Emicizumab for Von Willebrand Disease

(BCDI-XII Trial)

Overseen By Lisa Weber, BS

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Bleeding and Clotting Disorders Institute Peoria, Illinois

Must be taking: Emicizumab

Must not be taking: Investigational drugs

Disqualifiers: Other bleeding disorders, Thromboembolic disease, Autoimmune diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are currently on a prophylaxis treatment for Von Willebrand Disease or VWD/hemophilia A that is not emicizumab, you may need to stop your current treatment to participate in the trial. The protocol requires that you have not taken emicizumab in the last 18 months and are willing to discontinue your current prophylaxis.

What data supports the effectiveness of the drug Emicizumab for Von Willebrand Disease?

Emicizumab, a drug that mimics a blood clotting factor, has been shown to reduce bleeding in patients with hemophilia A, and there are reports of its off-label use in other bleeding disorders like Von Willebrand Disease. It may help improve blood clot formation in certain types of Von Willebrand Disease, similar to its effects in hemophilia A. ^{1 2 3 4 5}

Is emicizumab safe for humans?

Emicizumab has been shown to be safe in humans, as its safety has been proven in multicenter trials for hemophilia A, a different bleeding disorder. However, specific safety data for von Willebrand disease is not available. ^{1 2 6 7 8}

How is the drug emicizumab unique for treating von Willebrand disease?

Emicizumab is unique because it is a bispecific antibody that mimics the function of a natural blood clotting protein, factor VIII, by bridging two other factors (IX and X) to help blood clot, and it is administered as a subcutaneous injection, which is different from many traditional treatments that require intravenous administration. ^{1 2 3 9 10}

What is the purpose of this trial?

This trial tests Emicizumab, an injectable medication that helps blood to clot, in patients with severe Von Willebrand Disease (VWD) and those with both VWD and hemophilia A. These patients often have severe bleeding that current treatments can't easily manage. Emicizumab works by mimicking a natural blood-clotting protein to help prevent bleeding. It has been approved globally for reducing bleeding in hemophilia A patients.

Research Team

Jonathan C Roberts, MD

Principal Investigator

Bleeding and Clotting Disorders Institute

Eligibility Criteria

This trial is for individuals with severe Von Willebrand Disease (VWD) or VWD combined with Hemophilia A. Participants must be at least 2 years old, willing to adhere to the study's protocol and use emicizumab prophylaxis. They should not have used emicizumab in the past 18 months unless switching from a different prophylaxis. Menstruating participants must agree to effective contraception or abstinence.

Inclusion Criteria

I need treatment to prevent bleeding as advised by my doctor.

I have been diagnosed with severe type 3 VWD or a variant confirmed by genetic testing.

Signed informed consent

Exclusion Criteria

I haven't taken antibiotics for a serious infection in the last 30 days.

I have been treated for blood clots in the past year or have current signs of them, except for catheter-related ones.

Patients who are at high risk for thrombotic microangiopathy (TMA; e.g., have a previous medical or family history of TMA), in the investigator's judgment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Retrospective Chart Review

One-year retrospective chart review of annualized bleed rate and hemostatic therapies collected at the time of enrollment

1-2 weeks

Treatment

Participants receive emicizumab with a 3mg/kg weekly loading dose for 4 weeks, followed by once weekly prophylaxis of 1.5mg/kg for 1 year. Dose up-titration to 3 mg/kg once weekly allowed after 24 weeks if suboptimal efficacy observed.

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including collection of adverse events, hypersensitivity reactions, and thrombotic events.

6 months

Treatment Details

Interventions

• Emicizumab

Trial Overview The trial is testing Emicizumab, a monoclonal antibody designed as a preventive treatment for severe bleeding in patients with VWD and those who also have Hemophilia A. It aims to show that Emicizumab can safely replace intravenous treatments by being administered through subcutaneous injections.

Participant Groups

Group I: Open Label Emicizumab Experimental Treatment 1 Intervention

Emicizumab prophylaxis

Emicizumab is already approved in United States, European Union for the following indications:

Approved in United States as Hemlibra for:

• Hemophilia A
• Hemophilia A with inhibitors

Approved in European Union as Hemlibra for:

• Hemophilia A
• Hemophilia A with inhibitors

Who Is Running the Clinical Trial?

Bleeding and Clotting Disorders Institute Peoria, Illinois

Lead Sponsor

Trials

1

Recruited

40+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Emicizumab, a bispecific antibody that mimics factor VIII, was successfully used for 51 weeks as an off-label prophylactic treatment in a child with severe von Willebrand disease (VWD), leading to improved thrombin generation and well-tolerated therapy without adverse events.

Ex vivo analysis showed that emicizumab significantly increased thrombin generation in plasma from patients with type 3 VWD, suggesting it could provide effective hemostasis similar to healthy individuals, warranting further studies on its safety and efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential role of emicizumab prophylaxis in severe von Willebrand disease. Barg, AA., Avishai, E., Budnik, I., et al.[2021]

Emicizumab significantly shortened the activated partial thromboplastin time (APTT) in patients with severe hemophilia A after the first dose, indicating its effectiveness in improving blood clotting.

The standard one-stage APTT-based FVIII activity assay (sOSA) produced inaccurately high FVIII activity levels when using emicizumab, suggesting it should not be used for monitoring, while modified OSA (mOSA) effectively quantified emicizumab concentration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of emicizumab on APTT, one-stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors. Bowyer, A., Kitchen, S., Maclean, R.[2020]

Emicizumab enhances thrombus formation in patients with type 2A von Willebrand disease (VWD), showing a more rapid effect compared to factor VIII, which is important for patients with impaired platelet function.

The study suggests that emicizumab could serve as an alternative therapy for type 2A VWD, as its effects on thrombus formation do not rely on von Willebrand factor, which is deficient in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emicizumab improves thrombus formation of type 2A von willebrand disease under high shear condition. Yaoi, H., Shida, Y., Kitazawa, T., et al.[2021]

Emicizumab has shown effectiveness as a haemostatic therapy in patients with acquired haemophilia A (AHA) and von Willebrand disease (VWD), with all 41 patients in the review responding positively to the treatment.

Despite its efficacy, there are concerns regarding safety, as one patient experienced a stroke while on emicizumab, highlighting the need for larger clinical trials to better assess the risks and benefits of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature. Thomas, VM., Abou-Ismail, MY., Lim, MY.[2022]

Emicizumab significantly improved thrombus formation in patients with Type 2N von Willebrand disease (2NVWD), enhancing surface coverage and thrombus height, which could lead to better hemostatic management for these patients.

The study found that emicizumab's effects on thrombus formation were independent of von Willebrand factor (VWF), suggesting it could serve as an alternative therapy for 2NVWD, especially since traditional FVIII supplementation alone did not enhance thrombus formation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activated factor VIII-mimicking effect by emicizumab on thrombus formation in type 2N von Willebrand disease under high shear flow conditions. Yaoi, H., Shida, Y., Kitazawa, T., et al.[2021]

In a study of 17 elderly patients with Haemophilia A, emicizumab was found to be well tolerated and significantly reduced the annualized bleeding rate, indicating its efficacy in this population.

No serious adverse events like thrombosis or thrombotic microangiopathy were reported, suggesting that emicizumab is a safe option for elderly patients, even those with cardiovascular risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: Real-world data. Misgav, M., Brutman-Barazani, T., Budnik, I., et al.[2021]

Emicizumab is safe and effective in preventing bleeding in very young children with hemophilia A, as shown in a study of 11 children with a median age of 26 months followed for 36 weeks, where none experienced spontaneous bleeds.

While emicizumab was sufficient for most patients to maintain hemostasis, caution is advised during surgeries, as some procedures may still require additional treatment to prevent bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Barg, AA., Avishai, E., Budnik, I., et al.[2020]

In a phase 3 trial with 152 participants, emicizumab significantly reduced the annualized bleeding rate in hemophilia A patients without factor VIII inhibitors, showing a 96% reduction compared to no prophylaxis.

Emicizumab was well-tolerated, with the most common side effect being low-grade injection-site reactions, and it did not lead to serious complications like thrombotic events or the development of factor VIII inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. Mahlangu, J., Oldenburg, J., Paz-Priel, I., et al.[2022]

Emicizumab-kxwh (Hemlibra®) is a bispecific monoclonal antibody that effectively restores the function of missing activated FVIII in patients with hemophilia A, facilitating better blood clotting.

It is approved in the USA for routine prophylaxis to prevent bleeding episodes in hemophilia A patients with FVIII inhibitors, and is currently undergoing phase 3 trials for those without FVIII inhibitors, indicating its potential broad application in hemophilia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emicizumab-kxwh: First Global Approval. Scott, LJ., Kim, ES.[2019]

In a case study of an adult hemophilia A patient with FVIII inhibitors, the efficacy of emicizumab decreased due to the development of anti-drug antibodies (ADAs) that neutralized its activity, leading to repeated bleeding events.

The study found that the concentration of emicizumab in the patient's plasma decreased over time, and the presence of ADAs was linked to accelerated clearance of the drug, which ultimately reduced its effectiveness in managing bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detailed analysis of anti-emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A. Kaneda, M., Kawasaki, R., Matsumoto, N., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

The potential role of emicizumab prophylaxis in severe von Willebrand disease. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Effects of emicizumab on APTT, one-stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Emicizumab improves thrombus formation of type 2A von willebrand disease under high shear condition. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Activated factor VIII-mimicking effect by emicizumab on thrombus formation in type 2N von Willebrand disease under high shear flow conditions. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: Real-world data. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Emicizumab-kxwh: First Global Approval. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Detailed analysis of anti-emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A. [2023]