Long-term Safety and Efficacy Evaluation of Fitusiran in Hemophilia A or B Patients With or Without Factor VIII or IX Inhibitory Antibodies

The primary objective of this study is to characterize the long-term **safety** and tolerability of fitusiran in patients with **Hemophilia A** or **Hemophilia B**, with or without inhibitory antibodies to Factor VIII or IX. This is clinically relevant as it aims to ensure that fitusiran, a therapeutic agent, can be safely administered over an extended period, which is crucial for chronic conditions like hemophilia that require ongoing management.

Secondary objectives include:

• Characterizing the efficacy and long-term efficacy of fitusiran by assessing the frequency of bleeding episodes, spontaneous bleeding episodes, and joint bleeding episodes. This is important for understanding the therapeutic impact of fitusiran on reducing bleeding events, which are a significant concern for patients with hemophilia.
• Evaluating the effects of fitusiran on health-related quality of life measures in participants aged 17 years or older. This objective is significant as it addresses the broader impact of treatment on patients' overall well-being and daily functioning.

The clinical trial involves a total of **263 participants** diagnosed with **Hemophilia A or Hemophilia B**. The study population is exclusively male, with participants required to be at least 12 years of age at the time of consent. All participants have previously completed a Phase 3 clinical trial involving fitusiran. The trial does not include a vulnerable population, and participants are expected to be capable of providing informed consent. The selection criteria emphasize the inclusion of individuals with severe forms of hemophilia who have prior experience with the investigational drug. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is designed to evaluate the long-term safety and efficacy of **fitusiran** in patients with **hemophilia A** or **hemophilia B**, with or without inhibitory antibodies to Factor VIII or IX. This study is structured as an open-label, long-term investigation, with a primary focus on characterizing the safety and tolerability of fitusiran. The trial is expected to span from April 24, 2019, to June 18, 2026, encompassing a total duration of approximately seven years. Participants eligible for this study must be male, at least 12 years of age, and have completed a previous Phase 3 fitusiran clinical trial. The study employs a **randomized, controlled** design, ensuring robust data collection and analysis.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria. This initial visit will involve a comprehensive assessment to ensure compliance with the study's requirements. Following the screening, participants will attend regular follow-up visits throughout the treatment period, during which the primary endpoint of treatment-emergent adverse events (TEAEs) will be monitored. Secondary endpoints include the annualized bleeding rate, spontaneous bleeding rate, joint bleeding rate, and changes in the Haemophilia Quality of Life Questionnaire for adults (Haem-A-QoL) physical health score for participants aged 17 and older.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term effects of the treatment. The expected length of participant involvement is contingent upon the completion of the study's duration, with early termination possible under specific conditions such as non-compliance with the protocol or the occurrence of significant adverse events. The study's design and procedures are meticulously crafted to ensure the collection of high-quality data, contributing to the understanding of fitusiran's safety and efficacy in the target population.

The clinical trial involves the administration of **fitusiran**, an experimental medication identified by the product code SAR439774. Fitusiran is a **solution for injection** and is administered via the **subcutaneous** route. The maximum daily dose is 80 mg, with a total maximum dose of 6240 mg over a treatment period of 78 weeks. The active substance, fitusiran, is a synthetic double-stranded siRNA oligonucleotide directed against antithrombin mRNA, covalently linked to a ligand containing three N-acetylgalactosamine residues. The pharmaceutical form is a solution for injection, and the medication is not a pediatric formulation.

In addition to the experimental treatment, the study includes several non-experimental treatments. One such treatment is the **Factor VIII Inhibitor Bypassing Fraction**, a human plasma protein administered intravenously. This treatment is a mixture of substances, including a human plasma fraction with Factor VIII inhibitor bypassing activity, also known as an anti-inhibitor coagulant complex or activated prothrombin complex concentrate. The pharmaceutical form is denoted as PHF00230MIG, and the treatment is not specified for pediatric use.

Another non-experimental treatment is **Antithrombin III Human**, administered subcutaneously. This protein-based treatment is also in the pharmaceutical form PHF00230MIG. It is used as an auxiliary treatment in the trial and is not specified for pediatric use.

**Eptacog Alfa (Activated)**, also known as recombinant human coagulation Factor VIIa, is administered intravenously. This protein-based treatment is in the pharmaceutical form PHF00231MIG and is used as an auxiliary treatment in the trial. It is not specified for pediatric use.

**Simoctocog Alfa**, a coagulation Factor VIII, is administered intravenously. This protein-based treatment is in the pharmaceutical form PHF00231MIG and is used as an auxiliary treatment in the trial. It is not specified for pediatric use.

Lastly, **Nonacog Alfa**, a coagulation Factor IX, is administered intravenously. This protein-based treatment is in the pharmaceutical form PHF00231MIG and is used as an auxiliary treatment in the trial. It is not specified for pediatric use.

The clinical trial titled "ATLAS-OLE: An Open-label, Long-term Safety and Efficacy Study of Fitusiran in Patients with Hemophilia A or B, with or without Inhibitory Antibodies to Factor VIII or IX" aims to assess the efficacy of **fitusiran**. Efficacy will be evaluated using several secondary endpoints, including the annualized bleeding rate, annualized spontaneous bleeding rate, and annualized joint bleeding rate during the treatment period. Additionally, changes in the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) physical health score will be assessed in participants aged 17 years and older.

The collection and analysis of these efficacy parameters will be conducted throughout the treatment period, with specific timepoints not explicitly detailed. The Haem-A-QoL is a validated tool used to measure the quality of life in individuals with hemophilia, focusing on physical health aspects. The trial is designed to provide comprehensive data on the long-term efficacy of fitusiran in managing bleeding rates and improving quality of life in patients with severe hemophilia A or B.