Results of a phase 3 trial suggest the recombinant von Willebrand factor (rvWF) product BAX 111 can safely control bleeding in patients with severe von Willebrand disease (vWD).
BAX 111, given with or without recombinant factor VIII (rFVIII), controlled bleeding episodes in 100% of patients treated.
None of the patients developed vWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins.
There were 8 adverse events (AEs) associated with BAX 111, 2 of which were serious.
Investigators reported these results in Blood. The trial was sponsored by Baxalta, Inc., the company developing BAX 111.
Compared to other marketed vWF concentrates, BAX 111 contains a more consistent concentration of ultra-large-molecular-weight multimers. And the product is developed using a plasma- and albumin-free manufacturing method.
For the phase 3 trial, investigators set out to test BAX 111 in 49 patients who had received vWF concentrate treatment for at least 1 severe vWD-related bleed within the last 12 months. The patients’ median age was 37 (range, 18 to 64), and there were slightly more females (54.1%) than males (45.9%).
To observe BAX 111’s activity at varying doses and in different treatment scenarios, the investigators administered BAX 111 at 50 IU/kg or 80 IU/kg either alone or with rFVIII.
The majority of patients received as-needed treatment of BAX 111 at 40-60 IU/kg for regular bleeding episodes and up to 80 IU/kg for major bleeds. About 32% of treated subjects (7/22) also received an antifibrinolytic agent, such as tranexamic acid, during bleeding episodes.
In all, 22 patients experienced at least 1 bleeding episode that was treated with BAX 111. Seventeen of these patients had type 3 vWD, 4 had type 2A, and 1 had type 2N.
The investigators assessed 192 bleeding episodes treated with BAX 111 for hemostatic efficacy. Most bleeds (n=122) were minor, 61 were moderate, 7 were major/severe, and 2 were of unknown severity.
Efficacy
All 192 bleeds were treated successfully. When vWD specialists rated BAX 111’s ability to control bleeds on a scale of “excellent” to “no response,” they rated BAX 111 as “excellent” (96.9%) or “good” (3.1%).
One infusion of BAX 111 was sufficient in treating most bleeds (81.8%, n=157). One mucosal bleed (occurring in the genital tract and oral cavity simultaneously) required 4 infusions, which was the maximum number of infusions administered during the study.
The median doses of BAX 111 and rFVIII administered per bleed were 46.5 IU/kg and 33.6 IU/kg, respectively.
The activity of BAX 111 remained the same whether it was given with or without rFVIII. Patients who received BAX 111 alone experienced a rapid increase in their naturally produced FVIII.
In fact, within 6 hours of an infusion, patients had produced enough of the protein for proper clotting. This response was sustained through 72 hours post-infusion, suggesting that patients who receive BAX 111 are not likely to require additional rFVIII infusions.
Safety
There were 125 AEs in this trial, but only 8 were considered related to BAX 111. Six AEs (occurring in 4 patients) were not serious. These included mild infusion site paresthesia, moderate dysgeusia, moderate tachycardia, mild ECG T-wave inversion, mild generalized pruritus, and mild hot flush.
One patient experienced 2 simultaneous serious AEs—chest discomfort and increased heart rate. The symptoms improved after 10 minutes of oxygen treatment, and the subject fully recovered within 3 hours. The subject had a history of allergic responses to cryoprecipitate and a plasma-derived vWF concentrate.
None of the patients developed anti-VWF neutralizing or binding antibodies, FVIII neutralizing antibodies, or antibodies against recombinant furin, Chinese hamster ovary host cell proteins, or murine immunoglobulin G.
There were no clinical signs of thrombotic events and no clinically significant abnormal D-dimer values post-treatment.
“These efficacy and safety data . . . represent a major advance in our quest to develop an optimal treatment for people living with vWD,” said study investigator Bruce Ewenstein, MD, PhD, of Baxalta, Inc.
“As this product is specifically designed to be administered without FVIII, it will allow physicians to dose vWF and FVIII separately and precisely based on the needs of each individual patient. This treatment strategy has the potential to become the standard of care for patients with severe von Willebrand disease.”
