BIVV001 Safely Treats Severe Hemophilia A as Weekly Injection, Trial Reports

A single dose of BIVV001 is safe and effectively increases factor VIII (FVIII) activity over one month in men with severe hemophilia A, lasting longer in the body than the replacement therapy Advate, results from the EXTEN-A clinical trial suggest.

Gains in half-life seen with BIVV001 “could signal a new class of factor VIII replacement therapy with a weekly treatment interval,” its researchers wrote.

A larger Phase 3 trial (NCT04161495) is now enrolling up to 150 people with severe hemophilia A, ages 12 and older, at three sites in the U.S.

Trial findings were published in The New England Journal of Medicine in the study, “BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A.”

Replacement therapy for hemophilia A, caused by either a lack of or problems with the blood clotting protein FVIII,  involves administering that protein. But these therapies require frequent injection, which contributes to a less-than-optimal adherence to treatment.

BIVV001 consists of an FVIII variant fused with fragments of the proteins VWF and XTEN. This design aims to increase the medication’s half-life — the time it takes for the treatment’s levels in the blood to fall by half — and is expected to require once weekly administration as a prophylactic (preventative) treatment to  prevent bleeding episodes.

BIVV001, being developed by Bioverativ, a Sanofi company, and Sobi, was assessed in a Phase 1/2a clinical trial, EXTEN-A (NCT03205163), that enrolled 16 men with severe hemophilia A, meaning FVIII activity levels under 1%.

Patients were given a single dose of conventional recombinant therapy with Advate. That was followed, after a washout period, by either a single 25 international units (IU)/kg dose of BIVV001, or a higher 65 IU/kg dose. All  therapies were given by intravenous injection (directly into the bloodstream).

Seven patients (mean age, 33) were enrolled in the low-dose group, and nine (mean of 44 years old) in the high-dose group. One in the low-dose group withdrew prior to being given BIVV001 after a motor vehicle accident.

During treatment with Advate, eight adverse events were reported in three patients, including abnormal levels of clotting proteins, but they did not progress into clinically meaningful side effects.

In turn, 18 adverse events were reported in nine patients during treatment with BIVV001. One of these — an intestinal obstruction — was serious, but was deemed related to a prior appendectomy and not the treatment. The most common side effects were headache, and asymptomatic increases in the level of blood coagulation proteins.

According to the investigators, the higher number of adverse events after BIVV001 is probably due to the safety observation period for Advate’s use having been significantly shorter than that for BIVV001 (up to four days vs. 28 days).

BIVV001 was generally well-tolerated, with no development of inhibitors (neutralizing antibodies), allergic reactions, or clinically meaningful treatment-related adverse events during the four weeks of analysis.

“Overall, single-dose BIVV001 elicited no safety concerns,” the scientists wrote. “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.”

The mean half-life of Advate was 9.1 hours in the low-dose group and 13.2 hours in the high-dose group. BIVV001 showed a half-life about four times as long — 37.6 hours — with the low dose, and  more than three times as long — 42.5 hours — with the high dose.

Mean FVIII activity in the blood was 17% after four days and 5% after a full week in the low-dose group. In the high-dose group, FVIII activity was at least 51% after four days, and 17% after seven days. Notably, FVIII activity higher than 5% is considered mild disease.

“BIVV001 represents a potential new class of factor VIII replacement therapies. The sustained factor activity levels and three- to four-fold increase in half-life observed underscore its potential to provide near-normal bleed protection while reducing the dosing frequency of a prophylactic treatment to once a week,” Barbara A. Konkle, MD, lead study investigator and a professor at the University of Washington, said in a press release.

“These results support the conclusion that BIVV001 may be a significant advancement for patients and we look forward to exploring this further in the ongoing Phase 3 study,” Konkle added.

The ongoing Phase 3 XTEND-1 (NCT04161495) trial is further evaluating BIVV001’s safety and efficacy. Treatment with BIVV001, as a weekly prophylactic at a 50 IU/kg dose or as on-demand treatment at the same dose, will be assessed over one year. Additional information on recruiting sites is available here.

Patients completing this trial will have the option of continuing treatment in a long-term extension study of BIVV001’s safety.

BIVV001 was designated an orphan drug by the U.S. Food and Drug Administration in 2017, and by the European Commission in 2019.

In an editorial accompanying the Phase 1/2 study, Pier Mannucci, MD, of the University of Milan wrote: “The investigators provide pharmacokinetic evidence that BIVV001 attains plasma [blood] levels that are high enough to predict the prevention of most spontaneous bleeding episodes after a single intravenous infusion.

“This effect would transform severe hemophilia A into a mild disease,” Mannucci added.