Phase 1/2 Open-Label Study of BAY 2599023 (Peboctocogene Camaparvovec) in Adults with Severe Hemophilia A

The primary objective of this study is to **investigate the safety and tolerability** of single ascending intravenous doses of BAY 2599023 (DTX201) in adult patients with severe **hemophilia A** who have been previously treated with Factor VIII (FVIII) products. This is clinically relevant as it aims to ensure that the gene therapy is safe for use in this patient population, potentially offering a new therapeutic option for managing severe hemophilia A.

Secondary objectives include identifying a dose of BAY 2599023 (DTX201) that will achieve sustained expression of vector-derived B-domain deleted human factor VIII above 5% at 6 months and 12 months following an intravenous administration. This is important for determining the efficacy of the treatment in maintaining therapeutic levels of factor VIII, which is crucial for reducing bleeding episodes and improving quality of life in patients with severe hemophilia A.

The clinical trial involves a total of **5 male participants** diagnosed with **severe hemophilia A**, a condition characterized by a baseline FVIII activity of less than 1%. The study population consists of adult males aged 18 years and older, who have been previously treated with FVIII products for a minimum of 150 exposure days. Participants are required to have been on prophylactic treatment or have experienced more than four bleeding events in the past year if on-demand therapy was used. The trial does not include female or vulnerable populations. Participants must adhere to specific contraception guidelines and agree not to donate biological materials during the study period. The selection criteria ensure that the participants are representative of the target population for assessing the safety and tolerability of the investigational drug BAY 2599023 (DTX201).

The clinical trial is designed to evaluate the **safety** and tolerability of BAY 2599023, an adeno-associated virus vector encoding human factor VIII, in adult patients with severe **hemophilia A**. This is a Phase 1/2 open-label, dose-finding study. The trial involves the administration of single ascending intravenous doses of BAY 2599023 to assess the incidence of adverse events and the expression pattern of factor VIII activity. The study is expected to run from November 2018 to May 2026, with participant involvement lasting up to 12 months post-administration.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, severity of hemophilia A, and prior treatment history. Following successful screening, participants will receive the investigational product and be monitored through regular follow-up visits to assess safety and factor VIII expression levels. The end-of-study visit will conclude the participant's involvement, provided no adverse events necessitate earlier termination. Conditions for early withdrawal include the occurrence of serious adverse events or non-compliance with study protocols.

Inclusion criteria require male participants aged 18 years or older with severe hemophilia A, previously treated with factor VIII products, and willing to adhere to contraception guidelines. The primary endpoint focuses on the incidence of adverse events, while secondary endpoints include the proportion of patients achieving a factor VIII expression above 5% at specified time points. The study is not categorized as low intervention and does not involve a pediatric formulation. Participants must agree to refrain from donating biological materials during the study period.

The clinical trial involves the administration of **BAY 2599023**, an experimental gene therapy product. BAY 2599023 is a **concentrate for solution for injection/infusion** and is designed for intravenous administration. The active substance in BAY 2599023 is **peboctocogene camaparvovec**, which is an adeno-associated virus serotype hu37 (AAVhu37) vector encoding the sequence for the expression of B-domain deleted human factor VIII (BDD hFVIII). This gene transfer product is intended to address the underlying genetic deficiency in patients with severe hemophilia A. The trial aims to evaluate the safety and tolerability of single ascending intravenous doses of BAY 2599023 in adult patients who have been previously treated with factor VIII products. The pharmaceutical form of BAY 2599023 is specifically formulated for intravenous use, ensuring direct delivery into the bloodstream for optimal therapeutic effect.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of BAY 2599023 to assess its safety profile and dose-response relationship. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure accurate assessment of the investigational product's effects. The trial does not include a pediatric formulation, and BAY 2599023 has been designated as an orphan drug, highlighting its potential to address a rare medical condition. The study is conducted under the sponsorship of Bayer AG, with adherence to regulatory standards for investigational medicinal products.

Efficacy in this clinical trial will be assessed through secondary endpoints focusing on the **expression pattern of FVIII activity**. The trial will evaluate the proportion of patients in each dose step who achieve an expression of FVIII above 5% at 6 months and 12 months following the intravenous administration of BAY 2599023. These measurements will provide insights into the therapeutic potential of the gene transfer treatment in adult patients with severe hemophilia A. The assessment will involve collecting and analyzing data at specified time points to determine the sustained expression levels of FVIII, which is critical for evaluating the efficacy of the treatment.