Evaluation of Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Infants with Hemophilia A Without Inhibitors

The primary objective of this study is to evaluate the **efficacy**, safety, pharmacokinetic (PK) profile, pharmacodynamics (PD) parameters, and immune response to treatment with subcutaneous **emicizumab** in patients from birth to 12 months of age diagnosed with **Hemophilia A** without inhibitors. This is clinically relevant as it aims to provide insights into the therapeutic potential and safety profile of emicizumab in a very young patient population, which is critical for optimizing treatment strategies and improving patient outcomes in this vulnerable group.

The clinical trial involves a total of **34 participants** diagnosed with **Hemophilia A**. The study population consists exclusively of male subjects, as female subjects are not included. Participants are categorized within the age range of **2** years and are considered a vulnerable population. The selection criteria for the trial population include individuals with severe congenital hemophilia A, characterized by an intrinsic factor VIII (FVIII) level of less than 1%. Participants must have no history of documented FVIII inhibitor, a negative test for FVIII inhibitor during the screening period, and must be previously untreated or minimally treated patients. Additionally, the trial requires documentation of hemophilia-related treatments and bleeding episodes since birth. The sponsor has not provided specific information regarding lifestyle considerations such as diet, physical activity, or habits for the participants.

The clinical trial is designed as a **phase IIIb**, multicenter, open-label, single-arm study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of subcutaneous **emicizumab** in patients from birth to 12 months of age with **Hemophilia A** without inhibitors. The trial will involve the administration of **Hemlibra**, a solution for injection, with a maximum treatment period of 96 weeks. The study will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as no history of documented FVIII inhibitor and a diagnosis of severe congenital Hemophilia A. Participants will be required to have a negative test for FVIII inhibitor during the 2-week screening period.

The trial will include regular follow-up visits to monitor the number of treated bleeds, joint health, and the incidence of adverse events, among other primary endpoints. The study will also assess the incidence of thromboembolic events, changes in physical examination findings, and laboratory abnormalities. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 96 weeks, unless early termination is warranted due to adverse events or other protocol-specified conditions. The trial is estimated to end by May 18, 2030, with recruitment having started on April 8, 2021. The study aims to provide comprehensive data on the safety and efficacy of **emicizumab** in the specified patient population, contributing to the understanding of its pharmacokinetic and pharmacodynamic profiles.

The clinical trial involves the administration of **Hemlibra** (emicizumab), a **solution for injection**. Two formulations are utilized: Hemlibra 150 mg/mL and Hemlibra 30 mg/mL. Both formulations are designed for **subcutaneous use**. The active substance, emicizumab, is a protein-based therapeutic agent, specifically categorized as "Protein - Other." The pharmaceutical form for both products is a solution for injection, and they are re-labeled for clinical trial use. The maximum treatment period for the trial is 96 weeks. The dosing regimen is based on a milligram per kilogram (mg/Kg) basis, although specific daily and total dose amounts are not predetermined in the trial protocol.

Hemlibra 150 mg/mL solution for injection is manufactured by Roche Registration GmbH and is identified by the marketing authorization number EU/1/18/1271/004. The product is associated with the European Medicines Agency (EMA) number EMEA/H/C/004406 and is authorized for use in the European Union. The product is identified by the sponsor product code RO5534262/F03-01. The administration route is subcutaneous, and the product is not a pediatric formulation.

Similarly, Hemlibra 30 mg/mL solution for injection is also produced by Roche Registration GmbH, with the marketing authorization number EU/1/18/1271/001. It shares the same EMA number, EMEA/H/C/004406, and is authorized for use in the European Union. The sponsor product code for this formulation is RO5534262/F05-01. Like the 150 mg/mL formulation, it is administered subcutaneously and is not a pediatric formulation. Both formulations are used to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in patients with **hemophilia A** without inhibitors.

The efficacy of **emicizumab** in the clinical trial will be assessed using a range of primary endpoints. These include the number of treated bleeds over time, the number of all bleeds over time, the number of treated spontaneous bleeds over time, and the number of treated joint bleeds over time. Joint health will be evaluated through the Hemophilia Joint Health Score (HJHS) and magnetic resonance imaging (MRI) scores of specific joints, assessed at specified timepoints during the 7-year long-term follow-up period. Additional parameters include the incidence and severity of adverse events, incidence of thromboembolic events and thrombotic microangiopathy (TMA), changes from baseline in physical examination findings and vital signs, incidence of laboratory abnormalities, and incidence and severity of injection-site reactions. The incidence of adverse events leading to study drug discontinuation, severe hypersensitivity, anaphylaxis, and anaphylactoid events will also be monitored.

Furthermore, plasma trough concentrations (Ctrough) of **emicizumab** prior to study drug administration will be measured. The effect of **emicizumab** on pharmacodynamic parameters, including activated partial thromboplastin time (aPTT), thrombin generation (TG), and reported factor VIII (FVIII) activity, as well as factor IX (FIX) antigen and factor X (FX) antigen levels, will be evaluated. These assessments will be conducted using validated scales and laboratory tests at predetermined timepoints throughout the study duration. The trial is designed to provide comprehensive data on the efficacy of **emicizumab** in patients with Hemophilia A without inhibitors, from birth to 12 months of age.