Long-Term Follow-up of Autologous CD34+ Cells Transduced with Lentiviral Vector Carrying FANCA Gene in Patients with Fanconi Anemia Subtype A

The primary objective of this clinical study is to evaluate the long-term (**LT**) safety and efficacy of the infusion of autologous **CD34+** cells transduced with a lentiviral vector carrying the **FANCA** gene in patients with **Fanconi anemia** subtype A. This involves assessing the LT safety after infusion of hematopoietic cells transduced with the therapeutic lentiviral vector, determining the LT persistence of the therapeutic lentiviral vector (provirus) in hematopoietic cells in the bone marrow and blood, and evaluating potential correlations between provirus/transgene persistence and hematologic stability. Additionally, the study aims to determine LT clonality patterns beyond the 3-year follow-up stipulated in the Phase I/II study, evaluate replication-competent lentivirus (RCL) in serum and peripheral blood cells when relevant, and determine LT stability and normalization of blood counts in patients after infusion of autologous FANCA-corrected hematopoietic cells. Furthermore, the study seeks to determine the phenotypic correction of bone marrow and peripheral blood cells in long-term follow-up after gene therapy and enable preliminary assessment of the incidence of hematologic malignancies and solid organ tumors.

The clinical trial involves participants diagnosed with **Fanconi anemia (subtype A)**. The sponsor has not provided the total number of participants. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on their previous enrollment in the clinical phase 1/2 study FANCOLEN-I, where they received an infusion of autologous CD34+ enriched gene-corrected hematopoietic cells. The trial includes a vulnerable population, indicating that special considerations are in place for their protection. Participants are required to adhere to the study visit schedule and other protocol requirements, and they must have provided written informed consent. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not disclosed further details regarding the general health status of the participants.

The clinical trial is designed to evaluate the long-term safety and efficacy of **autologous CD34+ enriched cells** transduced with a lentiviral vector carrying the FANCA gene in patients with **Fanconi anemia subtype A**. This study is a continuation of a Phase I/II trial and follows a **randomized, double-blind, controlled** design. The trial is expected to run until October 2034, with participant recruitment having commenced in November 2019. The primary objectives include assessing the long-term safety of the therapeutic lentiviral vector, its persistence in hematopoietic cells, and the stability and normalization of blood counts post-infusion. Secondary objectives involve evaluating the phenotypic correction of bone marrow and peripheral blood cells and the incidence of hematologic malignancies.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility, which requires prior enrollment in the initial Phase I/II study and receipt of the gene-corrected hematopoietic cells. Follow-up visits will be scheduled to monitor safety and efficacy outcomes, including blood-based evaluations and assessments of adverse events. The end-of-study visit will conclude the participant's involvement, summarizing the long-term effects of the treatment. The expected duration of participant involvement is contingent upon the study's timeline, with conditions for early termination including non-compliance with protocol requirements or the development of significant adverse events.

Safety assessments will focus on integration site analysis in peripheral blood mononuclear cells, evaluation of replication-competent lentivirus, and documentation of adverse events such as hospitalizations or the development of malignancies. Efficacy assessments will include monitoring peripheral blood counts and evaluating phenotypic correction through chromosomal fragility tests. Participants who have undergone allogeneic hematopoietic stem cell transplantation will also be followed, although specific evaluations may be omitted if prior assessments show no presence of the transgene. The trial aims to provide comprehensive data on the long-term impact of the gene therapy in this patient population.

The clinical trial involves the administration of the experimental medication **Fancalen**, which is an **infusion** of **autologous CD34+ enriched cells** derived from patients with **Fanconi Anemia Subtype A**. These cells are transduced ex vivo with a **lentiviral vector** carrying the **Fanconi Anemia Complementation Group A (FANCA) gene**. The pharmaceutical form of Fancalen is an infusion, and it is administered via the **intravenous route**. The frequency of administration is determined by the study protocol, and the medication is classified as an orphan drug, with the designation number EU/3/10/822. The active substance is a structurally diverse substance used in cell therapy, specifically targeting hematopoietic stem cells. The product is developed by Rocket Pharmaceuticals, Inc., and is identified by the sponsor product code RP-L102.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on evaluating the long-term safety and efficacy of the gene therapy provided by Fancalen. The trial aims to assess the persistence of the therapeutic lentiviral vector in hematopoietic cells, the stability and normalization of blood counts, and the phenotypic correction of bone marrow and peripheral blood cells. Participant compliance with the dosing schedule is monitored according to the study protocol, ensuring adherence to the treatment regimen. The trial does not specify a maximum daily dose or total dose amount, and the treatment period is determined by the study's objectives and design.

Efficacy in the clinical trial will be assessed through a series of blood-based evaluations and ongoing assessments. The primary efficacy parameters include the evaluation of peripheral blood counts and the assessment of phenotypic correction via peripheral blood T-lymphocyte **DEB chromosomal fragility**. These assessments aim to determine the long-term stability and normalization of blood counts in patients following the infusion of autologous FANCA-corrected hematopoietic cells. The efficacy assessments will be conducted at specified intervals throughout the trial to monitor the persistence of the therapeutic lentiviral vector (LV) in hematopoietic cells and to evaluate potential correlations between provirus/transgene persistence and hematologic stability. The trial will also enable a preliminary assessment of the incidence of hematologic malignancies and solid organ tumors, providing insights into the long-term therapeutic benefits of the gene therapy.