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Encapsulated Factor VIII shows promise for hemophilia A with inhibitors
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SAN DIEGO — Encapsulating Factor VIII in a microcapsule that uses platelets to target and deliver therapy may help in the treatment of bleeding in patients with hemophilia A that has formed inhibitors, according to study results presented at the ASH Annual Meeting and Exposition.
Because the development of inhibitory antibodies in patients with hemophilia A renders most delivered Factor VIII (FVIII) therapy ineffective, treatment of bleeds in these patients is extremely challenging. These patients often instead receive costly immune tolerance induction therapy that has a low success rate, or use bypassing agents that carry a risk for thrombosis.
“These patients are left with very few alternative treatment options, all with severe drawbacks,” Caroline E. Hansen, BS, PhD candidate at the school of chemistry and biochemistry at Georgia Institute of Technology, said during a press conference. “We postulated that if we could encapsulate Factor VII and deliver it in a targeted fashion, we could make it work with patients with inhibitor antibodies.”
Researchers developed FVIII–loaded microcapsules that have fibrinogen on their exterior, which allows them to adhere to the patient’s platelets after IV administration. The microcapsules circulate until they reach vascular injury sites, where localized agonists activate the adherent platelets. The contractile force made by these adherent platelets and nearby platelets will cause the microcapsule to rupture, releasing the FVIII.
FVIII is then incorporated into the nascent clot before the inhibitory antibodies can take effect.
“Importantly, for patients with inhibitor antibodies, the microcapsule physically shields the Factor VIII from the patients antibodies, and so the antibodies will not bind to it during circulation,” Hansen said. “That will facilitate coagulation upon its delivery.”
In vitro experiments of this technique showed platelets adhered to the microcapsule surface, and the microcapsules incorporated into the fibrin network upon platelet activation, causing the microcapsule to rupture during clot contraction.
Because this rupture only occurs in the presence of contracting platelets, the drug will only be delivered at sites of active clot formation.
Researchers then introduced FVIII inhibitory antibody into healthy blood samples to mimic hemophilia A with inhibitors. They compared outcomes after systemically infusing FVIII at 0.05 U/mL and 0.5 U/mL with infusing microcapsules loaded with 0.01 U/mL FVIII.
Results showed significantly greater production of fibrin in samples with microcapsules than either sample with systemic FVIII infusion (P < .05 for both). Researchers hypothesized the shielding effect of the microcapsule prevented its exposure to the inhibitor antibodies, causing greater efficacy.
Hansen and colleagues then assessed whether this approach would promote clot formation in the presence of inhibitor antibodies. They conducted a well-plate study to determine the time it took blood to clot. Results showed a systemic infusion of FVIII led to clotting within 1 hour, whereas the FVIII microcapsules took only 20 to 30 minutes to lead to blood clot, which is comparable to clotting time of a healthy individual.
“This is a completely new paradigm in targeted delivery using platelet biomechanisms to target and delivery a drug,” Hansen said. “It provides an efficacious solution to achieve hemostasis for hemophilia A patients with inhibitor antibodies.” – by Alexandra Todak
Reference: Hansen CE, et al. Abstract 81. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: Hansen reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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Margaret V. Ragni, MD, MPH
This is very exciting work, and no one has done anything like this. These are microcapsules that contain Factor VIII that is protected when it is in circulation, because the outer exterior is fibrinogen. This provides an easy monitoring system to measure fibrin, its activation, when it goes to a site of injury. If this pans out and can be shown to be effective in animal models and subsequently in humans, it will be really exciting for a patient with an inhibitor — a very difficult patient to manage to manage, with ten times the hospitalizations, two times the costs and twice the mortality of any other noninhibitor patient — because it promises a way to protect Factor VIII as it circulates to where it’s needed at the time of an injury or a bleed. This delivers a high level of Factor VIII right where you need and when you need it before an inhibitor gets to attach to it — this is a novel approach to inhibitors that has never been doing before.
We used to only have bypass therapy, which is not nearly as effective as the promise of some of these novel therapeutics. Now we have a cornucopia of wonderful and exciting approaches for hemophilia, and this is clearly one of them.
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