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Earlier this week, Star Therapeutics’ von Willebrand disease candidate – VGA039 – was granted Fast Track designation by the U.S. Food and Drug Administration (FDA). While it is the most common inherited bleeding disorder and affects about 1% of the population, you don’t hear about von Willebrand disease every day. With Star Therapeutics’ candidate getting some recognition from the FDA, this is the opportunity to talk a bit more about what is going on in this space.
Adam Rosenthal, chief executive officer (CEO) of Star Therapeutics said research around von Willebrand disease has been relatively stagnant. “Other bleeding disorders, like hemophilia, have seen the introduction of new therapies, including subcutaneous therapies. In contrast, drug innovation for von Willebrand disease has lagged.”
So what’s currently available for von Willebrand disease patients, what are the challenges, and how biotech is aiming to address them? Let’s find out.
Table of contents
Von Willebrand disease: What is it and how is it currently treated?
Von Willebrand disease is a hereditary bleeding disorder resulting from a deficiency or dysfunction of VWF, a protein involved in the blood clotting process. VWF facilitates platelet adhesion to sites of vascular injury and stabilizes factor VIII, another essential clotting protein.
“In von Willebrand disease, patients have insufficient platelet adhesion and insufficient thrombin generation. It is a bleeding disorder where the coagulation system is out of balance and this leads to significant bleeds that affect the quality of life and some that can even be life-threatening,” explained Rosenthal.
The bleeding disorder has different degrees of gravity, type 1 and 2 being the milder forms of the condition and type 3, the most severe. Symptoms can consequently vary but include frequent nosebleeds, easy bruising, excessive bleeding following injuries or surgery, and heavy menstrual bleeding in women. In the most severe cases, individuals can experience spontaneous bleeding into joints and muscles, similar to hemophilia patients.
The inherited disease is managed with different strategies depending on the type and severity of the disorder. The primary goal remains controlling bleeding episodes.
Desmopressin is one of the standard solutions for von Willebrand disease. It is a synthetic hormone that stimulates the release of stored VWF, thereby increasing their levels in the bloodstream. It is often used in patients with type 1 and some subtypes of type 2 for minor bleeding episodes or prior to minor surgical procedures. However, its efficacy varies among individuals, and it is generally ineffective in type 3 von Willebrand disease.
For patients who do not respond to desmopressin or require more attention because of more severe bleeding, VWF replacement strategies are used. These include plasma-derived concentrates, derived from human plasma, and contain both VWF and factor VIII.
Recombinant VWF is another approach with Vonvendi being the first and only recombinant treatment approved for von Willebrand disease. This is used as an on-demand control treatment of bleeding episodes as well as a routine treatment to reduce the frequency of these episodes.
Antifibrinolytic agents such as tranexamic and aminocaproic acids are used as adjunctive therapies to prevent the breakdown of blood clots. More specifically, hormonal therapies can be useful for women suffering from the disease.
While von Willebrand patients do have options, the heterogeneity of the disorder poses a challenge to provide durable treatment. Many patients still experience a diminished quality of life as the field has been relatively stagnant in the last 30 years.
“The spectrum of von Willebrand disease is highly diverse, encompassing multiple types, each associated with distinct abnormalities in VWF protein and biology. This complexity has often discouraged drug companies from tackling the challenge, as they must navigate not only the three main types but also additional subtypes,” said Rosenthal.
Star Therapeutics and VGA039, the new wave in von Willebrand disease?
“VGA039 is a first-in-class antibody therapy with a novel mechanism of action that modulates protein S – a key component in restoring balance to the blood clotting process. By promoting thrombin generation through targeting protein S, VGA039 addresses a fundamental mechanism of clot formation in von Willebrand disease,” said Rosenthal.
A notable advantage of VGA039 is its subcutaneous administration, which contrasts with the intravenous infusions required by current von Willebrand disease prophylaxis therapies. This method has the potential to reduce the treatment burden for patients. “The current standard of care in VWD is IV infusions of factor replacement therapy two to three times a week. This high treatment burden prevents some patients from going on chronic prophylaxis,” added Rosenthal.
Interim clinical data from the VIVID 2 study presented at the American Society of Hematology (ASH) 2024 meeting demonstrated that a single subcutaneous dose of VGA039 sustained multi-week therapeutic concentrations. In patients with high baseline bleeding rates, this dosing was associated with substantial reductions in annualized bleeding rates (ABR), achieving reductions of 75% to 88%. These results are consistent with those observed in clinical trials of approved von Willebrand disease prophylactic therapies that require multiple intravenous infusions each week.
Rosenthal also thinks the company’s candidate has potential beyond von Willebrand disease. “Looking at VGA039 more broadly, while our focus has been on its potential in treating von Willebrand disease, the mechanism it targets has relevance across other bleeding disorders as well. This opens the door to exploring its utility beyond its initial focus.”
While still in the early stages of development, the recent Fast Track designation indicates that Star Therapeutics might have a new, more convenient solution for von Willebrand disease. But Star Therapeutics isn’t the only one exploring new treatments for von Willebrand disease.
Who else is developing treatments in the space?
Emicizumab is a bispecific monoclonal antibody that mimics the function of factor VIII by bridging activated factor IX and factor X, facilitating effective clot formation. Originally developed for hemophilia A by Chugai Pharmaceutical, a member of the Roche Group, its potential application in von Willebrand disease, particularly in severe cases like type 3, is under exploration. Preliminary studies have indicated that emicizumab may improve hemostasis in patients, offering a subcutaneous prophylactic option that could reduce bleeding episodes.
A 2024 ASH publication detailed the use of emicizumab in two patients with type 3 von Willebrand disease, indicating a reduction in bleeding episodes during a six-month prophylactic regimen. A clinical trial is underway for both von Willebrand and hemophilia A.
Band Therapeutics – a Guardian Therapeutics company – is also developing a candidate for the indication. BT200 is a pegylated aptamer – a short, single-stranded RNA molecule attached by a polyethylene glycol molecule to enhance stability – that binds to the A1 domain of VWF. This binding leads to a reduction in the clearance of VWF and its associated factor VIII, resulting in elevated plasma levels of both proteins. The increased levels of VWF and factor VIII enhance hemostasis, which is particularly beneficial in treating bleeding disorders.
Band Therapeutics’ BT200 is currently in multiple clinical trials for different subtypes of von Willebrand disease – it is most advanced for type 2B where it’s in phase 3 and it’s in phase 2 for type 1 and 3.
Nanotechnology could also prove to be an interesting alley for the bleeding disorder. For instance, platelet-inspired nanoparticles are designed to mimic natural platelet functions, promoting clot formation and stability. These nanoparticles could potentially offer targeted treatment options, reducing the need for frequent dosing and minimizing side effects.
More tangible perhaps, in December 2023, the FDA granted expanded approval to Octapharma’s VWF concentrate, making it the first VWF concentrate indicated for prophylactic treatment across all forms of VWD.
As new treatments advance to reach the clinic the burden on von Willebrand disease patients could become lighter in the years to come.
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