Fusing a small protein to a natural blood clotting factor made the factor last significantly longer in the human body, according to a new clinical study that has raised hopes for a vastly improved treatment for hemophilia. Currently, people with severe forms of hemophilia—a condition in which blood fails to clot properly—often infuse themselves at home with the clotting factor three to four times a week to prevent bleeding; the new fusion protein could decrease those treatments to just once a week.
The therapy, which includes an experimental fusion protein named BIVV001, still hasn’t been shown to stop bleeding in hemophilia patients in a large-scale clinical trial, but the extended duration of the clotting factors has excited some researchers.
“[This] is potentially a clinically significant advance, not withstanding some open questions,” wrote Pier Mannucci, a hematologist at the Policlinico of Milan, in an editorial that accompanied the new paper. He compared the new fusion protein to long-acting factors that have similarly improved treatment for people with hemophilia B.
Known commonly as a “royal disease” because it afflicted many of Europe’s ruling families during the 19th and 20th centuries, hemophilia manifests in two forms: types A and B. Together, both types are estimated to affect more than 1 million men globally. (The X-linked disease is extremely rare among women.) Hemophilia A is the more common of the two and is caused by a gene mutation that results in a defective form of blood coagulation factor VIII. Those affected experience a clotting disorder, joint issues, and life-threatening bleeding episodes—sometimes more than 30 per year—unless they receive prophylactic treatment of synthetic factor VIII or other proteins that aid clotting.
Frequent infusions can also be a tremendous burden for patients, says Barbara Konkle, a hematologist at the research institute Bloodworks Northwest and lead author of the new study. She and others in the field have focused efforts on ways to decrease that burden.
Normally, most factor VIII is stabilized in the body by another protein, von Willebrand factor (VWF), which also protects the clotting factor from disintegrating. However, VWF sets a cap on factor VIII’s time in the body, limiting its half-life to about 15 hours. When factor VIII is infused, it typically latches on to VWF. But researchers at Sanofi and Sobi, the sponsors of the new study, developed a fusion protein that had one small portion of VWF already fused to it. Their hope was that it would be enough to stabilize the clotting factor and prevent it from binding to the body’s own VWF. “Just part of [VWF] stabilizes factor VIII,” Konkle said. “You don’t need the rest of the protein.”
Sixteen men with hemophilia A and a history of prophylactic treatments were included in the new phase I/IIa, open-label study, which was designed primarily to assess safety and the half-life of BIVV001. The men were divided into low- and high-dose groups. Each patient was given a single injection of recombinant factor VIII, followed by a washout period of at least 3 days before an injection of the fusion protein BIVV001. Patients were then observed for a 28-day period to determine the safety of each dose.
Before patients received their BIVV001 injections, plasma factor VIII had a half-life of 9.1 hours in people in the lower dose group and 13.2 hours in people in the higher dose group. After the BIVV001 injections, those half-lives averaged 37.6 hours and 42.5 hours, respectively, the researchers report today in The New England Journal of Medicine. No patients developed resistance to factor VIII during the study, and no hypersensitivity or anaphylaxis events were reported.
Konkle said the phase III trial of the drug is now underway. If that confirms BIVV001 halts bleeding episodes as well as factor VIII but with fewer infusions, the company hopes to submit those data to the Food and Drug Administration by 2022 and seek approval to sell the drug.