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Engineered protein safely, effectively controls bleeding in severe von Willebrand's disease

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August 6, 2015

Recombinant von Willebrand’s factor appeared safe and effective for the treatment of bleeding episodes in patients with severe von Willebrand’s disease, according to the results of a phase 3 study.

Recombinant von Willebrand’s factor stabilized endogenous factor VIII (FVIII) levels, which may eliminate the need for engineered FVIII (rFVIII) after the initial infusion.

Patients with von Willebrand’s disease lack a sufficient quality of fully functioning von Willebrand’s factor — a protein that stops bleeding when a blood vessel becomes damaged — and often experience excessive, hard-to-treat bleeding.

Standard treatment for severe von Willebrand’s disease consists of an infusion of purified von Willebrand’s factor, which circulates in combination with FVIII. Although this approach is usually effective, the purification of von Willebrand’s factor from plasma can potentially introduce patients to blood-borne contaminants, according to the researchers.

Bruce Ewenstein, MD, PhD, vice president of clinical affairs at Baxalta in Cambridge, Massachusetts, and colleagues, thus, sought to evaluate whether a highly active, recombinant von Willebrand’s factor (BAX 111, Baxalta) would safety and effectively treat the disease without the disadvantages of blood-derived products.

The analysis included 37 patients (median age, 37 years; 54.1% female) with type 3 (n = 29) or severe type 1 (n = 2), 2A (n = 5) or 2N (n =1) disease.

Researchers assigned patients to one of four arms composed of recombinant von Willebrand’s factor (50 IU/kg or 80 IU/kg) with or without rFVIII (Advate, Baxalta). Most patients also received as-needed treatment with recombinant von Willebrand’s factor of 40 IU/kg to 60 IU/kg for regular bleeding episodes and up to 80 IU/kg for major bleeds.

In total, 22 patients experienced 192 bleeding episodes (minor bleeds, n = 122; moderate bleeds, n = 61; major bleeds, n = 7).

A single infusion proved effective for 81.8% of bleeding episodes.

Using a 4-point scale (1 = excellent; 4 = no response), the researchers rated 96.9% of bleed control as excellent (minor bleeds, 119/122; moderate, 59/61; major, 6/7). Further, 100% of patients achieved treatment success, defined as a mean efficacy rating of less than 2.5.

Plasma concentrations of recombinant von Willebrand’s factor increased rapidly after a single infusion of 50 IU/kg, when administered with or without rFVIII.

Recombinant von Willebrand’s factor administered alone induced substantial stabilization of endogenous FVIII. Median FVIII levels increased more than 40% 6 hours post-infusion to a peak of 86 U/dL 24 hours post-infusion. These levels were sustained through 72 hours post-infusion, which suggests these patients are unlikely to require additional rFVIII infusions.

Eight adverse events occurred, including two serious adverse events — chest discomfort and increased heart rate without cardiac symptomatology — that occurred concurrently in one patient. However, no thrombotic events or severe allergic reactions occurred.

The researchers did not detect the development of any von Willebrand’s factor or FVIII inhibitors, anti-von Willebrand’s factor–binding antibodies or antibodies against host-cell proteins.

“These efficacy and safety data of [recombinant von Willebrand’s factor] represent a major advance in our quest to develop an optimal treatment for people living with [von Willebrand’s disease],” Ewenstein said in a press release. “As this product is specifically designed to be administered without FVIII, it will allow physicians to dose [von Willebrand’s disease] 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’s disease].” – by Cameron Kelsall

Disclosure: Baxalta provided funding for this study. Ewenstein reports an employment role with Baxalta. Please see the full study for a list of all other researchers’ relevant financial disclosures.

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George M. Rodgers

George M. Rodgers

There are currently three approved plasma-derived Factor VIII/ von Willebrand’s factor (vWf) products for treating patients with von Willebrand’s disease. Gill and colleagues report results of a clinical trial with a recombinant vWf in patients with nonsurgical, severe von Willebrand’s disease. The recombinant vWf product demonstrated good safety and efficacy in treating bleeding episodes, similar to results seen with the plasma-derived products. An advantage of the recombinant vWf product is the potential for eliminating all blood-borne pathogen risk. Disadvantages may include cost and the necessity for using concomitant initial Factor VIII therapy. Data with recombinant vWf in treating surgical patients with von Willebrand’s disease is eagerly awaited.

George M. Rodgers, MD, PhD
University of Utah Health Sciences Center

Disclosure: Rodgers reports no relevant financial disclosures.