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THE SEARCHLIGHT MESSENGER

Von Willebrand Disease Phase 3 Trial Reports 100% Bleed Control

Von Willebrand disease (VWD) is an inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of the protein called Von Willebrand factor (VWF). This protein is a necessary step in the coagulation cascade, but also involved in the initiation of platelet aggregation for proper blood clotting.

Consequently, defective VWF interaction between platelets and the vessel wall impairs primary hemostasis. Von Willibrand factor circulates in blood plasma at concentrations of approximately 10 mg/mL. In response to numerous stimuli, VWF is released from storage granules in platelets and vascular bed endothelial cells.

VWF performs two major roles in hemostasis, wether intrinsic or extrinsic. First, it mediates the adhesion of platelets to sites of vascular injury. Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII).

The disease is divided into three major categories: Partial Quantitative Deficiency (type I), Qualitative Deficiency (type II), and Total Deficiency (type III). VWD type II is further divided into four variant conditions (IIA, IIB, IIN, IIM), based on characteristics of dysfunctional VWF.

According to data pre-published online August 3rd, 2015, in Blood, successful management of bleeding episodes were observed in 100% of subjects treated with BAX 111 for von Willebrand disease (VWD) during a recently completed Phase 3 clinical trial.

Bleeding-episode-management success was the primary endpoint of the clinical trial.
BAX 111 is a highly purified recombinant von Willebrand factor (VWF) analog manufactured by Baxalta, Inc.
VWD is a rare, inherited, incurable, gene-based bleeding disorder in which a missing or defective clotting protein (VWF) fails to bind with platelets in blood vessel walls.

Normally, a blood-vessel tear initiates bleeding and  VWF assists in the repair. When VWF is absent or under-represented, the formation of platelet plugs are inhibited during the clotting process, resulting in excessive bleeding and easy bruising.

In more severe forms of VWD, the bleeding can be life-threatening and require emergency treatment.

Efficacy and Safety of BAX 111

Gill et al derived their findings from a Phase 3, multicenter, international, open-label study which evaluated the safety, efficacy and pharmacokinetics of BAX 111 in 37 patients with severe VWD.
Study participants evidenced a mean efficacy rating of < 2.5 on a 4-point scale wherein lower numbers correlated with a higher degree of bleed control (see sidebar below). Bleed control for all treated bleeding events (N=192 bleeds in 22 subjects) was rated as good or excellent (96.9% excellent; 119/122 minor, 59/61 moderate, and 6/7 major bleeds). In 81.8% of bleeds, 1 infusion was sufficient to attain control. For major bleeds, the infusion median was

Sidebar: Hemostatic Efficiency Rating Scale

1 (Excellent)
 
• Minor and Moderate Bleeding Events
o Actual number of infusion less than or equal to estimated number of infusion required to treat that bleeding episode. No additional VWF-containing/coagulation factor containing product required.
• Major Bleeding Events
o Actual number of infusion less than or equal to estimated number of infusion required to treat that bleeding episode. No additional VWF-containing/coagulation factor containing product required.

2 (Good)

• Minor and Moderate Bleeding Events
o 1 to 2 infusions greater than estimated required to control that bleeding episode. No additional VWF-containing/coagulation factor containing product required.
• Major Bleeding Events
o Less than 1.5x greater than estimated required to control that bleeding episode. No additional VWF-containing/coagulation factor containing product required.

3 (Moderate)

• Minor and Moderate Bleeding Events
o 3 or more infusions greater than estimated used to control that bleeding event. No additional VWF-containing/coagulation factor containing product required.
• Major Bleeding Events
o Greater than or equal to 1.5x greater than estimated used to control that bleeding event. No additional VWF-containing/coagulation factor containing product required.

4 (None)

• Minor and Moderate Bleeding Events
o Severe uncontrolled bleeding or intensity of bleeding not changed. Additional VWF-containing/coagulation factor containing product required.
• Major Bleeding Events
o Severe uncontrolled bleeding or intensity of bleeding not changed. Additional VWF-containing/coagulation factor containing product required.References:
 
Safety and tolerability outcomes - evaluated via clinical assessments of adverse events, hematology panels, coagulation panels, serum chemistry, urinalysis, viral serology and immunological assessments - were also encouraging. With the exception of 1 patient, adverse events were minor or unrelated to treatment. No thrombotic events or severe allergic reactions occurred, and none of the participants developed anti-VWF binding or neutralizing antibodies to VWF.

Researchers concluded that the data offer evidence that BAX 111 is “safe and hemostatically effective in severe VWD patients in a variety of clinical bleeding presentations.”

Addressing a Pressing Therapeutic Need

“Von Willebrand disease is the most common hereditary bleeding disorder, yet few treatment options exist,” noted John Orloff, MD, Head of Research & Development and Chief Scientific Officer, Baxalta. BAX 111, Dr. Orloff asserted, “has the potential to transform the standard of care for patients with severe von Willebrand disease by offering an effective, individualized treatment option.”

Both the FDA and the European Medicines Agency granted orphan drug designation to BAX 111 back in November 2010.2 Currently, BAX 111 remains under FDA review, a pending Biologics License Application having been filed in December 2014.5 While no official Prescription Drug User Fee Act (PDUFA) date has been set, December 22, 2015, has been cited by industry insiders as a speculative estimation.

The PDUFA date is an FDA approval deadline for new drugs. If approved, BAX 111 would become the first recombinant replacement treatment indicated for the management of VWD-related bleeding episodes.

References
  1. 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 2015. DOI 10.1182/blood-2015-02-629873. http://www.bloodjournal.org/content/bloodjournal/early/2015/08/03/blood-2015-02-629873.full.pdf?sso-checked=true Advance copy pre-published online August 3, 2015. Accessed online August 4, 2015.
  2. Blood Publishes Phase III Data on Baxalta’s Investigational Treatment for Von Willebrand Disease, the Most Common Type of Inherited Bleeding Disorder [press release]. Deerfield, Illinois. Baxalta Incorporated August 3, 2015. http://www.businesswire.com/news/home/20150803005068/en/Blood-Publishes-Phase-III-Data-Baxalta%E2%80%99s-Investigational#.VcCXYfmUf4Z
  3. National Hemophilia Foundation website. von Willebrand Disease. https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Von-Willebrand-Disease Accessed August 4, 2015.
  4. National Heart, Lung and Blood Institute. What is von Willebrand Disease? http://www.nhlbi.nih.gov/health/health-topics/topics/vwd Updated June 1, 2011. Accessed August 4, 2015.
  5. Burden A. Large cap PDUFA dates have been added to BioPharmCatalyst. http://www.biopharmcatalyst.com/2015/01/large-cap-pdufa-dates-have-been-now-added-to-biopharmcatalyst-20-in-total-today/  BioPharmCatalyst. Published January 26, 2015. Accessed August 4, 2015.




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