflicts of interest to declare.

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