Hemlibra in Mild Hemophilia A

This is a single arm, phase 4, prospective, open-label, United States single-center study to develop laboratory data and assess the clinical hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of mild hemophilia A patients (baseline FVIII activity, >5 to 30%). Males aged ≥5 years to ≤45 years without inhibitors are eligible for enrollment. Secondary outcomes will assess changes in quality of life and joint health in treated patients.

Approximately 20 patients will be enrolled. As much as possible, the patient population will be selected to provide a variety of FVIII activity levels and F8 genetic defects.

Carrier females are not eligible for the study as the goal is to examine the effect of altered FVIII on Hemlibra (emicizumab) binding; carrier females with FVIII levels in the mild range of deficiency have one altered and one normal F8 gene that results in a mixture of both normal and altered FVIII proteins thereby complicating the interpretation of study results.

Patients with a FVIII inhibitor (or a history of a FVIII inhibitor) are not eligible for this study; if a subject develops a FVIII inhibitor during the study, they will be withdrawn from the study and offered the current standard of care.

Patients <5 years of age will be excluded from the study due to 1) the number of blood draws and the quantity of blood required; and 2) likelihood of reaching a minimum weight to utilize Stimate (~20 kg).

Patients with risk factors for thrombosis or TMA will be excluded from the study. Patients >45 years of age, >30 BMI, with a history of CVD, or >20% risk of CVD over a 10-year period using the atherosclerotic cardiovascular disease (ASCVD) risk estimator will also be excluded to minimize potential adverse events.

Patients with any number of FVIII exposure days are eligible for enrollment, as are previously untreated patients (PUPs). Although expected to be an uncommon occurrence, PUPs may be at risk of developing FVIII inhibitors while enrolled in the study due to exogenous FVIII exposure if required; as such they will be tested (bovine chromogenic modified inhibitor assay) after FVIII exposure per IHTC standard guidelines (after an episode of intensive treatment, between 3-5 EDs and then at 10 ED, etc.) Should a FVIII inhibitor develop in a PUP while on study, they will be removed from the study and offered the current standard of care.

To ensure no other bleeding disorders are present that might confound responses or lead to the development of a bleeding event unrelated to the underlying diagnosis of mild hemophilia A, a VWD panel and blood group will be obtained during screening.

Hemlibra (emicizumab) will be administered as weekly prophylaxis using the FDA-approved weekly dosing regimen following the enrollment/screening visit (first study visit) and the administration of the 4 weekly loading doses (second study visit). A choice of other approved dosing regimens (Q2W or Q4W) will not be offered as the primary regimen to limit variability in Cmin/Cmax exposure levels. The weekly prophylaxis regimen was selected to be the easiest for mild hemophilia A patients to remember as they are rarely on FVIII prophylaxis and infrequently need to administer on-demand hemostatic agents.

Bleeding events will be recorded and treated with locally available hemostatic agents (eg, Stimate [DDAVP/desmopressin acetate], pdFVIII, rFVIII, etc) as required. If FVIII is required for treatment of a bleeding event, the dose expected to achieve hemostasis will be utilized.

The enrollment period is 37 months; with a total study period of 60 months. The study comprises 2 parts following screening. Subjects will initially be enrolled in Part A (12 months) including a 1-month period of Hemlibra dose administration and collection of baseline laboratory data, with the option of enrolling in part B (12 months) upon successful completion of Part A and approval of the Study Investigator. Up to a 1-month window is provided between screening and administration of the first loading dose, depending on the return of required laboratory testing data and subject availability. When subjects complete the study, they will be requested to meet with their IHTC hemophilia physician to resume their previous therapeutic regimen or be offered the current standard of care.

Part A Loading dose administration (month 1 ±2 days):

This is a 1-month (±2 days) period during which the 4 weekly loading doses of Hemlibra (emicizumab) will be administered. Additionally, baseline laboratory data, banked plasma samples, MSKUS imaging and quality of life questionnaires will be completed.

Part A Maintenance Hemlibra therapy [months 2-13 (±2 weeks)]:

The purpose of this section of Part A is to collect laboratory data to determine the impact of Hemlibra (emicizumab) on laboratory coagulation parameters including thrombin generation in patients with circulating levels of endogenous altered FVIII (>5% to 30% baseline FVIII activity). Laboratory data will be collected at month 4 (±2 weeks), month 7 (±2 weeks) and month 13 (±2 weeks). Additional data, including bleeding events, bleed treatment, intercurrent procedures, quality of life (Haemo-QoL and CATCH questionnaires if <17 years of age; Haem-A-QoL and CATCH questionnaires if ≥17 years of age) and joint health (MSKUS) will be collected at baseline and 12 months (±2 weeks).

A Stimate/DDAVP challenge may occur at either the 4-month (±2 weeks) or 7-month (±2 weeks) study visit to investigate the hemostatic characteristics of Hemlibra (emicizumab) in the presence of elevated levels of altered FVIII using coagulation laboratory assays. The Stimate/DDAVP challenge will not be performed if the patient has a documented history of lack of response as defined by an increase of FVIII < 2 times baseline level. The Stimate/DDAVP challenge may be delayed to a later study visit due to recent treatment (within the previous 4 days) with a FVIII concentrate or Stimate (DDAVP/desmopressin acetate) or for convenience (at the discretion of the Study Investigator). The Stimate/DDAVP challenge may also be delayed or its route of administration altered if a subject weighs ≥10kg to <20kg; a weight-based subcutaneous dose of DDAVP/desmopressin acetate may be administered for subjects <20 kg at the discretion of the Study Investigator). The Stimate/DDAVP challenge may be delayed to a later study visit if the intranasal route of administration is compromised and subcutaneous administration of DDAVP/desmopressin acetate is not planned. See Section 3.1.9 for full details on the Stimate/DDAVP challenge.

Part B [months 14-25 (±2 weeks)]:

Upon successful completion of Part A, subjects may continue Hemlibra (emicizumab) treatment by enrolling in Part B if approved by the Study Investigator and per patient desire to continue treatment. The goal of Part B is to acquire additional data on bleeding events, bleed treatment, intercurrent procedures, changes in quality of life (Haemo-QoL and CATCH questionnaires if <17 years of age; Haem-A-QoL and CATCH questionnaires if ≥17 years of age) and joint health (MSKUS). This extended collection period is desired due to the infrequent and variable ABR in individuals with mild hemophilia A. Subjects will receive Hemlibra (emicizumab treatment in Part B for 12 months.

The study is seeking to address the following knowledge gaps:

• Is Hemlibra (emicizumab)-conferred hemostatic coverage additive to the activity of the endogenous altered FVIII protein in mild hemophilia A patients or is there evidence that endogenous altered FVIII protein is competitive with Hemlibra (emicizumab)?
• Do specific FVIII mutations confer more or less additive or competitive effect? In silico simulations of the altered protein (based upon the patient's genetic alteration) may be investigated to predict the protein's in vivo function and interaction with Hemlibra (emicizumab) binding (secondary exploratory goal)
• What is the hemostatic contribution of Hemlibra (emicizumab) in the presence of maximal endogenous altered FVIII protein release (Stimate/DDAVP challenge with coagulation laboratory assays)?
• Are there patients with specific genetic mutations who would benefit from Hemlibra (emicizumab) usage, or can a sub-population of patients of mild hemophilia be identified for whom Hemlibra (emicizumab) would not represent optimal therapy?
• Is weekly Hemlibra (emicizumab) safe to administer in patients with mild hemophilia A and does it reduce the incidence of bleeding events or the need for alternate hemostatic agents, including during/following surgeries and procedures?
• Does weekly prophylactic Hemlibra (emicizumab) result in an increase in QoL and/or activity in mild hemophilia A patients?
• Does weekly prophylactic Hemlibra (emicizumab) result in an improvement in joint health (ie, the control of progression, stabilization or regression of joint damage) using 6 joint point of care musculoskeletal