Single-dose BIVV001 Appears Safe, Effective for Men with Severe Hemophilia A

A phase 1-2a open-label trial published in The New England Journal of Medicine found that in men with severe hemophilia A, single-dose BIVV001 (rFVIIIFc-VWF-XTEN) elicited no safety concerns.

Moreover, the small, early phase study found that high levels of sustained factor VIII activity, which followed a normalization period after BIVV001 administration, might possibly offer better protection against all types of bleeding and a longer interval between administration of the product in this patient population.

“Therapeutic goals for the treatment of hemophilia are expanding beyond a reduction in the annualized bleeding rate to include maintenance of joint health and improved quality of life for adults and children in all clinical situations,” the authors explained. “Accordingly, the prophylactic targets are being reevaluated as data have emerged that sustained factor VIII levels of more than the established standard of care (≥1%) are required to prevent all nontraumatic bleeding.”

In this study, 16 previously treated men between the ages of 18 and 65 with severe hemophilia A (factor VIII activity, <1%) were consecutively assigned to receive a single intravenous (IV) injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight or 65 IU per kilogram. This was followed by a washout period of at least 3 days. Patients then received a single IV injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram.

Overall, no inhibitors to factor VIII were identified and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. Following the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggests the potential of a weekly interval between treatments.

Notably, the geometric mean half-life of BIVV001 was 3 to 4 times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group). Further, the area under the curve (AUC) for product exposure was 6 to 7 times as great in the 2 dose groups (4470 hours vs. 638 hours x IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours x IU per deciliter in the higher-dose group).

Throughout the receipt of recombinant factor VIII, the most common adverse event (AE) observed was an asymptomatic increase in the level of thrombin–antithrombin III complex (in 2 patients, 1 in each group). These 2 events were found to be related to treatment, as was an increased fibrin d-dimer level in 1 of these patients; however, no associated clinical sequelae were reported in either patient.

Eighteen AEs were reported in 9 patients during the BIVV001 treatment period. These events included a serious AE of a small-intestinal obstruction, which was attributed to complications from a prior appendectomy. Moreover, the most common AEs during the BIVV001 treatment period were an asymptomatic increase in the level of thrombin–antithrombin III complex and headache (in 2 patients each, 1 in each group). Of these events, the increased levels of thrombin–antithrombin III complex, which were reported in the same 2 patients who had these AEs during the receipt of recombinant factor VIII, were deemed to be related to BIVV001, as was the increased level of fibrin d-dimer. Again, no associated clinical sequelae were reported.

“The higher number of adverse events reported after BIVV001 treatment than after recombinant factor VIII treatment (18 events vs. 8 events) can probably be attributed, at least in part, to the longer duration of the safety observation period for BIVV001 (28 days vs. 3 or 4 days),” the authors noted. “The frequency and type of adverse events during BIVV001 treatment were similar in the low-dose and high-dose groups, and most events were assessed as being unrelated to the study product.”

Moving forward, the efficacy and safety of BIVV001 as a factor VIII replacement product, including the risk of inhibitor development, are being evaluated further in a phase 3 trial (NCT04161495) involving patients with severe hemophilia A who were previously treated. In addition, future evaluation of BIVV001 in previously untreated patients is anticipated, according to the researchers.

Reference:

Konkle BA, Shapiro AD, Quon DV, et al. BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. The New England Journal of Medicine. doi: 10.1056/NEJMoa2002699