Hemlibra in Mild Hemophilia A

Prospective, Single-Arm, Open-Label Use of Hemlibra (Emicizumab) in the Treatment of Mild Hemophilia A

This is a single arm, phase 4, prospective, open-label, United States single-center study to determine the hemostatic characteristics of Hemlibra (emicizumab) as measured by coagulation laboratory parameters in the mild hemophilia A male patient population with endogenous altered FVIII (baseline FVIII activity of >5% to 30%). The safety and hemostatic efficacy of Hemlibra (emicizumab) in this patient population will be investigated. Secondary outcomes will assess changes in joint health and quality of life in treated patients.

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 30-40 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inhibitor) are not eligible for this study; if a subject develops a FVIII inhibitor during the study, they will be withdrawn from the study and offered the current standard of care.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 9 months; with a total study period of 35 months. The study comprises 3 parts following screening. Subjects will initially be enrolled for loading dose administration and collection of baseline laboratory data (1 month) and Part A (12 months), 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. 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 [months 2-13 (±2 weeks)]: Part A is a 12-month study 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

Patients with mild hemophilia A (without inhibitors) will be treated with prophylactic emicizumab. The clinical hemostatic efficacy and safety will be assessed. Secondary outcomes will assess changes in quality of life and joint health in treated patients.

Interaction of Hemlibra (emicizumab) binding with endogenous altered FVIII protein in an individual with mild hemophilia A and the combined effect on thrombin generation and hemostatic characteristics

Change in FVIII human chromogenic activity, FVIII bovine chromogenic activity, and Thrombin Generation Assay relatively to one another

Baseline presence of joint disease through 6 joint POC MSKUS and its stabilization, resolution, or progression

Rate of adverse events (AEs) and serious adverse events (SAEs) including lack of efficacy and development of neutralizing anti-drug antibodies (ADA)

Rate of use of alternate hemostatic therapies (eg, FVIII, Stimate/DDAVP, etc) during surgeries and procedures and their hemostatic efficacy to prevent or treat bleeding

Change in quality of life as measured by Haemo-QoL (haemophilia-specific quality of life questionnaire) if <17 years of age; and Haem-A-QoL-A (haemophilia-specific quality of life questionnaire for adults) if ≥17 years of age. Scores range from 0 to 100, with higher scores indicating a lower quality of life.

Change in activity level as measured by CATCH (Comprehensive Assessment Tool of Challenges in Hemophilia) questionnaire. Change from baseline in the daily activity risk perception and impact domain score over time. This is not a scaled assessment.

Inclusion Criteria: Signed informed consent form from the subject, parent or guardian Male sex Diagnosis of mild congenital hemophilia A (baseline FVIII level of >5% to 30%) without a current FVIII inhibitor or a history of FVIII inhibitor Any number of FVIII exposure days, including PUPs BMI <30 Age ≥5 years to ≤45 years Medical documentation of bleeding events, outcomes and hemostatic product usage for 12 months prior to study enrollment Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including the health-related questionnaires, activity tracking, and bleed diaries, using systems provided during the study Willingness to undergo a Stimate/DDAVP challenge (only if the subject reports no adverse event associated with prior Stimate [DDAVP/desmopressin acetate] use); 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 Adequate hepatic function, defined as total bilirubin ≤1.5 × age-adapted upper limit of normal (ULN) (excluding Gilbert's syndrome) and both AST and ALT ≤3 × age-adapted ULN at the time of screening, and no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis Adequate hematologic function, defined as a platelet count ≥100,000/μL and a PT≤1.5 times the ULN at the time of screening Adequate renal function, defined as serum creatinine ≤2.5 × age-adapted ULN and creatinine clearance ≥30 mL/min by Cockcroft-Gault formula Exclusion Criteria: Inherited or acquired bleeding disorder other than mild congenital hemophilia A (baseline FVIII level of >5% to 30%) Any bleeding disorder other than or in addition to mild hemophilia A Current or prior inhibitor to FVIII (any titer) Female sex History of CVD, risk of CVD by the ASCVD risk estimator (defined as a subject having >20% risk of a cardiovascular event within the next 10 years if the subject is ≥20 years of age) and/or a history of ischemic heart disease [ICD codes 120-125] High risk for TMA (eg, have a previous medical or family history of TMA), in the Study Investigator's judgment History of illicit drug or alcohol abuse by report or in the Study Investigator's judgment Previous (within the last 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 signs of thromboembolic disease Other conditions (eg, certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the Hemlibra (emicizumab) injection Known HIV infection with CD4 counts <200 cells/μL. HIV infection with CD4 counts ≥200 cells/μL permitted Use of systemic immunomodulators (eg, interferon) at enrollment or planned use during the study, with the exception of anti-retroviral therapy Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the Study Investigator, pose an additional unacceptable risk in administering study drug to the patient Receipt of any of the following: Hemlibra (emicizumab) in a prior investigational study An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter Any other investigational drug currently being administered or planned to be administered Inability to comply with the study protocol in the opinion of the Study Investigator

The investigators will share resources and data from this project through collaborative publications in the scientific literature as well as through national, regional and international conference presentations. The investigators will also share our methods and findings in a prompt manner with regional, national and international stakeholders to ensure that findings will be readily available to other researchers and clinicians with clinical or scientific interest in the subject area. Individual participant data that underlie the results reports in publications, reports or presentations (including text, tables, figures and appendices) will be shared after de-identification.

IPD and additional information on study methods will be made available starting 9 months after publication or conclusion of the study and ending 36 months following publication or study conclusion.

IPD and study information will be shared with investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary"), whose proposals are methodologically sound, and for purposes that are consistent with the aims of the underlying research. Proposals will be reviewed by the Principle Investigator, Dr. Amy Shapiro, and may be submitted to ashapiro@ihtc.org. Requestors will be required to sign a data access and use agreement.

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