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Efficacy and safety of low-dose IL-2 (ld-IL-2) as a Treg enhancer for anti-neuroinflammatory therapy in newly diagnosed Amyotrophic Lateral Sclerosis (ALS) patients

Periodic Reporting for period 3 - MIROCALS (Efficacy and safety of low-dose IL-2 (ld-IL-2) as a Treg enhancer for anti-neuroinflammatory therapy in newly diagnosed Amyotrophic Lateral Sclerosis (ALS) patients)

Reporting period: 2018-09-01 to 2020-02-29

Amyotrophic Lateral Sclerosis (ALS) is a fatal degenerative disorder of the brain and spinal cord affecting some 40,000 individuals in Europe, causing 11,000 deaths each year. Nerve cell death in ALS is associated with inflammation making it a logical target for therapy. Regulatory T cells (Tregs) are key players in controlling inflammatory processes. In ALS, Treg numbers and function predict rates of disease progression and survival. Low-dose interleukin-2 (ld IL-2) safely and specifically increases and activates Tregs in conditions such as type 1 diabetes, Hepatitis Bc-vasculitis and chronic graft-versus-host disease, so ld IL-2 has the potential to significantly improve survival and deliver a therapeutic breakthrough in ALS. Our ambition is to develop a new therapy for ALS and through this novel trial design break the impasse in drug development in ALS. The impact will be to enhance quality of life and care for people with ALS, and provide a robust model for Industry to encourage investment in ALS and other neurodegenerative diseases.

The program is structured into 7 work packages (WP): WP1 dedicated to the strategic and administrative management of the project; WP2 developing all Good Clinical Practice (GCP) Essential Documents, get approval from regulatory bodies and Institutional Review Boards, and organize the preparation of treatment units, clinical data collection, sample collection, banking and assays, all in compliance with the Good Clinical Practices and Good Clinical Laboratory Practices; WP3 to conduct the clinical trial; WP4 to establish the effect of low dose IL-2 on key effectors and regulators of the neuro-inflammatory process and their relationship with response to treatment and disease activity; WP5 to try to establish proof of concepts that will shorten and simplify future trials by investigating a number of candidate biomarkers in different body fluids; WP6 to see what genes are expressed in the blood in response to treatment with riluzole and a low dose of interleukin-2 (ld-IL2) over a period of time and to screen the patients for rare variants sequences in genes associated with ALS or T-lymphocyte regulation (the process the IL2 treatment is targeting); WP7 to ensure the dissemination and communication through international visibility as well as the optimal exploitation of the results of MIROCALS.
In the first 3 periods of the project the following work has been done:
In WP1, management tools and templates for the scientific and financial monitoring of the project have been set up. Three physical meetings with all partners have been organised. Partners have been briefed at those meetings on the general H2020 rules and reporting procedures.
In WP2, dossier files for Regulatory and IRBs review were developed and successfully submitted to France and UK Regulatories and IRBs. 17 Centres were selected, trained, contracted and activated. Three Study Committees were constituted and installed (TMT, TSC, and DSMB). All tools necessary for running the trial were developed, assembled or purchased, and distributed to Clinical Centres. The Central lab was selected and contracted; Validation studies for cytometry were successfully performed and SOPs were drafted. The CMO for treatment preparation was selected and contracted. In WP3, during Period 3, 149 patients were screened and 143 patients completed the 3-month run-in period and were randomised. In total, from June 19th 2017 to October 29th 2019, end of recruitment period, 17 Centres included 304 patients (33% more than expected), of whom 220 completed the 3-month run-in period and were randomised in the RCT (102% of overall target), while 84 dropped-out before randomisation.
During Period 3, 740 blood samples were collected by centres, transported (y courier UPS, and 732 were analysed for cytometry by the subcontracted Central Lab Biocytex. Overall, 1139 cytometry blood samples were collected by centres and transported to BioCytex.
Overall 2481 treatments packages were ordered (by Centres) for the 220 patients randomised, manufactured (by the CMO - BathAsu), transported to centres by courier and dispensed to patients either during patient visit to centre or at patient’s home by courier.
Database management was performed on the collected data, and a data file ready for analysis was blindly prepared for the Independent DSMB statistician April 2019 before the second DSMB Trial assessment.
In WP4, technical approaches have been set-up to perform comprehensive analysis of Treg frequency, phenotype, and function in peripheral blood, to examine monocytes/macrophages subsets and polarized activation in peripheral blood and CNS, to measure soluble markers of innate immunity and inflammation in peripheral blood and CNS, to measure inflammation-associated circulating microRNA in peripheral blood, and to measure sensitivity of Treg to IL-2. These approaches have been validated on banked samples from a preliminary phase II study of IL2 in ALS patients (IMODALS study).
In WP5, for serum and plasma analyses of pNFH UGOT has evaluated new assays, both commercial and in-house, for various neurofilaments. These efforts have resulted in one manuscript that is under review in Neuroscience Letters and another manuscript is under preparation. An assay for NFL has been developed and validated for NFL in serum/plasma. This assay has been tested on banked samples from a preliminary phase II study of IL2 in ALS patients (IMODALS study). A project for developing an in-house assay for NFM has been initiated.
In WP6, preliminary activities were conducted to see what genes are expressed in the blood in response to treatment with riluzole and a low dose of interleukin-2 (ld-IL2) over a period of time and to screen the patients for rare variants sequences in genes associated with ALS or T-lymphocyte regulation (the process the IL2 treatment is targeting).
In WP7, were (i) established the MIROCALS logo and website; (ii) established an area within the Motor Neurone Disease Association (MNDA) website for MIROCALS and drafting an information sheet to be released directly after site activations; (iii) disseminated information about MIROCALS throughout National (UK, French) professional networks and internationally via MNDA through the International ALS/Motor Neurone Disease Alliance and the Annual Symposia.
Living with ALS is a constant burden, due to muscle weakness and respiratory impairment. Finding a cure early in the course of the disease, before severe disability occurs, would mean dramatically improving quality of life for the patients and families, and reducing the burden on society. We firmly believe that by building on a strong model of ALS pathogenesis, we are proposing a sound approach towards effective interventions in ALS. MIROCALS proposed clinical trial, designed to demonstrate efficacy, should prove the potential of low dose IL-2 as a treatment aimed at stopping neuronal damage. In addition, we have designed the trial in order to identify biomarkers that could assess early responses to treatment. The validation of these biomarkers would be a major achievement in ALS trial methodology, notably for investigation of novel therapies.