TUDCA-ALS will focus on amyotrophic lateral sclerosis (ALS) a rare neurodegenerative disorder, 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 at about 40.000 patients at European level. Treatments are modestly effective at best, and the majority of patients die within 3-5 years of diagnosis, often from respiratory failure. TUDCA-ALS is based on the results of a successful proof-of-concept trial and has the ambition to develop a novel therapy in patients with ALS, based on administration of tauroursodeoxycholic acid (TUDCA) in addition to riluzole. TUDCA-ALS aims to perform a state-of-art randomized control trial on safety and efficacy of TUDCA in patients with sporadic ALS, without cognitive involvement and to exploit the project results into a novel therapeutic treatment for ALS. The trial primary endpoint is deterioration of function measured with the ALS Functional Rating Scale Revised. The secondary endpoints are: (1) Survival time to invasive ventilation (tracheostomy) or death; (2) changes in quality of life parameters measured by the ALSAQ-40 questionnaire; (3) functional changes measured by Forced Vital Capacity, and the EQ-5D scale. Muscle force will be assessed by the MRC scale and a correlated analysis of function and survival will be performed. Two biomarkers will be measured: neurofilament levels in the CSF and serum and MMP-9 expression in serum. The latter is a possible biomarker of TUDCA efficacy. TUDCA-ALS is grounded on promising phase IIb clinical data and is expected to impact positively on the international research efforts on ALS. TUDCA-ALS aims to obtain concrete benefits for patients with ALS. If the trial will prove successful, the consortium will support the development of this treatment at European level by combining expert knowledge and patient cooperation.

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. Our pioneering work on riluzole showed that it is possible to modify ALS progression but all subsequent trials of potential neuroprotective agents have failed. Thus, drug development in ALS, including trial design, patient selection, and outcome measures must be re-engineered to break the current impasse. Nerve cell death in ALS is associated with inflammation, which contributes to cell damage, and is a logical target for therapy. Although therapeutic attempts to modify this have failed so far, the discovery of regulatory T cells (Tregs) as key players in controlling inflammatory processes opens new possibilities since defective Treg function is important in ALS. In fact, 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, HBc-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. We also integrate biomarkers for nerve cell damage into the trial design to provide proof of concept/mechanism. “Modifying Immune Response and OutComes in ALS” (MIROCALS) will test the hypothesis that ld IL-2-induced increases in Tregs result in decreased rates of nerve cell damage and that this effect can be detected early in the course of the disease using a range of blood and cerebrospinal fluid biomarkers. Our ambition is to develop a new therapy for ALS and through this novel trial design break the impasse in drug development of other disease-modifying agents 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.