Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII

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

doi:10.1016/j.thromres.2013.06.017

Cited by 44 publications

(36 citation statements)

References 22 publications

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“…on May 10, 2018. by guest www.bloodjournal.org From A clinical program for rVIII-SingleChain is under way, but prior preclinical studies have shown improved pharmacodynamic efficacy comparable to full-length and BDD human rFVIII. 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.…”

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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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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“…11 The single-chain design results in a stable and homogenous drug product with increased binding affinity for VWF, and PK properties that are superior to those of full-length rFVIII. 12 Of note, these favorable PK attributes were achieved without glycopegylation or fusion to antibody fragments.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

Mahlangu

Kuliczkowski

Karim³

et al. 2016

Blood

146

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“…In vitro studies suggest that, in addition to protecting FVIII from proteolysis, VWF limits rFVIII recognition by antigen-presenting cells, which may reduce the risk of inhibitor development [7,8]. Further, preclinical studies have demonstrated the efficacy and safety of this novel molecule in mice, rabbits and non-human primates [9].…”

Section: Introductionmentioning

confidence: 99%

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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Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII

Abstract: rVIII-SingleChain showed convincing hemostatic efficacy and excellent tolerability in animal studies, warranting continued investigation in human Phase I/III trials (AFFINITY).

Cited by 44 publications

References 22 publications

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

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

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

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

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Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII

Abstract: rVIII-SingleChain showed convincing hemostatic efficacy and excellent tolerability in animal studies, warranting continued investigation in human Phase I/III trials (AFFINITY).

Cited by 44 publications

References 22 publications

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

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

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

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

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