Concizumab for Hemophilia A and B

(Explorer10 Trial)

Recruiting at142 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Novo Nordisk A/S

Must be taking: Coagulation factors

Disqualifiers: Thromboembolic disease, Coagulation disorders, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This study will test how well a new medicine called concizumab works for participants who have haemophilia A or B with or without inhibitors. The purpose is to show that concizumab can prevent bleeds and is safe to use. Participants will have to inject the study medicine every day under the skin with a pen-injector. The study will last for at least 2 years and up to about 4 years. The length of time the participant will be in the study depends on if the study medicine will be available for purchase in their country.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It is best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drug Concizumab for treating Hemophilia A and B?

Concizumab has been shown to restore thrombin generation, which helps blood clotting, in both laboratory and animal studies. It has been approved in Canada for preventing bleeding in patients with Hemophilia B who have inhibitors, and studies have shown it can reduce bleeding episodes. ^{1 2 3 4 5}

How is the drug Concizumab unique for treating hemophilia A and B?

Concizumab is unique because it is a subcutaneously administered monoclonal antibody that targets the tissue factor pathway inhibitor (TFPI), helping to promote blood clotting in patients with hemophilia A and B, including those with inhibitors. This mechanism of action and administration route differ from traditional treatments that often involve intravenous infusions of clotting factors. ^{1 2 5 6 7}

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This trial is for individuals with severe haemophilia A or moderate/severe haemophilia B, with or without inhibitors. Participants must have a history of treatment for at least 26 weeks in the past year and give informed consent. It's not open to those allergic to concizumab, undergoing Immune Tolerance Induction, with thromboembolic disease or risk factors for it, other coagulation disorders besides haemophilia, or a history of thrombosis.

Inclusion Criteria

I have severe haemophilia A, moderate/severe haemophilia B, or haemophilia with inhibitors.

I have haemophilia A or B without inhibitors.

I have been on preventive treatment for at least 26 weeks in the past year.

Exclusion Criteria

I am undergoing or will undergo immune tolerance therapy.

I have had blood clots in the past.

I am currently being treated for or showing signs of blood clots.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily injections of concizumab under the skin with a pen-injector

At least 32 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may continue treatment until the study medicine is available for purchase in their country

Up to 4 years

Treatment Details

Interventions

• Concizumab (Monoclonal Antibodies)

Trial Overview The study tests concizumab's effectiveness in preventing bleeding episodes in people with haemophilia A/B. Participants will self-inject concizumab daily using a pen-injector. The trial spans 2-4 years depending on when the drug becomes commercially available.

Participant Groups

Group I: Patients coming from compassionate use Experimental Treatment 1 Intervention

Patients previously treated with concizumab via compassionate use, either on an individual patient basis or through the concizumab compassionate use programme NN7415-4807

Group II: Concizumab-naïve patients Experimental Treatment 1 Intervention

Concizumab-naïve participants below 12 years of age at the time of consent/assent

Concizumab is already approved in Canada for the following indications:

Approved in Canada as Alhemo for:

• Hemophilia A with inhibitors
• Hemophilia B with inhibitors

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Findings from Research

Concizumab is a monoclonal antibody that effectively prevents tissue factor pathway inhibitor (TFPI) from inhibiting activated Factor X, which is crucial for blood clotting, making it a promising treatment for hemophilia A and B.

In March 2023, concizumab received approval in Canada for use in adolescents and adults with hemophilia B who have FIX inhibitors, marking a significant advancement in prophylactic treatment options to reduce bleeding episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concizumab: First Approval. Keam, SJ.[2023]

Concizumab effectively binds to and neutralizes the inhibitory function of tissue factor pathway inhibitor (TFPI), promoting coagulation, which could be beneficial for patients with hemophilia.

Pharmacokinetic studies in rabbits showed a non-linear, dose-dependent clearance profile for concizumab, indicating that its distribution and elimination are influenced by its interaction with TFPI on the endothelium of blood vessels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz-type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor. Hansen, L., Petersen, LC., Lauritzen, B., et al.[2019]

mAb 2021, a high-affinity monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), effectively enhances clot formation in hemophilia by preventing TFPI's inhibition of the coagulation pathway, as demonstrated in both blood and plasma samples.

In a rabbit model of hemophilia, mAb 2021 significantly reduced bleeding for at least 7 days after a single intravenous dose, showing comparable efficacy to standard treatments like rFVIIa, suggesting it could be a promising new treatment option for hemophilia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Hilden, I., Lauritzen, B., Sørensen, BB., et al.[2022]

Concizumab, a monoclonal antibody that inhibits tissue factor pathway inhibitor (TFPI), effectively restores thrombin generation in hemophilia patients, showing promise in reducing bleeding episodes as demonstrated in both plasma studies and a rabbit model.

In Phase 1 trials, Concizumab led to a dose-dependent decrease in TFPI levels and increased thrombin generation without significant thrombosis risk, indicating its potential as a safe and effective alternative to traditional factor replacement therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab. Chowdary, P.[2023]

Concizumab is a humanized monoclonal antibody that targets the Kunitz-2 domain of Tissue Factor Pathway Inhibitor (TFPI), showing promise in restoring thrombin generation and enhancing blood clotting in hemophilia patients.

Preclinical and clinical studies, including those from the EXPLORER program, support concizumab's potential as a new treatment option for hemophilia, with ongoing trials eagerly awaited for further results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concizumab as a Subcutaneous Prophylactic Treatment Option for Patients with Hemophilia A or B: A Review of the Evidence and Patient's Perspectives. Pasca, S.[2022]

In the explorer7 trial involving 133 patients with hemophilia A or B with inhibitors, concizumab prophylaxis significantly reduced the annualized bleeding rate to 1.7 episodes compared to 11.8 episodes in the no prophylaxis group, demonstrating its efficacy in preventing bleeding events.

After a treatment pause due to nonfatal thromboembolic events, no further thromboembolic incidents were reported once concizumab therapy resumed, indicating a favorable safety profile for the drug in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. Matsushita, T., Shapiro, A., Abraham, A., et al.[2023]

Concizumab, an anti-tissue factor monoclonal antibody, enhances thrombin generation in hemophilia A/B patients, and its effects are concentration-dependent, indicating its potential efficacy in improving hemostasis during prophylaxis.

When combined with bypassing agents like rFVIIa, APCC, or factor replacement therapies like rFVIII and rFIX, concizumab further increases thrombin generation, but the interactions are mostly additive rather than synergistic, suggesting careful dose adjustments are needed to ensure safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses. Kjalke, M., Kjelgaard-Hansen, M., Andersen, S., et al.[2023]

References

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

Concizumab: First Approval. [2023]

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

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz-type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor. [2019]

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

Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. [2022]

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

Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab. [2023]

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

Concizumab as a Subcutaneous Prophylactic Treatment Option for Patients with Hemophilia A or B: A Review of the Evidence and Patient's Perspectives. [2022]

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

Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses. [2023]