Long-Term Safety Evaluation of Valoctocogene Roxaparvovec in Patients with Severe Hemophilia A Following Prior Gene Therapy with BMN 270

The primary objective of this study is to evaluate the long-term **safety** of BMN 270, also known as valoctocogene roxaparvovec, in subjects with severe **hemophilia A** who have previously received this gene therapy in a prior BioMarin clinical trial. This objective is clinically relevant as it aims to ensure the sustained safety profile of BMN 270, which is crucial for its potential use as a long-term treatment option for hemophilia A, a condition characterized by a deficiency in clotting factor VIII leading to excessive bleeding.

Secondary objectives include:

• Evaluating the long-term effects of BMN 270 in participants with hemophilia A who were previously treated in a BioMarin clinical trial. This is important for understanding the enduring efficacy and potential benefits of the therapy.
• Assessing the use of hemostatic agents, such as emicizumab, FVIII replacement therapy, efanesoctocog, and all approved hemostatic agents, which is essential for determining the necessity and frequency of additional treatments post-gene therapy.
• Evaluating the long-term impact of BMN 270 on health-related quality of life (HRQoL), which provides insights into the overall well-being and life satisfaction of patients receiving this treatment.

The clinical trial involves a total of **184 participants** diagnosed with **Hemophilia A**. The study population consists exclusively of male subjects, with an age range that includes both adults and adolescents. Participants were selected based on their completion of the End of Study Visit in their primary treatment study or their current enrollment in one of the specified studies, with a minimum of 24 months of post-infusion follow-up. The trial does not include a vulnerable population, and participants are required to provide informed consent. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial aims to evaluate the long-term safety of BMN 270.

The clinical trial is designed to evaluate the long-term safety of **valoctocogene roxaparvovec** in subjects with severe **Hemophilia A** who have previously participated in a BioMarin clinical trial. This is a Phase IV, non-randomized, open-label study. The trial will monitor participants over an extended period, with an estimated end date in November 2036. Participants eligible for this study must have completed the end-of-study visit in their primary treatment study or have completed a minimum of 24 months of post-infusion follow-up. The primary endpoint focuses on the occurrence of adverse drug reactions, serious adverse events, and events of special interest, such as hepatotoxicity, thromboembolic events, development of FVIII inhibitors, transmission to third parties, and integration with a theoretical risk of tumorigenesis. Secondary endpoints include changes in annualized bleeding rate, FVIII activity over time, annualized use of concomitant hemostatic medications, and changes in Haemo-QoL-A.

The trial involves a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the criteria outlined. Follow-up visits will be conducted periodically to assess safety and efficacy parameters, including laboratory tests and clinical evaluations. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any ongoing safety concerns are addressed. The expected length of participant involvement is contingent upon the study's duration, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Participants may also be withdrawn if they fail to comply with the study protocol or if the sponsor decides to terminate the study for any reason. The investigational product, **ROCTAVIAN**, is administered as a solution for infusion via intravenous use, with a maximum treatment period of one day. The study aims to provide comprehensive data on the long-term safety profile of the gene therapy in a real-world setting.

The clinical trial involves the administration of **valoctocogene roxaparvovec**, marketed under the name **ROCTAVIAN**, which is a **solution for infusion**. This experimental medication is an adeno-associated viral vector serotype 5 containing a B-domain deleted variant of the human coagulation factor VIII gene, also known by its synonyms **AAV-hFVIII-SQ** and **BMN 270**. The pharmaceutical form is a solution for infusion, with a concentration of 2 × 10¹³ vector genomes/mL. The route of administration is **intravenous use**, and the maximum total dose administered is 60 trillion vector genomes. The treatment is designed for a maximum period of one day. The medication is not a pediatric formulation and is designated as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the long-term safety of the experimental gene therapy in subjects with severe **hemophilia A**. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial is conducted under the sponsorship of BioMarin International Limited, and the product is authorized for use in the European Union.

Efficacy in the clinical trial will be assessed using several secondary endpoints. These include changes in the annualized bleeding rate (ABR), which will account for both treated bleeds and all bleeds. Additionally, **Factor VIII (FVIII)** activity will be measured over time using chromogenic substrate assay (CSA) and one-stage assay (OSA) methods. The annualized use of concomitant hemostatic medications will also be evaluated, focusing on the annualized FVIII utilization and infusion rate. Furthermore, changes in the Haemophilia Quality of Life Questionnaire for Adults (Haemo-QoL-A) will be assessed to determine the impact on quality of life. These parameters will be collected and analyzed at specified intervals throughout the study to provide a comprehensive evaluation of the treatment's efficacy.