A Global, Open-label, Adaptive Design Study to Investigate the Efficacy and Safety of SerpinPC in Subjects With Severe Hemophilia A or Moderately Severe to Severe Hemophilia B (PRESent-2)

The primary objective of this study is to evaluate the **efficacy** and **safety** of prophylactic SerpinPC administered subcutaneously in subjects with moderately severe to severe **hemophilia B**. This is clinically relevant as it aims to provide a potential therapeutic option for managing bleeding episodes in this patient population, thereby improving their quality of life and reducing disease burden.

Secondary objectives include:

• To evaluate the **tolerability** of SerpinPC.
• To evaluate the efficacy and safety of prophylactic SerpinPC in subjects with **hemophilia**.
• To further characterize the **pharmacokinetic (PK) profile** of SerpinPC.

The clinical trial involves a total of **100 participants** diagnosed with either **Severe Hemophilia A** or **Moderately Severe to Severe Hemophilia B**. The study population consists exclusively of male subjects aged between 12 and 65 years. Participants were selected based on specific inclusion criteria, including the severity of their condition and their current treatment regimen, whether prophylactic or on-demand. All subjects are required to have adequate hematologic, hepatic, and renal function, and a D-dimer level of ≤750 μg/L. The trial does not include female subjects and focuses on a vulnerable population. Participants' lifestyle considerations, such as diet and physical activity, are not specified in the available data. The selection process ensures that subjects have a documented history of bleeding episodes and are not experiencing active bleeding at the time of baseline assessment.

The clinical trial is designed to evaluate the **efficacy** and safety of SerpinPC, a **solution for injection** containing **human alpha-1 proteinase inhibitor, modified**, in subjects with severe Hemophilia A or moderately severe to severe Hemophilia B. This is a global, open-label, adaptive design study, categorized as Phase IIb, and is not considered low intervention. The trial will involve male subjects aged 12 to 65 years who meet specific inclusion criteria, such as being part of a prophylaxis program or having a history of acute bleeding episodes. The study will exclude individuals with high titer inhibitors or those requiring bypass agents.

The trial will be conducted over an estimated period ending in July 2026, with recruitment starting in August 2023. Participants will receive SerpinPC via subcutaneous injection, with a maximum daily dose of 1.2 mg/kg and a treatment period of up to 48 weeks. The primary endpoint is the annualized bleeding rate (ABR) of treated bleeds in subjects with Hemophilia B previously on an on-demand treatment regimen. Secondary endpoints include ABR of treated spontaneous bleeds, joint bleeds, and total coagulation factor consumption, among others.

Study visits will follow a structured sequence, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Baseline assessments will be conducted, and participants will be monitored for any bleeding episodes in the 7 days prior to dosing. Follow-up visits will occur at regular intervals to assess safety, efficacy, and pharmacokinetic concentrations of SerpinPC. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced during the trial.

Participant involvement is expected to last up to 48 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide comprehensive data on the safety and efficacy of SerpinPC in managing bleeding episodes in the target population, contributing valuable insights into the treatment of Hemophilia A and B.

The clinical trial involves the administration of **SerpinPC**, an experimental medication formulated as a **solution for injection**. The active substance in SerpinPC is a **human alpha-1 proteinase inhibitor, modified**, which is classified under the origin category of "Protein - Other." The pharmaceutical form of SerpinPC is a solution intended for subcutaneous injection. The dosage regimen for this trial specifies a maximum daily dose of 1.2 mg/kg, with the same maximum total dose amount. The treatment period is set for a maximum of 48 weeks. The administration route is subcutaneous injection, and the medication is not formulated for pediatric use. The trial aims to evaluate the efficacy and safety of SerpinPC in subjects with moderately severe to severe hemophilia B.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of SerpinPC. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the prophylactic potential of SerpinPC in the specified patient population, with the primary objective being the evaluation of its efficacy and safety profile.

The efficacy of SerpinPC in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the annualized bleeding rate (ABR) of treated bleeds during the observation period and under SerpinPC at the end of Part 2, Week 24, in subjects with **Hemophilia B** who were previously receiving "on-demand" treatment. Secondary endpoints include the ABR of treated bleeds other than those defined by the primary endpoint, such as bleeds during the first 48 weeks and in subjects receiving prior "prophylaxis" treatment. Additionally, the ABR of treated spontaneous bleeds and treated spontaneous joint bleeds will be evaluated. The study will also measure all bleeds requiring treatment, expressed as ABR, including all treated bleeds and those that would typically be treated with factor concentrate or bypass agents if therapy were available.

Other secondary endpoints include the total consumption of coagulation factor and/or bypass products, pharmacokinetic (PK) concentrations of SerpinPC throughout the study, and the Haemophilia-specific Quality of Life Instrument for Adults (Haem-A-QoL) Physical Health scale in subjects aged 17 to 65 years with hemophilia at the end of Part 3, Week 24. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the impact of SerpinPC on bleeding rates and quality of life in the target population.