Novel protein offers 10-day dosing of factor VIII therapy in haemophilia A

Treatment of haemophilia A may be revolutionised by a novel engineered protein that extends the half-life of Factor VIII four-fold by decoupling it from endogenous von Willebrand factor (VWF).

US researchers says extended half life Factor VII products have already improved therapy of haemophilia A by allowing for twice weekly injections, but they say a “VWF chaperone effect” constrains the pharmacokinetics and puts a ceiling on the half life.

To address this, scientists engineered a novel protein known as BIVV001 (rFVIIIFc-VWF-XTEN)  that is designed to uncouple recombinant factor VIII from VWF in circulation. By attaching to a key factor VIII–binding site of VWF (D′D3 domain), the protein has been shown to result in a half-life of factor VIII that is three to four times as long as that of recombinant factor VIII.

And in a newly-published phase 1–2a open-label trial involving 16 previously treated men with severe haemophilia A (factor VIII activity, <1%) the product has been shown to result in high sustained factor VIII activity levels.

The results in NEJM confirmed that the half-life with BIVV001 was three to four times as long as that of recombinant factor VIII.

The  mean half life was 37.6 vs. 9.1 hours in a lower-dose group of 25 IU per kg body weight and 42.5 vs. 13.2 hours in a higher-dose group of 65 IU/kg).

After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for four days and 17% at day 7, “which suggested the possibility of a weekly interval between treatments,” the researchers said.

Furthermore, the BIVV001 injection appeared to be safe, with no inhibitors to factor VIII detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the single dose.

They said the preliminary results suggested that BIVV001 could provide a high level of sustained factor VIII activity in patients with severe haemophilia A, and phase 3 trial is now underway.

An accompanying commentary described the development of BIVV001 as part of the “amazing progress” seen in treatment of haemophilia A I recent years.

“The marked improvement in factor VIII pharmacokinetic features, similar in magnitude to those achieved for long-acting factor IX products in haemophilia B, is potentially a clinically significant advance, notwithstanding some open questions,” wrote Professor Pier Mannucci, of the IRCCS Maggiore Policlinico Hospital, Milan.

“If the promises of this pharmacokinetic study are confirmed by the ongoing phase 3 study and the drug is licensed, it may become the first choice among factor VIII replacement products administered intravenously because the reduction of the dosing frequency to once weekly or even every 10 days could improve the patients’ quality of life,” he wrote.

“The product may also become a competitor for emicizumab, he said, though there were questions about cost and the inconvenience of intravenous over subcutaneous administration,” Professor Mannucci noted.

Other questions that remain to be answered include the degree to which the new product protects against spontaneous bleeding episodes in real-life prophylactic use, and whether blocking factor VIII binding to VWF impairs platelet adherence to sites of endothelial damage in vivo.

“Furthermore, it is unknown whether the lack of neoantigenicity in adults who have received multiple previous treatments would be replicated in previously untreated children, a group at a higher risk for the formation of alloantibody inhibitors,” he cautioned.

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