Long-Term Follow-Up (LTFU) for Gene Therapy of Leukocyte Adhesion Deficiency-I (LAD-I). Phase I/II clinical study to evaluate the safety and efficacy of the infusion of autologous hematopoietic stem cells transduced with a lentiviral vector encoding the ITGB2 gene

The primary objective of this study is to evaluate the **long-term safety** and **efficacy** of the infusion of RP-L201, a gene therapy product, in patients with **Leukocyte Adhesion Deficiency-I (LAD-I)**. This is clinically relevant as it aims to determine the sustained impact and potential risks associated with the use of autologous CD34+ hematopoietic stem cells genetically modified with a lentiviral vector encoding the ITGB2 gene. The study focuses on assessing the therapeutic benefits and safety profile over an extended period, which is crucial for understanding the viability of this treatment option for LAD-I.

The clinical trial involves a total of **8 participants** diagnosed with **Leukocyte Adhesion Deficiency-I (LAD-I)**. 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 the Phase I/II parent study RP-L201-0318 and must have received the investigational product RP-L201 in that study. The trial does not include a vulnerable population. Participants are required to adhere to the study visit schedule and other protocol requirements, and they must have provided written informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status of the participants.

The clinical trial is designed to evaluate the long-term safety and efficacy of **RP-L201**, a gene therapy product, in patients with **Leukocyte Adhesion Deficiency-I (LAD-I)**. This study follows a **randomized, double-blind, controlled** design and is a continuation of the Phase I/II parent study RP-L201-0318. The trial is expected to conclude by April 2037, with recruitment having commenced in October 2023. Participants must have been enrolled in the parent study and received RP-L201 to be eligible for this long-term follow-up. The investigational product, **LADICell**, is administered via **intravenous infusion** and consists of autologous CD34+ hematopoietic stem cells genetically modified with a lentiviral vector encoding the ITGB2 gene.

The study involves a series of visits, beginning with an inclusion (screening) visit to confirm eligibility based on the criteria from the parent study. Follow-up visits are scheduled to monitor the primary endpoints, which include the incidence of significant infections, new skin or oral lesions, late-occurring serious adverse events (SAEs), and any malignancies related to the treatment. The persistence of the transgene and CD18 neutrophil expression will also be assessed. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the therapy. Participants are expected to remain in the study for the entire duration unless conditions such as non-compliance, withdrawal of consent, or significant adverse events necessitate early termination.

The clinical trial involves the administration of **LADICell**, an experimental gene therapy product. LADICell is composed of **autologous CD34+ haematopoietic stem cells** that have been genetically modified using a lentiviral vector encoding the **CD18 gene**. This product is designed to treat patients with Leukocyte Adhesion Deficiency-I (LAD-I). The pharmaceutical form of LADICell is an infusion, and it is administered via **intravenous infusion**. The dosing schedule and frequency of administration are determined based on the individual patient's condition and response to therapy. The product is not formulated for pediatric use, and it has been designated as an orphan drug under the designation number EU/3/16/1753.

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 and efficacy of the infusion of RP-L201, which is the sponsor product code for LADICell. Participant compliance with the treatment regimen is monitored through regular follow-up visits and assessments to ensure adherence to the dosing schedule and to evaluate the therapeutic outcomes.

The efficacy of the investigational product, RP-L201, will be assessed in a long-term follow-up study for patients with **Leukocyte Adhesion Deficiency-I (LAD-I)**. The primary endpoints for evaluating efficacy include the reduction of significant infections requiring hospitalization or intravenous antimicrobials, improvement or resolution of LAD-I-related neutrophilia and leukocytosis, and resolution of LAD-I-related skin rash or periodontal abnormalities. Additionally, the persistence of the transgene in peripheral blood (PB) cells will be measured, demonstrated by a vector copy number (VCN) of at least 0.1 in peripheral blood mononuclear cells (PBMCs) and PB CD15+ granulocytes. The persistence of CD18 neutrophil expression, defined by PB neutrophil CD18 expression to at least 10% of normal, and the persistence of CD11 a/b neutrophil co-expression will also be evaluated.

These efficacy parameters will be collected and analyzed at specified intervals throughout the study duration, which is estimated to conclude by April 30, 2037. The study will monitor for any new skin or oral lesions potentially caused by underlying LAD-I disease, any late-occurring serious adverse events (SAEs) related to the investigational treatment, and any incidence of secondary graft failure. The study will also assess allogeneic hematopoietic stem cell transplantation (HSCT)-free survival and event-free survival, defined as survival in the absence of graft failure or graft-versus-host disease (GvHD). The reduction of infection-related hospitalizations and prolonged hospitalizations beyond the initial 24 months of the parent study will be evaluated as part of the efficacy assessment.