Design of a randomized, placebo-controlled, Phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers: The ATLAS study

Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS

Trial of antisense oligonucleotide tofersen for SOD1 ALS

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in METHODS: In this phase 3 trial, we randomly assigned adults with RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons wit

Relevance of the Lin's and Host hydropedological models to predict grape yield and wine quality

The adoption of precision agriculture in viticulture could be greatly enhanced by the diffusion of straightforward and easy to be applied hydropedological models, able to predict the spatial variability of available soil water. The Lin's and Host hydropedological models were applied to standard soil series descriptions and hillslope position, to predict the distribution of hydrological functional units in two vineyard and their relevance for grape yield and wine quality. A three-years trial was carried out in Chianti (Central Italy) on Sangiovese. The soils of the vineyards differentiated in structure, porosity and related hydropedological characteristics, as well as in salinity. Soil spatial variability was deeply affected by earth movement carried out before vine plantation. Six plots were selected in the different hydrological functional units of the two vineyards, that is, at summit, backslope and footslope morphological positions, to monitor soil hydrology, grape production and wine quality. Plot selection was based upon a cluster analysis of local slope, topographic wetness index (TWI), and cumulative moisture up to the root limiting layer, appreciated by means of a detailed combined geophysical survey. Water content, redox processes and temperature were monitored, as well as yield, phenological phases, and chemical analysis of grapes. The isotopic ratio δ<sup>13</sup>C was measured in the wine ethanol upon harvesting to evaluate the degree of stress suffered by vines. The grapes in each plot were collected for wine making in small barrels. The wines obtained were analysed and submitted to a blind organoleptic testing. <br></br> The results demonstrated that the combined application of the two hydropedological models can be used for the prevision of the moisture status of soils cultivated with grape during summertime in Mediterranean climate. As correctly foreseen by the models, the amount of mean daily transpirable soil water (TSW) during the growing season differed considerably between the vineyards and increased significantly along the three positions on slope in both vineyards. The water accumulation along slope occurred in every year, even during the very dry 2006. The installation of indicators of reduction in soils (IRIS) tubes allowed confirmation of the occurrence of reductive processes in the most shallow soil. <br></br> Both Sangiovese grape yield and quality of wine were influenced by the interaction between TSW content and salinity, sometimes contrary to expectations. Therefore, the studied hydropedological models were not relevant to predict grape yield and wine quality in all the hydrological functional units. The diffusion of hydropedological models in precision viticulture could be boosted considering salinity along with topography and soil hydrological characteristics

Prevalence of surgical procedures at symptomatic onset of prion disease

This case-control study examines the frequency of invasive procedures at the onset of prion disease symptoms to determine the scope of the risk of contamination to future patients