A New Treatment Option for Patients with Severe von Willebrand Disease?

Treatment options to limit the risk of life-threatening bleeds associated with severe von Willebrand disease (vWD), a condition caused by a deficiency in or impairment of the blood-clotting protein von Willebrand factor (vWF), are limited, but a study published in Blood shows safe and promising results with a new recombinant vWF product.

Effective treatment requires correction of the dual defect of hemostasis associated with vWD, Joan C. Gill, MD, of the Blood Center of Wisconsin and Medical College of Wisconsin in Milwaukee, and colleagues explained, including abnormal platelet adhesion and aggregation and defective secondary hemostasis. In the phase III, prospective, randomized, single-blind, crossover trial, they evaluated the safety and efficacy of recombinant (r)vWF. Human vWF produced by recombinant technology has the potential of overcoming the limitations associated with plasma-derived vWF concentrates – including the theoretical risk of pathogen transmission, limits of plasma donor availability, and the varying composition of the source plasma.

"[This] represents the most significant advancement for the treatment of people living with vWD in two decades," Dr. Gill told ASH Clinical News. "[This treatment] is specifically designed to be a pure vWF product without factor VIII (FVIII), allowing physicians and patients to dose vWF and FVIII independently to the precise levels needed, based on the individual patients' requirements and disease type, while avoiding the risk of FVIII accumulation."

Patients 18 to 65 years old with type 3 or severe type 1 and type 2A, type 2B, type 2N, type 2M, or type 3 vWD were included in this phase III trial. Patients were excluded if they had a history of vWF or FVIII inhibitors, immunologic disorders, or thromboembolic events. A total of 49 patients, all of whom had been treated for at least one bleed with a vWF concentrate within 12 months prior to enrollment, were evaluated.

Bleeding episodes were to be treated with an initial infusion of 40 to 60 IU/kg rvWF for minor to moderate bleeds (such as epistaxis, oral bleeding, and menorrhagia), and up to 80 IU/kg for major bleeds (including severe or refractory epistaxis or menorrhagia, gastrointestinal bleeding, central nervous system trauma, hemarthrosis, or post-traumatic hemorrhage). The initial dose of rvWF was administered together with rFVIII and subsequently alone, so long as hemostatic FVIII concentrate levels were maintained. Treatment of each bleed was rated by a predefined four-point scale based on the number of rvWF infusions administered to control the bleed versus the treating physician's estimated number of infusions required.

Subjects were enrolled into one of four treatment arms:

• 50 IU/kg rvWF:rFVIII or rvWF:placebo (crossover) only
• 50 IU/kg rvWF:rFVIII or rvWF:placebo (crossover), followed by 12 months of on-demand bleed treatment
• 80 IU/kg rvWF repeated after 6 months (for pharmacokinetic assessment), followed by 6 months of on-demand bleed treatment
• On-demand treatment of bleeding episodes for 12 months

To determine the extent of bleeding control (the study's primary endpoint), investigators rated hemostatic efficacy on a scale of 1 to 4 (excellent=1, none=4), with a lower score indicating fewer treatment infusions were needed to control the bleed. Secondary endpoints included the number of treated bleeding episodes with a hemostatic efficacy rating of excellent or good, and the number of infusions and units of rvWF/rFVIII or rvWF to control a bleed.

A total of 49 patients were enrolled and assessed for eligibility, and 37 patients (median age=37 years) were exposed to rvWF during the study, of whom 22 experienced at least one bleeding episode that was treated with rvWF.

A total of 192 bleeding episodes treated with rvWF were assessed for hemostatic efficacy:

• 122 minor
• 61 moderate
• 7 major/severe
• 2 unknown severity

Most of the bleeds were mucosal (55.2%; n=106), followed by joint bleeds (30.7%; n=59), episodes in other sites (19.3%; n=37), and gastrointestinal bleeds (3.1%; n=6). All bleeds were treated successfully, with an overall treatment rate of 100 percent (95% CI 87.3-100.0). In addition, hemostatic efficacy in all bleeding episodes was rated as "excellent" (96.9%) or "good" (3.1%). See TABLE for a summary of bleeding episodes.

The median dose of rvWF and rFVIII administered per bleed was 46.5 IU/kg and 33.6 IU/kg, respectively, and the majority of the bleeding events were adequately treated by one infusion (81.8%).

In the pharmacokinetic analysis, the profile of rvWF was not influenced by rFVIII, with FVIII concentrate levels increasing rapidly after rvWF alone. rvWF also provided a longer half-life than plasma-derived vWF products.

Hemostatic levels were quickly achieved (within 6 hours) and were sustained through 72 hours post-infusion. The sustained stabilization of endogenous FVIII "has the potential to obviate the need for rFVIII after the first infusion when additional infusions are required," the authors noted.

A total of 125 adverse events (AEs) were observed during the study, with eight AEs (6.4%) considered to have a causal relationship to rvWF, including tachycardia, infusion site paresthesia, chest discomfort, generalized pruritus, hot flush, dysgeusia, heart rate increase, and electrocardiogram T wave inversions. Six of the eight AEs were not considered serious.

The low number of patients with severe, non-type 3 vWD is a potential limitation of the study, the authors added, with only two patients with type 1 and six patients with type 2 vWD.

"The study showed that this product is safe and effective for treating bleeding in patients with severe forms of von Willebrand disease," Dr. Gill said. "Although the number of severe bleeding episodes treated in the study were limited, the patients responded to treatment, giving us positive results and an indication to move forward with surgical and other studies."

Reference

Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. August 3, 2015. [Epub ahead of print].