BIVV001 effective, safe in severe hemophilia A
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An IV injection of BIVV001 induced high sustained factor VIII activity levels among men with severe hemophilia A, according to results of a phase 1/phase 2 open-label trial published in The New England Journal of Medicine.
BIVV001 (rFVIIIFc-VWF-XTEN; Sanofi, Sobi), a novel fusion protein, demonstrated a half-life up to four times that of recombinant factor VIII, potentially representing a new class of factor VIII replacement therapy with a weekly treatment interval, researchers noted.
“The standard of care for severe hemophilia A is prophylactic therapy to prevent bleeding, and patients who receive this from early in life can lead normal lives and have normal life expectancy,” Barbara Konkle, MD, director of clinical and translational research, medical director of the Special Hemostasis Laboratory and associate director of the Hemophilia Treatment Center at the Puget Sound Blood Center and professor of hematology and medicine at University of Washington, told Healio. “Patients who receive prophylactic therapy have two options. One is to use factor VIII infusions; the other option is the bispecific antibody emicizumab-kxwh [Hemlibra, Genentech/Roche]. Another option still in study is gene therapy. There are several trials in phase 3 now.”
Factor VIII replacements have improved the care of patients with hemophilia A. However, the short half-life of recombinant factor VIII products — which ranges from 15 to 19 hours — negatively affects patients’ quality of life.
BIVV001 is designed to overcome the half-life ceiling and maintain high sustained factor VIII activity levels.
Konkle and colleagues sought to evaluate the safety and pharmacokinetics of a single dose of BIVV001. They assigned 16 men with severe hemophilia A — defined as factor VIII activity less than 1% — to a single IV injection of recombinant factor VIII dosed at 25 IU/kg (n = 7) or 65 IU/kg (n = 9), followed by a washout period of at least 3 days and then a single IV injection of BIVV001 at the same dose.
Incidence of adverse events and clinically significant abnormalities on laboratory testing, including the development of inhibitors or changes in von Willebrand factor (VWF) antigen levels or activity, served as the study’s primary endpoints. Researchers also calculated pharmacokinetic measurements as secondary endpoints.
Results showed that the geometric mean half-life of BIVV001 increased three to four times as long as that of recombinant factor VIII (25 IU/kg dose, 37.6 hours vs. 9.1 hours; 65 IU/kg dose, 42.5 vs. 13.2 hours).
Additionally, the area under the curve for product exposure was six to seven times greater in the two-dose groups (25 IU/kg dose, 4,470 hours x IU/dL vs. 638 hours x IU/dL; 65 IU/kg dose, 12,800 hours x IU/dL vs. 1,960 hours x IU/dL).
Researchers observed mean factor VIII plasma levels in the normal range (51%; range, 35-72) at 4 days, decreasing to 17% (range, 13-23) at 7 days, indicating the possibility of once-weekly treatments, according to researchers.
“It is so great for patients to have all of these options so that their care can be personalized to best meet their needs,” Konkle said. “I believe that having a truly longer-acting factor VIII will be an important option for patients.”
Researchers observed no inhibitors to factor VIII and no hypersensitivity or anaphylaxis events up to 28 days after the injection of BIVV001. They also detected no changes in VWF activity or antigen levels.
The most common adverse events associated with BIVV001 treatment included an asymptomatic increase in the level of thrombin-antithrombin III complex and headache.
The progress in treating and managing severe hemophilia has been impressive; however, there are still unanswered questions regarding this product, Pier M. Mannucci, MD, of IRCCS Ca' Granda Ospedale Maggiore Policlinico Hospital in Milan, wrote in an accompanying editorial.
“The study does not establish the degree to which this product protects against spontaneous bleeding episodes in real-life prophylactic use,” he wrote. “It is also not clear 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.”
Where this product will fit into existing therapies remains to be seen, although it may become a competitor for emicizumab, Mannucci wrote.
“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.
References:
- Konkle B, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2002699.
- Mannucci PM. N Engl J Med. 2020;doi:10.1056/NEJMe2024545.
For more information:
Barbara Konkle, MD, can be reached at barbarak@bloodworksnw.org.
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