VWF-FVIII Complex for Extravascular Hemophilia Treatment

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Solution Overview

Problem

Current treatments for hemophilia A and von Willebrand disease require frequent intravenous infusions of Factor VIII and von Willebrand Factor (VWF) concentrates, which are cumbersome, painful, and associated with risks of infection and scar formation, and exhibit low bioavailability when administered extravascularly due to the large and labile nature of these molecules.

Innovation Solution

A pharmaceutical composition suitable for extravascular administration comprising VWF in combination with FVIII, with a VWF:Ag to FVIII activity ratio greater than 2:1, which enhances the plasma levels and bioavailability of FVIII, allowing for prolonged activity and reduced immune responses, thereby facilitating subcutaneous, intramuscular, or intradermal administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If FVIII and VWF concentrates are administered intravenously, then therapeutic effect is achieved, but treatment is cumbersome and associated with infection risks and scar formation

Engineering Contradiction:

Improvetherapeutic effectVSAvoidtreatment convenience

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

VWF acts as a stabilizing intermediary for FVIII, protecting it from degradation and enabling extravascular administration. The patent utilizes the natural stabilizing interaction between VWF and FVIII to allow subcutaneous or intramuscular injection, thereby avoiding repeated intravenous access while maintaining therapeutic efficacy.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the administration route parameter from intravenous to extravascular (subcutaneous or intramuscular) by optimizing the FVIII:VWF ratio and formulation conditions, transforming a therapy that requires invasive venous access into one that can be administered via simpler routes.

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If FVIII is administered extravascularly alone, then administration route is simplified, but bioavailability is low due to large and labile nature of the molecule

Engineering Contradiction:

Improveadministration routeVSAvoidbioavailability

Core Design Contradiction:

Ease of operationVSQuantity of substance

Solution Approach 1:

VWF serves as a protective intermediary that binds to FVIII and shields it from degradation in the extravascular environment. This stabilization allows FVIII to survive the journey from subcutaneous or intramuscular injection site into circulation, dramatically improving bioavailability compared to administering FVIII alone.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent creates a composite preparation containing both FVIII and VWF in specific ratios. This composite formulation leverages the stabilizing properties of VWF to protect the labile FVIII molecule, enabling successful extravascular administration that would fail with FVIII alone.

Inventive Principle:

Principle #40Composite materials

3Productivity

If FVIII is administered extravascularly, then frequency of administration can be reduced, but immune responses and inhibitory antibody generation increase

Engineering Contradiction:

Improveadministration frequencyVSAvoidinhibitory antibodies

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

VWF acts as a protective intermediary that not only stabilizes FVIII but also modulates the immune response. By binding to FVIII and presenting it in a protected complex, VWF reduces the immunogenicity of FVIII when administered extravascularly, decreasing the generation of inhibitory antibodies that would otherwise neutralize the therapeutic effect.

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The composition significantly increases the bioavailability and duration of FVIII activity in plasma, reduces the frequency of administration, and minimizes the generation of inhibitory antibodies, providing a more convenient and effective treatment option for hemophilia A and von Willebrand disease.

Implementation Method 1

VWF is known to stabilize FVIII in vivo and, thus, plays a crucial role to regulate plasma levels of FVIII

Methodology Applied

Scientific EffectProtein stabilization:

Implementation Method 2

VWF serves as a carrier and stabilizing protein for procoagulant FVIII

Methodology Applied

Scientific EffectCarrier-mediated transport:

Implementation Method 3

a pharmaceutical composition suitable for extravascular administration comprising VWF in combination with FVIII, with a VWF:Ag to FVIII activity ratio greater than 2:1, which enhances the plasma levels and bioavailability of FVIII

Methodology Applied

Scientific EffectProtein-protein interaction:

Data Source

PatentUS9107902B2Use of VWF stabilized FVIII preparations and of VWF preparations without FVIII for extravascular administration in the therapy and prophylactic treatment of bleeding disorders

Publication Date: 2015.08.18 CSL BEHRING GMBH

AI summary

The present invention relates to the use of von Willebrand Factor (VWF) preparations or of a VWF preparation in combination with coagulation Factor VIII (FVIII) for extravascular administration in the therapy and prophylactic treatment of bleeding disorders.