New developments in the management of moderate-to-severe hemophilia B

Figures & data

Figure 1 rFIX forms with extended terminal half-lives.

Notes: (A) rFIXFc fusion protein with IgG1 Fc domain directly attached to C-terminus (no linker region), (B) rIX-FP fusion protein with albumin attached via linker peptide containing a proteolytic cleavage site, (C) N9-GP rFIX modified in a site-selective manner with a 40 kDa PEG moiety attached to one or both N-glycosylation sites in the activation peptide. The domain structure of the mature FIX protein is shown for each form with activation cleavage sites and posttranslational modifications as indicated.
Abbreviations: rFIX, recombinant FIX; FIX, factor IX; EGF, epidermal growth factor; GLA, gamma-carboxylation; PEG, polyethylene glycol.

Figure 2 Cross section of blood vessel indicating location of extravascular FIX pool.

Notes: Intravascular compartment consists of circulating FIX protein, extravascular compartment is represented by the endothelial monolayer plus the basement membrane that is enriched with collagen IV binding sites for FIX. The extravascular pool contributes to the in vivo hemostatic function of FIX in the hemophilia B mouse. The majority (∼80%) of injected FIX is sequestered rapidly in the liver, likely involving the sinusoidal endothelium. Other vascular organs show later peaks of FIX localization.
Abbreviation: FIX, factor IX.

Table 1 Therapeutic approaches to hemophilia B

Product	Half-life (hours)	Clinical phase	FDA approval	Population	Comments
pdFIX	17–23	Phase III, completed	Yes	PTP/PUP	AlphaNine SD Mononine
rFIX	17–19	Phase III, completed	Yes	PTP/PUP	Benefix Rixubis Ixinity
rFIX-Fc (Fc fusion)	82	Phase III, completed	Yes	PTP	Alprolix
rIX-FP (albumin fusion)	92	Phase II/III trial ongoing	No	PTP	BLA under review by FDA
N9-GP (rFIX-PEG)	93	Phase III, complete	No	PTP	Nonacog β pegol, once-weekly dose
Anti-TFPI Ab	NA	Phase I completed	No	PTP
ALN-AT3	NA	Phase I ongoing	No	PTP	siRNA targeting AT3 expression

Abbreviations: FDA, US Food and Drug Administration; pdFIX, plasma-derived FIX; rFIX, recombinant factor IX; PTP, previously treated patients; PUP, previously untreated patients; BLA, biologics license application; PEG, polyethylene glycol; TFPI, tissue factor pathway inhibitor; Ab, antibody; AT3, antithrombin III; NA, not applicable.