Novel, structurally altered rFVIII concentrates in development or recently approved, and the advantages and disadvantages of the technology used in their development
| Characteristic . | PEGylated FVIII . | Fc fusion platform . | Novel FVIII design . | ||
|---|---|---|---|---|---|
| N8-GP . | BAX 855* . | BAY 94-9027 . | rFVIIIFc† . | rVIII-SingleChain . | |
| Product description | B-domain–modified 40K O-glycoPEGylated rFVIII concentrate | 20-kDa PEGylated full-length rFVIII | BDD rFVIII with a site-specific branched 60-kDa PEG side chain | Recombinant BDD FVIII-Fc fusion protein | Recombinant single-chain FVIII construct |
| Spec.Act. 11 200 IU/mg‡ | Spec.Act. 8000 IU/mg‡ | Spec.Act. 9717 IU/mg‡ | Spec.Act. 9348 IU/mg‡ | Spec.Act. 12 000 IU/mg‡ | |
| Advantages of technology | • Well-established technology | • Established technology | • Increases the intrinsic stability of the FVIII molecule by reducing the potential dissociation of the heavy and light chains | ||
| • Improves solubility of proteins | • Extends half-life of proteins | • Increased affinity for and binding to VWF | |||
| • Extends half-life of non-PEG protein/drug | • May mitigate immunogenicity of the protein | ||||
| • Reduced kidney clearance because of larger hydrodynamic size | |||||
| • Protects the drug from proteolysis | |||||
| • May protect the drug from the immune system | |||||
| • Reduces aggregation | |||||
| Disadvantages of technology | • Random PEGylation (BAX 855) may result in loss or change in protein activity | • Potential for activation of the immune system (antibody-dependent or complement-dependent) | • Not specifically designed for extension of half-life | ||
| • Preexisting anti-PEG antibodies identified in the healthy population, which may result in the rapid clearance of PEGylated compounds124 | |||||
| Half-life (patients >12 y), h | 19.04125 | 14.3-16126 | ∼18.2-19.5127 | ∼19114,116 | — |
| Percentage increase in half-life vs rFVIII | 60%125 § | 40%-50%126 | 28.1%-40.5%127 | 53%-70%114,116 | — |
| Clearance, mL/h/kg | 1.79125 | — | — | 1.68 33%-35% decrease vs rFVIII114 | — |
| Characteristic . | PEGylated FVIII . | Fc fusion platform . | Novel FVIII design . | ||
|---|---|---|---|---|---|
| N8-GP . | BAX 855* . | BAY 94-9027 . | rFVIIIFc† . | rVIII-SingleChain . | |
| Product description | B-domain–modified 40K O-glycoPEGylated rFVIII concentrate | 20-kDa PEGylated full-length rFVIII | BDD rFVIII with a site-specific branched 60-kDa PEG side chain | Recombinant BDD FVIII-Fc fusion protein | Recombinant single-chain FVIII construct |
| Spec.Act. 11 200 IU/mg‡ | Spec.Act. 8000 IU/mg‡ | Spec.Act. 9717 IU/mg‡ | Spec.Act. 9348 IU/mg‡ | Spec.Act. 12 000 IU/mg‡ | |
| Advantages of technology | • Well-established technology | • Established technology | • Increases the intrinsic stability of the FVIII molecule by reducing the potential dissociation of the heavy and light chains | ||
| • Improves solubility of proteins | • Extends half-life of proteins | • Increased affinity for and binding to VWF | |||
| • Extends half-life of non-PEG protein/drug | • May mitigate immunogenicity of the protein | ||||
| • Reduced kidney clearance because of larger hydrodynamic size | |||||
| • Protects the drug from proteolysis | |||||
| • May protect the drug from the immune system | |||||
| • Reduces aggregation | |||||
| Disadvantages of technology | • Random PEGylation (BAX 855) may result in loss or change in protein activity | • Potential for activation of the immune system (antibody-dependent or complement-dependent) | • Not specifically designed for extension of half-life | ||
| • Preexisting anti-PEG antibodies identified in the healthy population, which may result in the rapid clearance of PEGylated compounds124 | |||||
| Half-life (patients >12 y), h | 19.04125 | 14.3-16126 | ∼18.2-19.5127 | ∼19114,116 | — |
| Percentage increase in half-life vs rFVIII | 60%125 § | 40%-50%126 | 28.1%-40.5%127 | 53%-70%114,116 | — |
| Clearance, mL/h/kg | 1.79125 | — | — | 1.68 33%-35% decrease vs rFVIII114 | — |
—, not available; BDD, B-domain deleted.
Adynovate (Baxalta US Inc), approved by the US Food and Drug Administration (FDA) in November 2015.
Eloctate (Biogen Idec Inc), approved by the FDA in June 2014.
Specific activities (Sp.Act.) have been derived using either chromogenic or 1-stage functional assays.
Versus patients’ previous treatment of plasma-derived FVIII or rFVIII.