ISTH 2025 – emerging therapies in haemophilia and VWD

ASHLEY FLETCHER

Ashley Fletcher is the AHCDO Australian Bleeding Disorders Registry (ABDR) Senior Research Fellow.

The International Society on Thrombosis and Haemostasis (ISTH) 2025 Congress, held in Washington D.C. in June 2025, brought together leading experts, researchers, and clinicians to share the latest advances in bleeding and clotting disorders.

This summary highlights emerging therapies in haemophilia and von Willebrand disease (VWD), focusing on innovative treatments that aim to improve patient outcomes and quality of life.

These therapies are currently being tested in clinical trials and are not available yet.

Treatments for bleeding disorders are evolving rapidly and researchers are always looking for new ways to advance treatment.

If you have a bleeding disorder, it’s important that you stay in touch with your HTC and discuss your treatment options regularly to determine what would best suit you and your situation and if new options are available.

WHAT ARE CLINICAL TRIAL PHASES?

Phase 1 is a very early stage clinical trial.

• Testing a new treatment in a small group of people
• Testing safety and possible side effects.

Phase 2 is the next stage.

• Testing a new treatment in a larger group of people
• Testing ‘efficacy’ – does it work as intended
• Evaluating safety in the larger group.

Phase 3 is an advanced clinical trial.

• Testing a new treatment in large groups – hundreds to thousands of people
• Comparing the treatment to other treatments
• Monitoring side effects and safety information.

Phase 4 is a ‘real world’ study.

• Monitoring what happens when the treatment is prescribed for the wider population with the condition
• Monitoring side effects over a longer period of time
• May test the treatment for another health condition or in combination with another treatment.¹

WHAT DOES IT MEAN?

anti-TFPI (Tissue Factor Pathway Inhibitors)	proteins that block TFPI, an anti-clotting protein, and increase how much thrombin the body makes, which then increases clotting
bispecific antibodies	connect two clotting factor proteins at once, helping clotting to occur
mimetic	imitating the function of a clotting factor, eg factor VIII (8)
monoclonal antibodies	laboratory made proteins that imitate human antibodies in the immune system
monovalent antibodies	bind only to one site
oral	by mouth
prophylaxis therapy	treatment administered regularly to prevent bleeds
small interfering RNAs (siRNAs)	treatments that ‘silence’ the clotting protein antithrombin, which then allows thrombin production to increase and help with clotting
subcutaneous	under the skin
thrombin	a protein that helps with clotting

Reference
1.Australian Government. Australian Clinical Trials. What is a clinical trial? 8 November 2023.

Information in blue above provided by Haemophilia Foundation Australia, September 2025

KEY THERAPIES BY CLASS

Haemophilia

Inno8
The first oral bispecific antibody1
For: haemophilia A
How it works: oral FVIIIa (factor 8a)-mimetic bispecific antibody (imitating FVIIIa). Bridges FIXa (factor 9a) and FX (factor 10)
Status: Phase 1 (VOYAGER1; NCT06649630) – in humans
Key points: Delivered orally using an absorption enhancer.High potency. Half-life is approx. 113 hrs (albumin binding).Potentially a daily tablet.
Significance: Very early days but potentially the first oral prophylaxis therapy for haemophilia A.

NXT007
Next generation emicizumab-like bispecific antibody2
For: haemophilia A (with or without inhibitors)
How it works: Bispecific antibody with enhanced FVIIIa (8a)-mimetic activity (imitating FVIIIa)
Status: Phase 2
Key points: It’s built to do the same job as emicizumabQuite potent.Maintains steady normal FVIII (factor 8)-equivalent levels.Subcutaneous dosing every 4 weeks or longer.
Significance: Improved bleed protection with extended length of time between doses.

Mim8
Potent next generation FVIII (factor 8)-mimetic3
For: haemophilia A with or without inhibitors
How it works: subcutaneous FVIII-mimetic bispecific antibody (imitating FVIII)
Status: Phase 3 (FRONTIER 2)
Key points: It works for people who have never had haemophilia treatment before and for those changing over from emicizumab.Very good at generating thrombin.Dose is weekly or less.
Significance: a new bispecific agent.

Concizumab
Anti-TFPI (Tissue Factor Pathway Inhibitor) rebalancing therapy4
For: haemophilia A and B with or without inhibitors
How it works: subcutaneous monoclonal antibody inhibiting TFPI and enabling more thrombin to be produced to help clotting.
Status: Phase 3 (explorer8 – in extension phase until 2028)
Key points: Significantly reduces the number of bleeds in a year. Effective in patients with target joints. Can be stored at room temperature for 28 days.
Significance: non-factor therapy option for a broad haemophilia population

Fitusiran
small interfering RNA (siRNA)-based antithrombin suppression5
For: haemophilia A and B with or without inhibitors
How it works: it’s a type of genetic medicine that tells the liver to make less of a natural clot-blocking protein (antithrombin), so blood can clot more easily.
Status: Phase 3 (ATLAS studies)
Key points: Monthly subcutaneous injection. Bleed rates reduced across all populations. Can be given at a lower dose, improving the safety profile. Can be stored at room temperature for 3 months.
Significance: Durable, long-acting prophylaxis; a long-lasting preventative treatment that’s showing a good balance between benefits and side effects.

Altuviiio (efanesoctocog alfa)
Extended Half-Life (EHL) FVIII (factor 8)6,7
For: haemophilia A
How it works: it’s a lab-made clotting protein that’s been modified with special attachments so it stays in the body longer, meaning fewer infusions are needed.
Status: XTEND-ed Study Phase 3 trial and approved in the USA (FDA 2023); new real-world data presented at ISTH 2025.
Key points: Once-weekly intravenous dosing. The drug keeps clotting factor levels much higher than the usual low point between doses, giving stronger ongoing protection from bleeding. Excellent bleed protection in adults and children.
Significance: good EHL-FVIII product; strong real-world uptake

Von Willebrand disease (VWD)

HMB-002
monovalent antibody,8,9
For: von Willebrand disease (VWD) – all types
How it works: prophylaxis therapy designed to increase and extend the half-life of von Willebrand factor (VWF) in the bloodstream.
Status: early clinical Proof-of-Mechanism data presented (does it work in the human body as it is meant to); ongoing development.
Key points: A therapy that is first in its class aimed at sustained elevation of VWF levels. Potential to provide longer-lasting protection against bleeds for patients.
Significance: offers promise for improved bleeding control with less frequent dosing, enhancing patient quality of life.

VGA039
monoclonal antibody10
For: von Willebrand disease (VWD)
How it works: targets Protein S, a crucial cofactor in coagulation, enhancing thrombin generation
Status: A large Phase 3 trial will begin in late 2025 to confirm how well it works and how safe it is in people with VWD.
Key points: Current treatments for VWD often require frequent IV (intravenous) infusions. VGA039 could become the first simple, under-the-skin option for routine prevention of bleeding.
Significance: This could greatly improve convenience, quality of life, and treatment consistency for people living with VWD.

Advanced diagnostic tools for VWD11,12

For: diagnostic evaluation and management of von Willebrand disease

How it works: new assays (laboratory tests) measuring platelet binding activity of VWF to improve the classification of VWD subtypes and the assessment of severity.

Status: emerging diagnostic tools undergoing evaluation and validation.

Key points: Enhanced ability to characterize VWD more accurately. Supports personalised treatment decisions.

Significance: Improves diagnosis and guides tailored therapies, potentially optimising outcomes for patients.

FINAL TAKEAWAYS

• haemophilia A is experiencing rapid therapeutic expansion: oral (Inno8), next-generation bispecifics (Mim8, NXT007), siRNA (Fitusiran), gene therapy, and weekly factor therapy (Altuviiio) are all viable and increasingly personalised.
• haemophilia B has reliable gene therapy and broader non-factor options like concizumab and fitusiran.
• von Willebrand disease has emerging therapies focussing on extending treatment durability, improving bleeding control, and enhancing diagnostic precision offering hope for more effective, personalised care for patients.

These innovative therapies represent important progress in reducing treatment burdens and enhancing quality of life for people living with haemophilia and von Willebrand disease. As research continues to evolve, collaboration with healthcare professionals remains essential to tailor these advances to individual patient needs and ensure the best outcomes.

REFERENCES

1. Lund J, Jensen K, Ezban M. In vitro activity of Inno8 in global hemostatic assays alone and with other hemostatic agents. [abstract OC39.5] ISTH 2025 Congress, 21-25 June 2025, Washington.
2. Shima M, You C-W, Park Y-S, et al. NXT007 prophylaxis in emicizumab-naive persons with hemophilia A without inhibitor: phase I/II study. [abstract OC20.3] ISTH 2025 Congress, 21-25 June 2025, Washington.
3. Oldenburg J, Benson G, Chowdary P, et al. FRONTIER5 direct switch study: safety of initiating Mim8 prophylaxis without washout of emicizumab. [abstract OC20.4] ISTH 2025 Congress, 21-25 June 2025, Washington.
4. Wheeler A, Angchaisuksiri P, Apte S, et al. Annualized bleeding rates in hemophilia A/B and target joints: concizumab Explorer8 study. [abstract OC59.2] ISTH 2025 Congress, 21-25 June 2025, Washington.
5. Young G, Kavakli K, Shen M-C, et al. Association of antithrombin levels with efficacy of fitusiran prophylaxis in people with hemophilia A or B with and without inhibitors: a predictive modeling approach. [abstract OC59.3] ISTH 2025 Congress, 21-25 June 2025, Washington DC.
6. Malec L, Königs C, Dunn A, et al. Treatment of bleeding episodes with efanesoctocog alfa in children: XTEND-ed second interim analysis. [abstract OC20.5] ISTH 2025 Congress, 21-25 June 2025, Washington DC.
7. Khoo L, Klamroth R, von Drygalski A, et al. Major surgical outcomes with efanesoctocog alfa: 4 years’ experience in the XTEND clinical program. [abstract OC64.4] ISTH 2025 Congress, 21-25 June 2025, Washington DC.
8. Raheja P, Tsiamita O, Knott A, et al. VELORA Pioneer: first-in-human safety and PK/PD study of HMB-002 in Type 1 Von Willebrand disease. [abstract LB 01.4] ISTH 2025 Congress, 21-25 June 2025, Washington DC.
9. Haeger M, Zivkovic M, Gandhi PS, et al. HMB-002: elevating von Willebrand Factor for prophylactic treatment of Von Willebrand Disease. [abstract OC 08.4] ISTH 2025 Congress, 21-25 June 2025, Washington DC.
10. Moser M, Leong L, Kovacevic-Miljevic K, et al. The anti-Protein S antibody VGA039 enhances ex vivo coagulation as assessed by thromboelastometry. [abstract PB0111] ISTH 2025 Congress, 21-25 June 2025, Washington DC.
11. Miller AP, Smith J, Lee K, et al. Furthering understanding of VWF copy number variants in patients with von Willebrand disease. [abstract OC28.3] ISTH 2025 Congress, 21-25 June 2025, Washington DC.
12. Christopherson P, Nguyen T, Patel R, et al. The value of VWF platelet- and factor VIII-binding assays versus genetic testing in diagnosing type 2 von Willebrand disease. [abstract OC 56.3] ISTH 2025 Congress, 21-25 June 2025, Washington DC.