Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Schmidbauer, Stefan; Witzel, Reinhild; Robbel, Lars; Sebastian, Petra; Grammel, Nicolas; Metzner, Hubert J.; Schulte, Stefan

doi:10.1016/j.thromres.2015.05.005

Cited by 42 publications

(54 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This single-chain design is unique among currently marketed and developed rFVIII products, which all have a two-chain structure. The two-chain design is also more labile in the manufacturing environment and can result in inactive dissociated FVIII chains being present in the final drug product [14]. Indeed, the unique rVIII-SingleChain design results in enhanced molecular stability and improved structural integrity of the FVIII molecule.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…CSL627 or rVIII-SingleChain is a recombinant single-chain FVIII molecule expressed in CHO cells, designed as a B-domain truncated rFVIII molecule where the light and heavy chains are covalently linked through a disulfide bond, thereby constituting a stable single-chain [43]. Nevertheless, the key thrombin cleavage sites required for its activation are unchanged and the active form structurally comparable with all the other available FVIII products [43].…”

Section: Extended Half-life Fviii Productsmentioning

confidence: 99%

“…Nevertheless, the key thrombin cleavage sites required for its activation are unchanged and the active form structurally comparable with all the other available FVIII products [43]. This novel compound has a higher affinity for VWF as compared with other FVIII molecules, with a binding capacity which is both faster and stronger than that of a full-length unmodified rFVIII [12].…”

Section: Extended Half-life Fviii Productsmentioning

confidence: 99%

Outcome of Clinical Trials with New Extended Half-Life FVIII/IX Concentrates

Mancuso

Santagostino

2017

JCM

110

View full text Add to dashboard Cite

The development of a new generation of coagulation factors with improved pharmacokinetic profile will change the paradigm of treatment of persons with hemophilia (PWH). The standard treatment in PWH is represented by regular long-term prophylaxis that, given intravenously twice or thrice weekly, is associated with a not-negligible burden on patients’ quality of life. The availability of drugs with improved pharmacokinetic profile may improve prophylaxis feasibility and protection against bleeding episodes. This article summarizes the main results obtained from clinical trials with modified factor VIII (FVIII) and factor IX (FIX) molecules. Published literature on new molecules for replacement treatment in hemophilia A and B was retrieved using PubMed search, and all ongoing clinical trials have been researched via . Such new molecules are usually engineered to have a longer plasma half-life than that which has been obtained by chemical modification (i.e., conjugation with polyethylene glycol, PEG) or by creating recombinant fusion proteins. Results from phase I/III studies in previously treated adults and children are now available for the vast majority of new products, including the results of their use in a surgical setting. On the contrary, trials involving previously untreated patients are still ongoing for all and results not yet available.

show abstract

“…rFVIIISingleChain shows improved intrinsic stability and a markedly increased affinity to vWF. This higher affinity to vWF leads to improved pharmacokinetic properties in terms of a prolonged halflife [22].…”

Section: Protein Sequence Modificationmentioning

confidence: 99%

Extended Half-Life Factor VIII and Factor IX Preparations

Graf¹

2018

Transfus Med Hemother

View full text Add to dashboard Cite

In the last couple of years, several extended half-life factor VIII and factor IX preparations were intensively studied and gained approval. In order to extend half-lives, techniques like fusion to protein conjugates (Fc part of IgG₁ or albumin), chemical modification (PEGylation), and protein sequence modification are implemented. With these techniques, it is possible to extend half-lives of factor IX products 4- to 6- fold, while half-life extension of factor VIII products is limited to 1.5- to 2-fold due to their interaction with von Willebrand factor. Nevertheless, both extended half-life factor VIII and IX products have improved and facilitated prophylactic factor replacement therapy in hemophilia A and B, respectively. Extended half-life factor concentrates pose challenges to coagulation laboratories because accurate therapy monitoring is not possible with all factor activity assays currently used.

show abstract

Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Cited by 42 publications

References 22 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

Outcome of Clinical Trials with New Extended Half-Life FVIII/IX Concentrates

Extended Half-Life Factor VIII and Factor IX Preparations

Contact Info

Product

Resources

About

Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Cited by 42 publications

References 22 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

Outcome of Clinical Trials with New Extended Half-Life FVIII/IX Concentrates

Extended Half-Life Factor VIII and Factor IX Preparations

Contact Info

Product

Resources

About

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