Emicizumab for Severe Von Willebrand Disease (VWD) and VWD/Hemophilia A

Von Willebrand Disease (VWD) is the most common inherited bleeding disorder affecting up to 0.1% of the population, is usually characterized by mucocutaneous bleeding, HMB, surgical bleeding or other hemostatic challenges. VWD currently has few therapies generally useful in management of bleeding events including antifibrinolytics, desmopressin (DDAVP), and VWF concentrates, which may be plasma-derived (VWF with and without FVIII) or recombinant. Minor bleeding may be successfully treated with antifibrinolytics and DDAVP; however, more severe bleeding requires VWF concentrates that are administered solely through intravenous access.

Similarly, it can be challenging to treat concomitant bleeding disorders with the existing therapeutic options available, and patients with concurrent VWD and hemophilia A primarily have VWF/FVIII concentrate or desmopressin (DDAVP) available for treatment. It has been well-recognized that patients, caregivers, and medical providers desire additional, simplified therapeutic options that are not intravenous to treat severe bleeding disorders. Therefore, a simplified, subcutaneous therapeutic that prevents bleeding would be strongly desired. Though its use in the hemophilia A population is growing, additional potential emicizumab applications for hemostatic control in other hemostatic disorders remain unknown. A recent case report highlighted the hemostatic efficacy of emicizumab off-label use in type 3 von Willebrand Disease (VWD), another severe bleeding disorder. This pediatric patient had type 3 VWD with alloantibodies and a bleeding phenotype similar to hemophilia A with inhibitor patients, requiring suboptimal bleeding management with rFVIIa and activated prothrombin complex concentrates (aPCC). Emicizumab prophylaxis was initiated and the patient no longer required aPCC prophylaxis and rare use of rFVIIa for acute bleeding events (only 1 trauma-induced soft tissue hematoma at the time of publication). The authors concluded their report suggested the bleeding phenotype in type 3 VWD is expressed mainly due to factor VIII deficiency. This study suggests a potential additional application for emicizumab in severe VWD.

A pilot multicenter, prospective open-label study of emicizumab prophylaxis in severe VWD and concomitant VWD/hemophilia A. Patients will have a one-year retrospective chart review of annualized bleed rate and hemostatic therapies collected at the time of enrollment. Patients will then be treated with emicizumab with 3mg/kg weekly for 4 weeks loading dose, followed by once weekly prophylaxis of 1.5mg/kg for 1 year. Per emicizumab FDA-approved prescribing information for hemophilia A, dose up-titration to 3 mg/kg once weekly will be allowed after 24 weeks on HEMLIBRA prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds) Treatment records will be maintained along with bleeding event logs. Breakthrough bleeding events may be treated with the patients usual on-demand therapy with antifibrinolytics or VWF/FVIII concentrates per clinician discretion. Patient reported outcome assessments will be collected throughout the clinical study to collect impact of the treatment on the individual patients, assessing quality of life, physical, emotional, social and general symptoms.

Inclusion criteria

• Signed informed consent
• Age 0 and older (infants weighing ≥3 kg)
• ability to comply with protocol in investigators judgement
• diagnosis of: severe VWD type 3, or VWD with VWF antigen, activity or collagen binding </= 20 U/dl or variant VWD confirmed by genetic mutation and VWF ag, activity or CB < 50 U/dl based on historical medical records of study site.
• diagnosis of VWD/hemophilia A defined as VWF:ag, activity or CB <50 U/dl, and mild moderate or severe hemophilia A(defined by ISTH criteria) based on historical medical records of the study site.
• plan to be adherent to emicizumab prophylaxis during the study
• Patient's bleeding phenotype necessitating prophylaxis per treating provider recommendations.
• Patient on current prophylaxis for VWD or VWD/hemophilia A may enroll if they are currently on a non-emicizumab agent, and if it has been > 18 months since last off-label dose of emicizumab, and are willing to discontinue current prophylaxis.
• For menstruating individuals: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the study period. A menstruating individual is considered to be of childbearing potential if they are post-menarchal, have not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and have not undergone surgical sterilization (removal of ovaries and/or uterus).

Examples of highly effective contraceptive methods with a failure rate of < 1% per year include proper use of combined oral or injected hormonal contraceptive, bilateral tubal ligation, male sterilization, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion criteria

• Patients and/or infants weighing < 3 kg.
• Patients with low VWF or non-severe VWD (ie.not meeting the above criteria)
• Other concomitant bleeding disorders including coagulopathy from liver cirrhosis.
• Current treatment with emicizumab or emicizumab therapy in the previous 18 months.
• Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or current signs of thromboembolic disease
• Other conditions (e.g., certain autoimmune diseases, including, but not limited to diseases such as systemic lupus erythematosus, inflammatory bowel disease, and antiphospholipid syndrome) that may increase the risk of bleeding or thrombosis
• 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
• Would refuse treatment with blood or blood products, if necessary.
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
• Treatment with any of the following:

An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration before Study Day 1 A non-hemophilia-related investigational drug within the last 30 days or 5 halflives- before Study Day 1, whichever is longer An investigational drug concurrently

• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
• Pregnant or lactating, or intending to become pregnant during the study
• Women of childbearing potential must have a negative serum pregnancy test result within 7 days before Study Day 1
• Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment
• Serious infection requiring oral or IV antibiotics within 30 days prior to screening