Long-Term Follow-up: Phase I/II clinical study to evaluate the safety and efficacy of the infusion of RP-L102

The primary objective of this study is to evaluate the **long-term safety** following the infusion of hematopoietic cells transduced with a therapeutic lentiviral vector in patients with **Fanconi anemia subtype A (FA-A)**. This is clinically relevant as it aims to ensure the safety of gene therapy interventions over an extended period, which is crucial for patient health and the advancement of gene therapy as a treatment modality.

The clinical trial involves a total of **11 participants** diagnosed with **Fanconi anemia subtype A (FA-A)**. The study population includes both male and female subjects, with an age range encompassing children and adolescents. Participants were selected based on their prior enrollment in one of the RP-L102 parent studies and having received an autologous infusion of CD34+ enriched cells transduced ex vivo with a lentiviral vector carrying the FANCA gene. The trial does not specifically target a vulnerable population. Participants are expected to adhere to the study visit schedule and other protocol requirements, having provided written informed consent. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the long-term safety and efficacy of **RP-L102**, a gene therapy product, in patients with **Fanconi anemia subtype A (FA-A)**. This study is a continuation of previous trials (RP-L102-0418, RP-L102-0319, RP-L102-0118) and involves participants who have already received an infusion of autologous CD34+ enriched cells transduced ex vivo with a lentiviral vector carrying the FANCA gene. The trial is structured as a long-term follow-up study, with an estimated end date of July 31, 2038, and began recruitment on November 1, 2022.

The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. Participants will undergo a series of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as previous enrollment in the parent studies and receipt of the investigational product. Follow-up visits will be conducted to monitor the persistence of the therapeutic lentiviral vector in hematopoietic cells, assess hematologic stability, and evaluate the incidence of hematologic malignancies and solid organ tumors. The end-of-study visit will conclude the participant's involvement, summarizing the long-term outcomes of the gene therapy.

Participants are expected to be involved in the study for the entire duration, unless conditions arise that necessitate early termination, such as non-compliance with the study protocol or withdrawal of consent. The primary endpoints include evaluating the long-term safety of the infusion, the persistence of the therapeutic vector, and the stability of blood counts. Secondary endpoints are not specified. The study aims to provide comprehensive data on the long-term effects of the gene therapy, contributing valuable insights into its potential as a treatment for FA-A.

The clinical trial involves the administration of **Fancalen**, an investigational gene therapy product. Fancalen is formulated as an **infusion** and is administered via **intravenous infusion**. The active substance in Fancalen consists of **autologous CD34+ enriched cells** derived from patients with **Fanconi Anemia subtype A**. These cells are genetically modified ex vivo using a lentiviral vector that carries the **Fanconi Anemia Complementation Group A (FANCA) gene**. The product is designed to correct the genetic defect in the patient's hematopoietic cells, potentially restoring normal function and stability to the bone marrow and peripheral blood cells. The administration of Fancalen is a single infusion, and the dosing schedule is determined based on the patient's specific cell count and clinical condition. Compliance with the treatment protocol is monitored through regular follow-up assessments and laboratory evaluations.

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 safety and efficacy of the investigational product, Fancalen. The trial aims to assess long-term safety, persistence of the therapeutic lentiviral vector, and potential correlations with hematologic stability. Additionally, the study will monitor for any replication-competent lentivirus and evaluate the phenotypic correction of bone marrow and peripheral blood cells. The trial also includes a preliminary assessment of the incidence of hematologic malignancies and solid organ tumors in the context of the underlying rates in the Fanconi Anemia patient population.

The efficacy of the clinical trial will be assessed through several primary endpoints focused on evaluating the long-term outcomes of the infusion of RP-L102, a gene therapy product for patients with **Fanconi Anemia**. The primary endpoints include determining the long-term persistence of the therapeutic lentiviral vector (LV) in hematopoietic cells within the bone marrow and blood, and evaluating potential correlations between the persistence of the provirus/transgene and hematologic stability, defined as the absence of bone marrow failure or hematologic malignancy. Additionally, the trial will assess long-term clonality patterns beyond the three-year follow-up stipulated in the parent studies.

Further efficacy assessments will involve evaluating the long-term stability and normalization of blood counts in patients following the infusion of autologous FANCA-corrected hematopoietic cells. The phenotypic correction of bone marrow and peripheral blood cells will also be determined by assessing their resistance to DNA-damaging agents in long-term follow-up after gene therapy. The incidence of hematologic malignancies, such as acute myeloid leukemia and myelodysplastic syndrome, as well as solid organ tumors, including squamous cell carcinoma of the head and neck, will be preliminarily assessed. These occurrences will be evaluated in the context of the underlying rates of these malignancies in Fanconi Anemia patient populations.