Periodic Reporting for period 3 - TUDCA-ALS (Safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS)) Reporting period: 2021-01-01 to 2022-06-30 Summary of the context and overall objectives of the project Amyotrophic lateral sclerosis (ALS) is a chronic non-communicable neurodegenerative rare disease that affects motor neurons in the brain, brainstem and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. ALS has an estimated prevalence of 5.40 cases per 100.000 population, corresponding to 40.000 patients at European level, and causes around 11,000 deaths each year. Although much has been achieved over the last two decades in understanding the disease complexity in ALS, there is a pressing need to find disease-modifying therapies that will slow disease progression and enable patients to gain any length in survival. Although this is a formidable challenge, there is one drug (riluzole) that slightly prolongs survival in ALS and is still the only agent with a “disease-modifying” effect. The effect of riluzole on survival in ALS is modest, but indicates that modifying disease progression is a realistic goal. Nonetheless, all subsequent drugs tested in ALS have failed to deliver advances in patient care.The “Safety and efficacy of tauroursodeoxycholic acid as add-on treatment in patients affected by amyotrophic lateral sclerosis” (TUDCA-ALS) study proposes a novel approach to overcome the current therapeutic impasse. TUDCA-ALS takes advantage of the results of a recent phase IIb study showing that, in patients who received TUDCA in addition to riluzole, the per-year decline rate in the revised-ALS functional rating scale (ALSFRS-R) was about 7 points smaller (on a 0-48 score) compared to riluzole only. This corresponds to a prolongation of median survival by 4-5 months. This strong indication of efficacy is further supported by the evidence that TUDCA has cytoprotective properties in animal models of neurodegenerative diseases.TUDCA-ALS aims to confirm and further measure the efficacy of TUDCA as a disease-modifier in ALS in a large-scale, phase III, clinical trial. We have assembled a consortium composed of leading European centres with established experience in ALS and a strong catching capability on this patient population. We plan to enrol 440 participants across seven countries in Europe (Italy, Germany, United Kingdom, France, Belgium, Netherlands and Ireland). We have also selected solid biomarkers related to disease progression and cytoprotective activity to test during the treatment period. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far During the first 36 months of the project, we have developed all the essential documents and tools needed to obtain regulatory approvals and to perform the clinical trial. Approximately 85% of the Investigational Medicinal Product (both TUDCA and placebo) supply required for the trial has been produced, packaged and labelled. All the required preparatory activities for the biomarker sub-study have been concluded. To guarantee quality control and regulatory compliance, we have selected a Contract Research Organisation with adequate experience in clinical trials at European level. Moreover, we have appointed an Independent Advisory Board and an Independent Ethics Board – Data Safety Monitoring Board to provide external guidance on scientific and ethics aspects related to the conduct of the project.In addition to the 7 clinical Consortium Partners, we have selected 18 other centres with relevant expertise in performing clinical trials on ALS. Involved clinical staff has been trained on trial procedures, in order to achieve harmonisation of clinical activities among centres. Regulatory approvals have been obtained in all the 7 countries involved in the project. Ethics approvals have been obtained for all the 25 centres taking part in the trial.A total of 328 patients has been screened for participation in the study in Italy, Germany, United Kingdom, France, Belgium, Netherlands and Ireland. Following a lead-in period of 3 months, patients meeting the eligibility criteria are randomly assigned to one of two treatment arms (TUDCA or identical placebo, in addition to riluzole) and followed-up for 18 months. Two-hundred forty-nine patients (63% of the target 440 participants) have been randomised to start treatment, while 26 patients are currently in the lead-in period, waiting to be randomised. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The TUDCA-ALS project represents today the best chance to find a new therapeutic strategy with a high potential to generate major advances in clinical practice for ALS. Should our proposed clinical trial prove the potential of TUDCA as a treatment aimed at reducing neuronal damage, its success will be a major breakthrough for the treatment of ALS, improving quality of life for the patients and families, as well as reducing the burden on society. In addition, we have designed the trial in order to identify innovative biomarkers that could assess early responses to treatment. The validation of these biomarkers, never assessed before in a main ALS trial, would be a major achievement in ALS trial methodology, notably for the investigation of novel therapies.Demonstration of TUDCA efficacy in ALS, combined with the validation of new biomarkers of cytoprotection, could be a milestone in developing novel neurodegenerative disease indications for TUDCA. This project implements all the regulatory requirements for obtaining marketing authorisation in case of a positive completion of the study project. This is expected to provide concrete benefits for patients with ALS.We also intend to valorise the entire dataset for further exploitation of results. Whether the trial produces a positive or negative outcome, the data generated can be used to help improve understanding of the disease natural history and heterogeneity, elucidate the value of candidate biomarkers and help improving future trial design and clinical staging studies. Overall, TUDCA-ALS will advance science in the field of ALS and more globally of neurodegenerative disorders, contribute to the development of novel therapeutic interventions, strengthen the competitiveness of European research, boost the European innovative capacity and reduce health care costs, ultimately benefiting patients and society as a whole. TUDCA-ALS logo Partners map
