Evaluation of Safety and Clinical Response of Intra-Arterial Autologous Mesenchymal Stem Cells in Pediatric Autoimmune Refractory Epilepsy and Rasmussen Encephalitis

The primary objective of this Phase I, open-label clinical trial is to evaluate the **safety** and tolerability of intra-arterial administration of autologous mesenchymal stem cells in patients with immune-mediated refractory epilepsies, including autoimmune refractory epilepsy and Rasmussen Encephalitis. This assessment is clinically relevant as it aims to determine the potential risks and adverse effects associated with this novel therapeutic approach, which could provide a new treatment avenue for patients with limited options due to the refractory nature of their condition.

Secondary objectives include:

• Assessing the clinical response to intra-arterial administration of autologous bone marrow mesenchymal cells by detecting changes in neurological assessments, neuropsychological evaluations, structural and functional neuroimaging tests, and neurophysiological tests.
• Determining the effect of therapy on the patient's immune system and mRNA profile, both peripherally in peripheral blood and locally in the primary sample obtained during surgery.
• Studying the molecular profile of the mesenchymal stem cells used in the trial and correlating them with the clinical outcome.

The clinical trial involves a **pediatric population** under 16 years of age, including both male and female participants. The study focuses on individuals diagnosed with **autoimmune refractory epilepsy** and **Rasmussen Encephalitis**, specifically those whose condition is refractory to first or second-line treatments, such as antiepileptic drugs and conventional immunomodulatory therapy. Participants may exhibit motor and/or cognitive impairments, and a subset includes those who have undergone epilepsy surgery related to Rasmussen's Encephalitis. The trial population is considered vulnerable, and the selection criteria require the acceptance of informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **Phase I** open-label study designed to evaluate the safety and clinical response of repeated-dose intra-arterial infusion of autologous mesenchymal cells in pediatric patients with **autoimmune refractory epilepsy** and **Rasmussen Encephalitis**. The primary objective is to assess the safety and tolerability of intra-arterial administration of autologous mesenchymal stem cells. The trial will measure dose-limiting toxicities, defined as MSC infusion-related grade 3 toxicities occurring within the first 28 days of treatment. The secondary endpoint is to assess the clinical response. The trial is expected to commence on January 24, 2025, and conclude by December 31, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age under 16 years, epilepsy of immune etiology refractory to first or second-line treatment, and the ability to perform necessary evaluations. Follow-up visits will be scheduled to monitor safety and efficacy, with assessments including CMR, electrophysiological tests, PET, and neuropsychological evaluations. The end-of-study visit will conclude the participant's involvement, summarizing the overall safety and clinical outcomes.

The expected length of participant involvement will vary depending on individual response and safety outcomes, with the possibility of early termination if dose-limiting toxicities are observed. Participants may also be withdrawn if they no longer meet the inclusion criteria or if they experience adverse events that compromise their safety. The trial will utilize a **cell suspension for injection** of **allogenic bone marrow-derived mesenchymal stem cells transduced with ICOVIR-5, ex vivo expanded**, administered via intra-arterial use. The study is not classified as a low-intervention trial, and it does not involve a pediatric formulation. The trial is conducted under the sponsorship of the Fundació Institut d'Investigació Biomèdica de Bellvitge IDIBELL.

The clinical trial involves the administration of **AloCelyvir**, an experimental medication formulated as a **cell suspension for injection**. The active substance in AloCelyvir consists of **allogenic bone marrow-derived mesenchymal stem cells transduced with ICOVIR-5**, which are ex vivo expanded. This investigational product is administered via **intra-arterial use**. The trial is designed to evaluate the safety and clinical response of repeated-dose intra-arterial infusion of these cells in children and adolescents with refractory epilepsies. The pharmaceutical form of AloCelyvir is specifically tailored for injection, ensuring the delivery of the therapeutic cells directly into the bloodstream through the arterial route. The frequency and dosage of administration are determined by the study protocol, with careful monitoring of participant compliance to ensure adherence to the dosing schedule.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies as deemed necessary by the clinical investigators. These non-experimental treatments are not specified in the trial data but are typically employed to manage the underlying condition or any adverse effects that may arise during the study. The trial does not include a placebo or comparator treatment, focusing solely on the evaluation of AloCelyvir's safety and efficacy. Participant compliance with the treatment regimen is monitored through regular assessments and follow-up visits, ensuring accurate data collection and analysis of the investigational product's impact on the target population.

Efficacy in this Phase I clinical trial will be assessed through the evaluation of clinical response in children and adolescents with refractory epilepsies. The primary endpoint focuses on measuring dose-limiting toxicities (DLTs), specifically **MSC infusion-related grade 3 toxicities** occurring within the first 28 days of treatment. This will help determine the safety and tolerability of the intra-arterial administration of autologous mesenchymal stem cells. Secondary endpoints include assessing the clinical response to the treatment. The trial will involve repeated-dose intra-arterial infusion of the investigational product, AloCelyvir, which consists of allogenic bone marrow-derived mesenchymal stem cells transduced with ICOVIR-5, ex vivo expanded. The clinical response will be monitored using various assessments, including CMR, electrophysiological tests, PET, and neuropsychological evaluations, as part of the eligibility criteria. The trial is designed to provide insights into the potential therapeutic benefits and safety profile of the treatment in the specified patient population.