Getting under the skin: a new route for factor VIII?

In this issue of Blood, Vollack-Hesse et al present an elegant study demonstrating a possible new path for administering factor VIII (FVIII) via subcutaneous injection.¹ 

The past few decades have seen major advances in the treatment of hemophilia, perhaps most notably the advent of gene therapy approaches that have led to sustained expression of both FVIII and FXI in patients with hemophilia A and B, respectively.²  But the mainstay of hemophilia treatment is still repeated with IV administration of recombinant protein concentrates. Although repeated IV injections are clinically effective, they are not pleasant, they can be particularly challenging in patients with poor vein access, and they are especially difficult for parents who have to inject small children.

Previous attempts to deliver FVIII via the subcutaneous route have been unsuccessful because FVIII binds to phospholipids, which results in proteolytic cleavage and poor absorption into the circulation.³  However, Vollack-Hesse et al overcame this pitfall by coadministering FVIII alongside a small recombinant fragment of its binding partner, von Willebrand factor (VWF) in hemophilia A mice. The authors expressed a dimer of the VWF-D′D3 domains with a double repeat of the C-terminal 1238-1268 region that contains a series of O-linked glycosylation sites. This fragment, which they name VWF-12, contains the FVIII binding site and has been previously shown to be the minimal fragment required to protect FVIII in the circulation.⁴  The authors show that although VWF-12 does not interfere with the function of full-length VWF, it prevents FVIII from binding to phospholipids and components of the subendothelial matrix and protects against proteolytic cleavage. The net result is that when VWF-12 is subcutaneously injected alongside FVIII into hemophilia A mice, absorption of FVIII into the circulation is enhanced. Not surprisingly, the subcutaneous route resulted in a slower time to peak FVIII concentration; however, the half-life of FVIII was increased 2.5-fold over FVIII injected into mice via the IV route (7.2 vs 2.8 hours) and with greater bioavailability. Significantly, it offered up to 24 hours of protection from bleeding. It should be noted that in this study, the concentration of FVIII injected via the subcutaneous route was 5 times higher than that via the intravenous route, but even so, the therapeutic goal was successfully achieved.

The concept of codelivering VWF alongside FVIII has been widely regarded as a means to enhance the half-life of FVIII. Modifications to FIX have resulted in molecules with extended half-lives, but this has proved to be more difficult to achieve with FVIII because its half-life is extrinsically linked to that of VWF, the so called “VWF ceiling."⁵  BIVV001 is a novel fusion protein of FVIII and VWF that overcomes the VWF ceiling and has been shown to have a significantly extended half-life.⁶  Although VWF-12 does not directly prolong the half-life of FVIII, because endogenous full-length VWF will outcompete it once it is in the circulation, these data from Vollack-Hesse et al clearly show the advantage of exploiting VWF fragments to protect FVIII. In the future, it may be interesting to see how BIVV001 performs after subcutaneous injection.

Subcutaneous delivery of a hemophilia A therapeutic agent has already been achieved by the bispecific antibody emicizumab, which mimics activated FVIII.⁷  There are no long-term data on the safety of emicizumab, but there is still a strong rationale for developing regular FVIII products. There are also concerns over the immunogenicity of therapeutics delivered via the subcutaneous route,⁸  but Vollack-Hesse et al show in their study that the FVIII/VWF-12 combination was no more immunogenic than FVIII delivered via IV and, in fact, was marginally less immunogenic, which indicates another potential advantage of this delivery route. Many questions still need to be addressed, but these data have great promise and clearly warrant further investigation. Detailed dissection of how this particular VWF fragment protects FVIII will be of scientific interest, and studies to enhance the affinity of VWF-12 for FVIII would also be useful. Ultimately, if successful in humans, this may offer a more patient-friendly alternative to repeated intravenous injections without compromising safety and efficacy.