Dr. Roberts: Hello, I'm Dr. Jonathan Roberts, Associate Medical Director of the Bleeding and Clotting Disorders Institute. Thank you for joining me. Let's begin the program by reviewing von Willebrand disease. Please see VONVENDI® [von Willebrand factor (Recombinant)] full Prescribing Information and Detailed Important Risk Information available at the top of the screen or at www.vonvendipro.com.

The underlying cause of von Willebrand disease is a deficiency or defect in von Willebrand factor, a multimeric protein important for clotting.

Von Willebrand factor plays multiple key roles in hemostasis. One is to bind collagen and platelets to facilitate platelet plug formation. Another is to bind factor 8 to protect it from clearance and stabilize plasma factor 8 levels. Since von Willebrand factor protects factor 8 in plasma, a deficiency or defect in von Willebrand factor leads to increased factor 8 clearance, resulting in low factor 8 levels in some patients with von Willebrand disease. Low levels of factor 8 below 30 to 40 IUs per deciliter may lead to prolonged activated partial thromboplastin time.

There are 3 types of von Willebrand disease. Type 1 is caused by quantitative reduction in von Willebrand factor. Type 2 is due to a functional deficiency in von Willebrand factor. In Type 3, von Willebrand factor is almost absent.

An important fact to note about all 3 types of von Willebrand disease is that they only impact production of functional von Willebrand factor and do not impair a patient's ability to produce factor 8.

So, why only replace what is deficient or defective in von Willebrand disease? Firstly, the underlying cause of bleeding in von Willebrand disease is a deficiency or defect in von Willebrand factor. Further, not every patient with von Willebrand disease, every bleed, or every surgery requires treatment with factor 8. Frequent repeated administration of von Willebrand factor and factor 8 complexes in these patients can lead to an excessive rise in factor 8 levels. Such levels have been associated with thromboembolic events in patients who have additional risk factors.

In my practice, I've seen patients with persistently elevated factor 8 levels, highlighting the need to address the deficiency or defect in von Willebrand factor and to treat the underlying cause of bleeding in von Willebrand disease. Further, patients with von Willebrand disease, Types 1, 2, and 3 have all reported a variety of bleeding episodes. This includes epistaxis, heavy menstrual bleeding, gingival bleeding, joint bleeding, and gastrointestinal bleeding. Patients with severe Type 3 experienced frequent bleeds. In an on-demand clinical trial in which a common von Willebrand factor was being investigated, 21 adult patients with severe Type 3 experienced a median of 5.7 bleeds in a year that required treatment. A range of 0 to 36.5.

There are 3 ways that von Willebrand factor replacement therapies can be used for patients with von Willebrand disease. These include on-demand use to treat acute bleeding episodes, perioperative use to manage bleeding around surgery, and prophylactic use to reduce the number of bleeds. The 2021 American Society of Hematology, the International Society on Thrombosis and Hemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia Treatment Guidelines have provided insight into when prophylaxis may be considered for recommendation in appropriate patients with von Willebrand disease.

Let's examine how VONVENDI, von Willebrand factor recombinant, uses only von Willebrand factor to prevent bleeds.

Please see VONVENDI full Prescribing Information and Detailed Important Risk Information available at the top of the screen or at www.vonvendipro.com.
Please join me in the next chapter as I review unique aspects of VONVENDI for adult patients with von Willebrand disease.

Dr. Roberts: Let's explore the unique properties of VONVENDI, von Willebrand factor recombinant, in the treatment of adult patients living with severe Type 3 von Willebrand disease.

Please see VONVENDI full Prescribing Information and Detailed Important Risk Information available at the top of the screen or at www.vonvendipro.com.

VONVENDI [von Willebrand factor (Recombinant)] is a recombinant von Willebrand factor indicated for use in adults age 18 and older diagnosed with von Willebrand disease for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy.

Contraindications.

Do not use in patients who have had life-threatening hypersensitivity reactions to VONVENDI or its components (tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, and hamster or mouse proteins).

Please see additional Detailed Important Risk Information available on the top of the screen or later in this presentation.

VONVENDI is produced and formulated without the addition of any exogenous raw materials of human or animal origin in the cell culture, purification, or formulation. The manufacturing process results in recombinant von Willebrand factor that is highly pure (greater than 99% purity) with only trace amounts of factor 8, mouse immunoglobulins, and hamster proteins. Because it is a recombinant product manufactured in the absence of animal or human plasma proteins, VONVENDI virtually eliminates the risk of bloodborne pathogen transmission.

Additionally, VONVENDI provides a full range of von Willebrand factor multimers found in the body, including ultra-large multimers and high-molecular-weight multimers. Because VONVENDI is recombinant, is never exposed to ADAMTS13 in the manufacturing process, allowing for ultra-large multimers to remain intact in the final product. Upon administration, VONVENDI is cleaved by the patient's own ADAMTS13 enzymes into multimers of various sizes, similarly to naturally produced von Willebrand factor. The adhesive activity of von Willebrand factor depends on the size of its multimers, with larger multimers being the most effective in supporting interactions with collagen and platelet receptors.

VONVENDI is the only recombinant von Willebrand factor product with ultra-large multimers. However, note that there are no data to indicate that VONVENDI efficacy is enhanced due to its multimeric composition or mechanism of action. The presence and in vivo degradation of VONVENDI multimers were studied in 16 patients as part of the on-demand clinical trial. The image on your screen shows the von Willebrand multimers pre- and postinfusion of recombinant von Willebrand factor in a patient with Type 3 von Willebrand disease. Fifteen minutes after infusion of VONVENDI, the median percentage of ultra-large multimers and high-molecular-weight multimers rose from 0% preinfusion to 30%. Levels declined between 12 and 24 hours, reaching baseline by 96 hours. There's no data to indicate that VONVENDI efficacy is enhanced due to its multimeric composition or mechanism of action.

The PK profile of VONVENDI was determined based on data analysis from 2 clinical trials. Subjects were evaluated in the nonbleeding state, as shown here. VONVENDI exhibited a mean half-life of 22.6 hours at a dose of 50 IUs per kilogram and 19.1 hours at a dose of 80 IUs per kilogram.

VONVENDI has been shown to enable a sustained rise in factor 8 levels from PK analysis performed post hoc from pooled data across on-demand and surgery trials. Results showed endogenous factor 8 levels rose at a mean rate of 7.7% per hour, ranging from 1% to 17.2%, for 40 participants for the first 6 hours and were sustained over 72 hours postinfusion. In my practice, I'm cognizant of factor 8 accumulation in on-demand or perioperative settings, and as such, have used VONVENDI to treat appropriate patients.

Additionally, VONVENDI prophylaxis led to a sustained rise in factor 8 in adult patients with severe Type 3 von Willebrand disease. The median predose factor 8 level at baseline after washout was 2%, ranging from 2% to 4%, for 10 participants and was 10.5% or more, ranging from 1% to 148%, for 8 participants from across prophylactic visits at months 1, 2, 3, 6, 9, and 12.

Now that we know VONVENDI alone can sustain factor 8 over time, let's discuss the first and only prophylaxis indication for adult patients with severe Type 3 von Willebrand disease receiving on-demand therapy.

Please join me in the next chapter as I review the efficacy and safety of VONVENDI for routine prophylaxis to reduce the frequency of bleeding episodes in adult patients with severe Type 3 von Willebrand disease receiving on-demand therapy.

Dr. Roberts: Let's learn more about the efficacy and safety of VONVENDI, von Willebrand factor recombinant, in routine prophylaxis of adult patients with severe Type 3 von Willebrand disease.

Please see VONVENDI full Prescribing Information and Detailed Important Risk Information available at the top of the screen or at www.vonvendipro.com.

A prospective, single arm, open label, international, multicenter study evaluated the efficacy and safety of VONVENDI in 10 adult patients with severe Type 3 von Willebrand disease who were previously treated on demand. These participants had 3 or more bleeding episodes (excluding menorrhagia) that required von Willebrand factor treatment in the 12 months prior to enrolling in the study.

Patients began treatment at 50 ± 10 IUs per kilogram per infusion twice weekly. Nine of 10 patients received twice-weekly dosing with VONVENDI and had a median maximum dose of 55.9 IUs per kilogram. One patient required dose adjustments for management of breakthrough bleeding. Efficacy was assessed based on the median annualized bleeding rate for all bleeds, spontaneous bleeds, and joint bleeds and was based on descriptive statistics. Adverse drug reactions were assessed by system organ class. As shown here, routine prophylaxis with VONVENDI helped reduce the number of bleeds for adults with severe Type 3 von Willebrand disease who were previously treated on demand.

The median percentage change of ABRs from historical on-demand to on-study prophylaxis were 54.7% for all bleeds, 75.9% for spontaneous bleeds, and 100% for joint bleeds. Additionally, the study recorded the number of breakthrough bleeds in patients with severe Type 3 von Willebrand disease who were previously treated on demand. This table shows the number of breakthrough bleeds and the number of patients who experienced 0 breakthrough bleeds. During the study, 9 of 10 patients received twice-weekly dosing with VONVENDI and had a median maximum dose of 55.9 IUs per kilogram. One patient required dose adjustments for management of breakthrough bleeding. Note that this secondary outcome analysis is based on descriptive statistics and is from a sample size of 10 patients. Therefore, results should be interpreted with caution.

This next table shows a summary of adverse drug reactions in adult patients with von Willebrand disease from the prophylaxis clinical trial. The ADRs from this study were headache, arthralgia, ALT, increased AST, increased super ventricular tachycardia, ventricular extrasystolase, diarrhea, purpura rash, rash pruritic, and injection site irritation. In summary, a key aspect of von Willebrand disease is that it only impacts production of functional von Willebrand factor and does not impair a patient's ability to produce factor 8. Not every person with VWD, every bleed, or every surgery requires treatment with factor 8. VONVENDI is a recombinant von Willebrand factor shown to enable a sustained rise in factor 8 levels from PK analysis performed post hoc from pooled data across on-demand and surgery trials. Because it is a recombinant product manufactured in the absence of animal or human plasma proteins, VONVENDI virtually eliminates the risk of bloodborne pathogen transmission. Additionally, VONVENDI provides the full range of von Willebrand factor multimers found in the body, including ultra-large multimers and high-molecular-weight multimers. Routine prophylaxis with VONVENDI helped reduce the number of bleeds for adults with severe Type 3 von Willebrand disease who were previously treated on demand.

Please listen now to some Detailed Important Risk Information.

Narrator: VONVENDI, von Willebrand factor Recombinant, Indications and Detailed Important Risk Information.

Indications

VONVENDI [von Willebrand factor (Recombinant)] is a recombinant von Willebrand factor (RVWF) indicated for use in adults (age 18 and older) diagnosed with von Willebrand disease (VWD) for:

Detailed Important Risk Information
CONTRAINDICATIONS

Do not use in patients who have had life-threatening hypersensitivity reactions to VONVENDI or its components (tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, and hamster or mouse proteins).

WARNINGS AND PRECAUTIONS

Embolism and Thrombosis

Thromboembolic reactions, including disseminated intravascular coagulation, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke can occur, particularly in patients with known risk factors for thrombosis, including low ADAMTS13 levels. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope, and institute prophylaxis measures against thromboembolism based on current recommendations.

In patients requiring frequent doses of VONVENDI in combination with recombinant factor VIII, monitor plasma levels for factor FVIII:C activity because sustained excessive factor VIII plasma levels can increase the risk of thromboembolic events.

One out of 100 subjects treated with VONVENDI in clinical trials developed proximal deep vein thrombosis in perioperative period after total hip replacement surgery.

Hypersensitivity Reactions

Hypersensitivity reactions have occurred with VONVENDI. These reactions can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, blurred vision, wheezing and/or acute respiratory distress. Discontinue VONVENDI if hypersensitivity symptoms occur and administer appropriate emergency treatment.

Neutralizing Antibodies (Inhibitors)

Inhibitors to VWF and/or factor VIII can occur. If the expected plasma levels of VWF activity, von Willebrand factor, ristocetin cofactor activity are not attained, perform an appropriate assay to determine if anti-VWF or anti-factor VIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either VWD or hemophilia A.

In patients with high levels of inhibitors to VWF or factor VIII, VONVENDI therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors.

ADVERSE REACTIONS

In clinical trials, the most common adverse reactions observed in ≥2% of subjects (n=100) were headache, vomiting, nausea, dizziness, arthralgia, joint injury, vertigo, ALT increased and generalized pruritus.

One subject treated with VONVENDI in perioperative setting developed deep vein thrombosis after total hip replacement surgery.

Please see VONVENDI full Prescribing Information available at the top of the screen or at www.vonvendipro.com.

Dr. Roberts: Thank you for your time and attention.

Narrator: This program is sponsored by Takeda Pharmaceuticals USA Incorporated and has been brought to you by Peer Direct Publishing.

Thank you for your participation.

VONVENDI® [von Willebrand factor (Recombinant)].

What is VONVENDI?

VONVENDI is used in adults (age 18 years and older) diagnosed with von Willebrand disease to:

Who should not use VONVENDI?

You should not use VONVENDI if you:

Tell your healthcare provider if you are pregnant or breastfeeding because VONVENDI may not be right for you.

Please see Detailed Important Risk Information at the end of this video. Talk to your healthcare provider to see if VONVENDI may be right for you.

Erica: Hi, my name is Erica, and I've been living with von Willebrand disease for close to 40 years now.

Erica: My experience with VWD has taught me the importance of having discussions about my bleeding management with my care team, and so here to help me provide a medical perspective on this topic is Dr. Janbain, an expert in bleeding disorders.

Erica: Hi, Dr. Janbain.

Dr. Janbain: Hello, Erica. It's nice to be here with you.

Erica: Dr. Janbain, can you explain VWD to our viewers who may have newly been diagnosed or just learned about VWD?

Dr. Janbain: Sure, von Willebrand disease is the most common inherited bleeding disorder, meaning you're usually born with it. But to better understand von Willebrand disease, we should first discuss von Willebrand factor, which is a protein that plays an important role in helping your body to form a blood clot in order to stop bleeding. Now, people living with von Willebrand disease either don't have enough von Willebrand factor or their von Willebrand factor doesn't work properly. Without enough functional von Willebrand factor, your body is unable to form a stable blood clot, which can result in prolonged or excessive bleeding.

Erica: While living with VWD, I've had to learn for myself how to raise the alarm or to raise my hand when I need to have care or change in care. So, Dr. Janbain, how do you help people living with VWD know when it's time to raise their hand and ask their HCP for help?

Dr. Janbain: You're raising a great question here, Erica. And I think that patients with VWD should share all of their symptoms with their doctors. I always tell my patients, for example, that no bleeding is minimal. If bleeding interferes with your daily activities and with your daily life, and if it has any impact on your schedule like school, work, or social activities, then you should bring it to the attention of your care provider.

Dr. Janbain: Now, Erica, tell me, when you are communicating with your care team, are there certain things you do to help ensure that they understand what you've been dealing with?

Erica: You know, Dr. Janbain, I do. I've always written it down. And now that we have technology, I put it in my phone so that I know when I had the bleed. What were the circumstances around the bleed? I try to track how long the bleed was. Was it a really heavy bleed, or was it a light bleed? And I write all this information down as soon as I can, either during the bleed or right after the bleed, so that when I do talk to my doctor, I have all that information right there and it's fresh.

Erica: So, on the subject of treatment, there are different types of treatment, and you should always talk to your doctor about which one is right for you. For me, I use a product called VONVENDI for adult on-demand treatment and control of bleeding episodes and for management of bleeding around the time of surgery. Dr. Janbain, could you explain to our viewers how VONVENDI works?

Dr. Janbain: Sure. VONVENDI is a type of infusion therapy that is known as factor replacement. It is a recombinant von Willebrand factor that replaces what is missing or not working in adults with von Willebrand disease. Now, one of the functions of von Willebrand factor is to associate and stabilize factor 8 longer in your blood. But not every patient with von Willebrand disease ends up having low factor 8 levels. So, depending on patients' needs and based on monitoring levels and the judgment of their healthcare providers, they could take VONVENDI with or without factor 8.

Erica: Well, I can honestly say this has been a very productive doctor-patient conversation. Thank you so much for your time, Dr. Janbain.

Dr. Janbain: My pleasure. Thank you for having me, Erica.

Erica: Viewers, please stick around to view Important Safety Information for VONVENDI and talk to your doctor to learn more.

VONVENDI [von Willebrand factor (Recombinant)] Important Information.

What is VONVENDI?

VONVENDI is used in adults (age 18 years and older) diagnosed with von Willebrand disease to:

Detailed Important Risk Information

Who should not use VONVENDI?

You should not use VONVENDI if you:

Tell your healthcare provider if you are pregnant or breastfeeding because VONVENDI may not be right for you.

How should I use VONVENDI?

Your first dose of VONVENDI for each bleeding episode may be administered with a recombinant factor VIII as instructed by your healthcare provider.

Your healthcare provider will instruct you whether additional doses of VONVENDI with or without recombinant factor VIII are needed.

What should I tell my healthcare provider before I use VONVENDI?

You should tell your healthcare provider if you:

What else should I know about VONVENDI and von Willebrand disease?

Your body can form inhibitors to von Willebrand factor or factor VIII. An inhibitor is part of the body's normal defense system. If you form inhibitors, it may stop VONVENDI or factor VIII from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to von Willebrand factor or factor VIII.

What are the possible side effects of VONVENDI?

You can have an allergic reaction to VONVENDI.

Call your healthcare provider right away and stop treatment if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea or fainting.

Side effects that have been reported with VONVENDI include: headache, nausea, vomiting, tingling or burning at infusion site, chest discomfort, dizziness, joint pain, joint injury, increased liver enzyme level in blood, hot flashes, itching, high blood pressure, muscle twitching, unusual taste, blood clots and increased heart rate.

Tell your healthcare provider about any side effects that bother you or do not go away.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see VONVENDI full Prescribing Information at VONVENDI.com.