Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Zollner, Sabine; Raquet, Elmar; Claar, Philipp; Müller-Cohrs, Jochen; Metzner, Hubert J.; Weimer, Thomas; Pragst, Ingo; Dickneite, Gerhard; Schulte, Stefan

doi:10.1016/j.thromres.2014.03.028

Cited by 44 publications

(52 citation statements)

References 28 publications

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“…Preclinical studies confirmed a high affinity for VWF, with improved pharmacokinetic (PK) and pharmacodynamic properties vs. FL-rFVIII [6]. These studies indicated that exposure to rVIII-SingleChain is greater than for FL-rFVIII at equal doses, without the need for PEGylation or fusion with other proteins.…”

Section: Introductionmentioning

confidence: 88%

“…Consistent with the protection against degradation that VWF confers upon FVIII [22], the observed correlations between VWF antigen levels and t 1/2 and CL of rVIII-SingleChain suggest that increased binding of rVIII-SingleChain to VWF contributes to the improved PK profile compared with octocog alfa. This hypothesis is supported by noting that under physiologic conditions,~1% of FVIII molecules circulate freely while the remaining 99% are VWF bound, but in patients treated with rVIII-SingleChain, the VWF bound fraction increases to 99.9% [6]. Binding of FVIII to VWF also limits its recognition and uptake by antigen-presenting cells, dose-dependently blocking endocytosis of FVIII by monocyte-derived dendritic cells [23], giving a potential mechanism for mitigating the risk of inhibitor development [7,8].…”

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confidence: 93%

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Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate^®) in patients with severe haemophilia A

et al. 2016

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Background: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. Aim: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. Methods: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg À1 octocog alfa (Advate â ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg À1 rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. Results: rVIII-SingleChain had a longer mean half-life (t 1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h À1 kg À1), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUC inf (2090 vs. 1550 IU·h dL À1 ) than octocog alfa, respectively. The mean AUC inf after rVIII-SingleChain infusion was~35% larger than after octocog alfa. A similar pattern was observed for AUC 0-last . No serious adverse events or inhibitors were reported. Conclusions: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t 1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.

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Section: Introductionmentioning

confidence: 88%

mentioning

confidence: 93%

Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate^®) in patients with severe haemophilia A

et al. 2016

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“…118 An unexpected observation was that the half-life of rVIII-SingleChain was approximately twofold greater than that of full-length rFVIII. 119 This half-life extension may be attributed to the threefold higher affinity of rVIIISingleChain for plasma-derived VWF compared with full-length rFVIII, 120 thus resulting in a smaller proportion of unbound and rapidly cleared rFVIII molecules. This pharmacokinetic behavior has been replicated in a recent phase 1/3 clinical trial and was stable with repeated infusions.…”

Section: Single-chain Designmentioning

confidence: 99%

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Pipe

Montgomery

Pratt

et al. 2016

Blood

173

186

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A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent complex, and each has a critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaperone for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) and reduce dosing frequency by utilizing bioengineering techniques including PEGylation, Fc fusion, and single-chain design. However, these approaches have achieved only moderate increases in halflife of 1.5-to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain is still regulated to a large extent by interaction with VWF. Therefore, the half-life of VWF (∼15 hours) appears to be the limiting factor that has confounded attempts to extend the half-life of rFVIII. A greater understanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival of VWF or limit VWF-mediated clearance of FVIII. (Blood.

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“…It has been reported that in a number of recombinant factor FVIII molecules [14]–[17], the cleavage at R1648 does not occur for a fraction of the secreted BDD rFVIII product, leading to the generation of non-processed single chain rFVIII isoform. Also, there are recent reports on different isoforms of SC rFVIII designed to improve in vivo activity and prolong half-life [18]–[20].…”

Section: Introductionmentioning

confidence: 99%

A Single Chain Variant of Factor VIII Fc Fusion Protein Retains Normal In Vivo Efficacy but Exhibits Altered In Vitro Activity

et al. 2014

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Recombinant factor VIII Fc (rFVIIIFc) is a fusion protein consisting of a single B-domain-deleted (BDD) FVIII linked recombinantly to the Fc domain of human IgG1 to extend half-life. To determine if rFVIIIFc could be further improved by maintaining the heavy and light chains within a contiguous single chain (SC), we evaluated the activity and function of SC rFVIIIFc, an isoform that is not processed at residue R1648. SC rFVIIIFc showed equivalent activity in a chromogenic assay compared to rFVIIIFc, but approximately 40% activity by the one-stage clotting assay in the presence of von Willebrand Factor (VWF), with full activity in the absence of VWF. Moreover, SC rFVIIIFc demonstrated markedly delayed thrombin-mediated release from VWF, but an activity similar to that of rFVIIIFc upon activation in FXa generation assays. Therefore, the apparent reduction in specific activity in the aPTT assay appears to be primarily due to delayed release of FVIII from VWF. To assess whether stability and activity of SC rFVIIIFc were affected in vivo, a tail vein transection model in Hemophilia A mice was utilized. The results demonstrated similar pharmacokinetic profiles and comparable efficacy for SC rFVIIIFc and rFVIIIFc. Thus, while the single chain configuration did not promote enhanced half-life, it reduced the rate of release of FVIII from VWF required for activation. This impaired release may underlie the observed reduction in the one-stage clotting assay, but does not appear to affect the physiological activity of SC rFVIIIFc.

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Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Abstract: rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.

Cited by 44 publications

References 28 publications

Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate^®) in patients with severe haemophilia A

Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate^®) in patients with severe haemophilia A

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

A Single Chain Variant of Factor VIII Fc Fusion Protein Retains Normal In Vivo Efficacy but Exhibits Altered In Vitro Activity

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Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Abstract: rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.

Cited by 44 publications

References 28 publications

Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate®) in patients with severe haemophilia A

Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate®) in patients with severe haemophilia A

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

A Single Chain Variant of Factor VIII Fc Fusion Protein Retains Normal In Vivo Efficacy but Exhibits Altered In Vitro Activity

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Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate^®) in patients with severe haemophilia A

Comparative pharmacokinetics of rVIII‐SingleChain and octocog alfa (Advate^®) in patients with severe haemophilia A