An open-label, parallel, Phase 3, two-arm study to investigate the efficacy and safety of fitusiran prophylaxis in male participants aged 1 to less than 12 years with hemophilia A or B with or without inhibitory antibodies to Factors VIII or IX

The primary objective is to evaluate treatment efficacy during fitusiran prophylaxis and standard of care periods in the fitusiran-naïve arm. This comparison is clinically relevant for establishing the therapeutic benefit of fitusiran prophylaxis in previously untreated pediatric patients with hemophilia A or B.

The secondary objectives include: • To characterize the frequency of treated spontaneous bleeding episodes and treated joint bleeding episodes during the fitusiran prophylaxis and standard of care periods in the fitusiran-naïve arm. • To characterize the frequency of treated bleeding episodes during the fitusiran treatment period in both arms. • To characterize the effect of fitusiran prophylaxis on health-related quality of life outcomes in the fitusiran-naïve arm. • To characterize the safety of fitusiran in both arms. • To characterize the effect of fitusiran prophylaxis on joint health outcomes in the fitusiran-naïve arm.

This clinical trial enrolled a total of **61 participants** diagnosed with **hemophilia**. The study population consisted exclusively of **male subjects** aged **1 to less than 12 years** at the time of enrollment, representing a **vulnerable population** of pediatric patients. Participants were required to have **severe hemophilia A or B**, defined as **Factor VIII levels below 1%** or **Factor IX levels at or below 2%**, as confirmed by central laboratory measurement or documented medical record evidence. The trial population was selected based on **inhibitor or non-inhibitor status**, with inhibitor participants requiring **bypassing agent (BPA)** use for prophylaxis or on-demand therapy, while non-inhibitor participants required **clotting factor concentrates (CFCs)** for at least three months prior to screening. Adequate peripheral venous access was necessary to allow for protocol-required blood draws. Participants with inhibitors were further characterized by specific **Nijmegen-modified Bethesda assay** results, including inhibitor titers and medical history of anamnestic response or severe allergic reactions. Enrollment required signed informed consent from parents or legal guardians and assent from participants according to local requirements.

This is an open-label, parallel, Phase 3, two-arm study designed to investigate the efficacy and safety of **fitusiran** prophylaxis in male participants aged 1 to less than 12 years with **hemophilia** A or B with or without inhibitory antibodies to Factors VIII or IX. The study involves the administration of SAR439774, a solution for injection containing fitusiran as the active substance of nucleic acid origin, delivered via **subcutaneous injection**. The investigational medicinal product has been designated as an **orphan drug** and is available in both standard and paediatric formulations. The maximum daily dose is 50 mg, with a maximum total dose of 50 mg and a maximum treatment period of 40 months. The study is classified as a Category 2 trial and is not considered a low-intervention clinical trial.

The primary objective is to evaluate treatment efficacy during fitusiran prophylaxis and standard of care (SOC) periods in the fitusiran-naïve arm. The **primary endpoint** is the annualized treated bleeding rate (ABR) in the fitusiran primary efficacy period and in the SOC period. **Secondary endpoints** include annualized spontaneous bleeding rate (AsBR) in the fitusiran primary efficacy period and in the SOC period, annualized joint bleeding rate (AjBR) in the fitusiran primary efficacy period and in the SOC period, ABR in the fitusiran treatment period for both fitusiran-naïve participants (160 weeks) and rolled-over participants (60 weeks), change in physical activity, change in pain intensity, change in health-related quality of life (HRQoL), incidence, severity, seriousness, and relatedness of adverse events, change in total score and domain scores, and target joints resolution.

Participants eligible for enrollment must be 1 to less than 12 years of age at the time of enrollment and must have severe hemophilia A or B, defined as Factor VIII less than 1% or Factor IX equal to or less than 2%, as evidenced by central laboratory measurement at screening or documented medical record evidence. Participants must meet either inhibitor or non-inhibitor status criteria. Those with inhibitor status must require use of bypassing agents (BPA) for prophylaxis or on-demand therapy for at least the last 3 months prior to screening and meet specific Nijmegen-modified Bethesda assay results criteria, including an inhibitor titer of at least 0.6 BU/mL at screening, or an inhibitor titer of less than 0.6 BU/mL at screening with medical record evidence of 2 consecutive titers of at least 0.6 BU/mL, or an inhibitor titer of less than 0.6 BU/mL at screening with medical record evidence of 1 inhibitor titer of at least 0.6 BU/mL and a history of anamnestic response or severe allergic reaction or nephrotic syndrome. Non-inhibitor participants must require use of clotting factor concentrates (CFCs) for prophylaxis or on-demand therapy for at least the last 3 months prior to screening, have a Nijmegen-modified Bethesda assay inhibitor titer of less than 0.6 BU/mL at screening, and have no use of BPA to treat bleeding episodes for at least the last 3 months prior to screening. Participants must have adequate peripheral venous access as determined by the investigator to allow the blood draws required by the study protocol. Signed written informed consent must be obtained from the parent or legal guardian, as well as written or oral assent obtained from the participant, per local and national requirements.

The estimated recruitment start date for the study is December 19, 2025, with an estimated end date of December 30, 2031, resulting in an overall trial duration of approximately 6 years. The expected length of participant involvement varies depending on the arm, with fitusiran-naïve participants receiving treatment for 160 weeks and rolled-over participants receiving treatment for 60 weeks. The study involves a screening visit to assess eligibility criteria, followed by treatment visits during the fitusiran prophylaxis period and the SOC period for comparison. Follow-up visits are conducted to monitor efficacy and safety parameters, including bleeding rates, physical activity, pain intensity, health-related quality of life, and adverse events. An end-of-study visit is performed to complete final assessments. Conditions that may lead to early termination from the study include withdrawal of informed consent, significant protocol violations, adverse events that preclude continued participation, or investigator decision based on safety concerns.

The experimental medication utilized in this clinical trial is SAR439774, which contains the active substance fitusiran, a nucleic acid-based therapeutic agent. SAR439774 is formulated as a solution for injection administered via subcutaneous injection. The maximum daily dose is 50 mg, with a maximum total dose of 50 mg per administration. The maximum treatment period extends to 40 months. The product has been designated as an orphan drug under the European Union designations EU/3/14/1297 and EU/3/14/1298, reflecting its development for rare disease indications.

Two formulations of SAR439774 are employed in this study. The first formulation is intended for general use, while the second represents a paediatric formulation specifically developed for younger participants. Both formulations share identical active substance composition, pharmaceutical form, route of administration, and dosing parameters. The paediatric formulation has been specifically designed to meet the therapeutic needs of male participants aged 1 to less than 12 years with hemophilia A or B, with or without inhibitory antibodies to Factors VIII or IX.

The study design incorporates a comparator period designated as standard-of-care (SOC) therapy in the fitusiran-naïve arm, allowing for evaluation of treatment efficacy during fitusiran prophylaxis relative to conventional hemophilia management approaches. This open-label, parallel, two-arm Phase 3 study structure enables direct comparison between fitusiran prophylaxis and SOC treatment periods within the same participant cohort.

Efficacy will be assessed using the annualized treated bleeding rate (ABR) during the **fitusiran** primary efficacy period and during the standard of care period as the primary endpoint. Secondary efficacy endpoints include the annualized spontaneous bleeding rate (AsBR) during the **fitusiran** primary efficacy period and the standard of care period, and the annualized joint bleeding rate (AjBR) during the **fitusiran** primary efficacy period and the standard of care period. Additional secondary endpoints comprise the ABR during the **fitusiran** treatment period of 160 weeks for **fitusiran**-naïve participants and the ABR during the **fitusiran** treatment period of 60 weeks for rolled-over participants. Changes in physical activity, pain intensity, and health-related quality of life will be evaluated. Changes in total score and domain scores will be assessed, along with target joints resolution.