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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TUDCA-ALS (Safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS))

Teaser

Summary

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 â€œdisease modifyingâ€ effect. The effect of riluzole on survival in ALS is modest, but indicates that modifying disease progression is a realistic goal in ALS. Nonetheless, all subsequent ALS drugs tested have failed to deliver advances in patient care.
The â€œSafety and efficacy of tauroursodeoxycholic acid as add-on treatment in patients affected by amyotrophic lateral sclerosisâ€ (TUDCA-ALS) study proposes a novel approach to overcome the current therapeutic impasse. TUDCA-ALS will take 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 of 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. Therefore, this large-scale, phase III, clinical trial aims to confirm and further measure the efficacy of TUDCA as a disease modifier in ALS. We have also selected solid biomarkers related to disease progression and cytoprotective activity to test during the 18-month treatment period. We have therefore assembled a consortium composed of leading European centres with established experience in ALS and a strong catching capability on this patient population.

Work performed

During the first eighteen 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 one third 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 on clinical trials at European level. Moreover, we have appointed an Independent Advisory Board and an Independent Ethics Board to provide external guidance on scientific and ethics aspects related to the conduct of the project.
In addition to the seven clinical Consortium Partners, we have selected seventeen 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 twenty-three centres, nine of which have started recruiting patients. A total of forty-one patients have been so far recruited in Italy, Germany, United Kingdom and France, and seventeen patients have been randomised to start treatment in Italy.

Final results

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 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.