Abstract Introduction Most published economic studies about the burden of amyotrophic lateral sclerosis (ALS) have measured direct and indirect costs but did not consider the perspective of patients and families. Materials and methods The French ALS patient association, ARSLA, contacted 15 ALS reference centers to recruit a random sample of ALS patients stratified by age and severity accepting to participate in a structured interview survey. The objective was to document the out-of-pocket (OOP) expenses associated with ALS for patients and families in 2024. Results Fifty patients with a mean age 61.5 years (SD 12) participated in the survey. The average time since diagnosis was 28.9 months (SD 26.8). Most patients had disabling motor impairment, half of them (n = 26, 52%) affected 4 limbs, 27 (54%) required noninvasive respiratory support and 11 (22%) nutritional support. A proportion of 48% of patients or caregivers reported Out-of-Pocket (OOP) expenses for mobility equipment, 50% for home modifications, 40% for vehicle adaptations, and 54% for paying for paid caregivers. The mean annual OOP expenses was €7,764 (SD 9,776) in total of which home adaptations averaged €3,074 (SD 6,583), personal vehicle adaptation €2,774 (SD 5,239) and paid caregivers €1,279 (SD 3,351). The factors statistically significant for higher overall OOP expenses were the duration of ALS since diagnostic (p = 0.026) and use of paid caregivers (p = 0.005). The support of family caregivers was almost systematic (88%), involving spouses (95.5%), children (22.7%) and relatives (13.6%). The mean annual loss of family income associated with professional change of patients and family caregivers was €7,633. When added to the OOP, the mean total annual economic burden was €15,397. Conclusion Despite the full coverage of all ALS-related health expenditures within the French healthcare system and additional associated financial support, it remains a substantial economic burden for patients and families to manage this condition. Clinical trial registration Not applicable.

A variety of common and rare genetic factors have been implicated in the development of amyotrophic lateral sclerosis (ALS), and the evidence is that a genetic component is present in most affected individuals. However, our current understanding of ALS genetics causally explains only a small proportion of sporadic ALS, which accounts for over 90

Objective To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort. Patients and Methods Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline. Results In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 ± 0.5 at baseline to 0.22 ± 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 ± 9.0 pg/ml at baseline to 29.2 ± 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03). Conclusion Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.

Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.

Objectives The identification of bi-allelic intermediate ATXN2 repeat expansions in a pedigree with amyotrophic lateral sclerosis (ALS) through clinical testing prompted us to investigate its relevance in the wider ALS population.Methods ATXN2 repeat size was assessed in a large international cohort of ALS patients (n=6653 from Project MinE) and in neurologically intact control populations (n=13 515 controls from Project MinE and gnomad). For bi-allelic cases, we retrieved medical records, family history and MRI imaging. For familial cases, we obtained DNA samples from relatives for segregation analyses.Results In total, we identified bi-allelic intermediate ATXN2 repeat expansions in five familial cases from three different pedigrees and five apparently sporadic cases. There is a relatively homogeneous phenotype characterised by lower limb onset and long survival (median 6 years) without significant cerebellar atrophy. Bi-allelic expansions were absent in controls (0 out of 13 515).Discussion Here we report an apparently novel autosomal recessive form of familial ALS caused by bi-allelic intermediate ATXN2 repeat expansions, which is characterised by high penetrance, lower limb onset and slow progression. Although rare, testing for ATXN2 expansions should be performed in the clinical setting given its relevance to prognosis and genetic counselling.

OBJECTIVE:Digital technologies hold promise for transforming healthcare by enhancing personalized treatments and offer valuable opportunities to improve patient care. Here, we evaluated several novel, self-administered, home-based, digital endpoints for their association with corresponding conventional standard clinical measures (primary) in people living with Amyotrophic Lateral Sclerosis (ALS). METHODS:This was a longitudinal study in people with ALS who were followed up to 9 months. A total of 33 participants were enrolled in the study. At each of six visits, participants were evaluated with a battery of conventional standard measurements to determine ALS disease progression and quality of life. Between visits, participants performed weekly home-based self-assessments with digital health technologies (DHT) and self-administered ALSFRS-R. Cross-sectional analysis of DHTs anchored to ALSFRS-R and longitudinal analyses were performed and compared to standard clinical measures. RESULTS:Of the 33 participants, 20 completed the study, and 13 discontinued before completing the planned 9-month follow-up mainly due to disease progression. The distribution of various digital metrics in home-based assessments corresponded well with the sub-scores of ALSFRS-R in the cross-sectional analyses, with the strongest construct validity for digital speaking rate. In the longitudinal analysis, a weak but significant trend in most metrics was observed, with the strongest trend in the duration of the Timed Up and Go (high variability between participants). INTERPRETATION:The findings from this study provide insights into the potential of digital endpoints to evaluate people living with ALS with the goal of reducing the burden of study participation and improving the efficiency of ALS clinical trials.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder with marked biological heterogeneity. Despite extensive research, reliable prognostic biomarkers remain limited, with neurofilament light chain (NfL) being the only marker increasingly implemented in clinical practice. The objective of this study is to assess and compare the prognostic value of NfL, circulating markers of central nervous system (CNS) barrier dysfunction, inflammatory mediators, kynurenine pathway metabolites, and global metabolomic profiles in patients with ALS. Seventy-two patients with ALS from the prospective multicenter METABALS cohort were included. Serum, cerebrospinal fluid (CSF), and urine samples were collected at diagnosis. NfL concentrations, markers of blood–brain and blood–spinal cord barrier permeability (albumin quotient, S100B, neuron-specific enolase [NSE]), 48 inflammatory mediators, kynurenine pathway metabolites, and untargeted metabolomic profiles were measured. Associations with clinical features, disease progression, and survival were investigated using univariate analyses and multivariate models. Serum and CSF NfL concentrations were strongly associated with ALS Functional Rating Scale–Revised scores, respiratory function, diagnostic delay, and survival. Higher serum NfL concentrations at diagnosis predicted shorter survival (ROC AUC = 0.86). In all multivariate and multi-block models, serum NfL was the only biomarker independently associated with survival. Markers of CNS barrier integrity, inflammatory mediators, and metabolomic signatures showed limited prognostic value but provided insights into metabolic remodeling and barrier dysfunction. In this integrated multi-omics study, serum NfL clearly outperformed inflammatory, metabolic, and CNS barrier markers as a prognostic biomarker in ALS, supporting its central role in clinical stratification while complementary biological markers highlighted several relevant pathophysiological mechanisms.

Background Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case–control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course. Methods We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes. Results In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern. Conclusions Our findings represent the first large-scale, case–control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.

A variety of common and rare genetic factors have been implicated in the development of amyotrophic lateral sclerosis (ALS), and the evidence is that a genetic component is present in most affected individuals. However, our current understanding of ALS genetics causally explains only a small proportion of sporadic cases which represent over 90% of all people with ALS. This limits the utility of genetic testing in screening, diagnosis and management to the 15-20% of people with ALS who carry a known pathogenic variant. Capsule Networks (CapsNets) constitute a deep learning method that has demonstrated strong performance in using genotyping data to predict individuals at risk for ALS. However, their use is constrained by a lack of generalised, flexible, and validated implementations across comprehensive datasets that account for the technical, biological, and clinical heterogeneity found in real-world disease scenarios. In this study, we build upon this method to address existing limitations, to develop a new model that is validated across diverse ALS populations, can handle discrepancies between genotyping technologies, and is applicable to individual external samples. Using large-scale datasets from over 47,000 individuals from 13 countries, genotyped with nine different genotyping platforms, our model achieved high precision and sensitivity in distinguishing between individuals with ALS and non-affected controls. Moreover, in simulations of population screening for ALS, its performance was comparable to that of conventional genetic screening for known ALS gene mutations, such as FUS and C9orf72. Our results demonstrate that this flexible and validated method could support the development of a genetic screening test for identifying individuals at risk and expediting ALS diagnosis. This would be applicable to all individuals, regardless of their family history or presence of known ALS mutations. ### Competing Interest Statement VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Amylyx, Novartis Pharma AG, Zambon Biotech SA, and Biogen. VS is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology, and Exploration of Neuroprotective Therapy. AAC reports receiving nonfinancial support from the National Institute for Health and Care Research (NIHR); consultant fees from Amylyx, Clene Therapeutics, GenieUs, GSK, Eli Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, SanoGenetics, Sanofi, Voyager Therapeutics, and Wave Pharmaceuticals; and having a patent for use of CSF-neurofilament determinations and CSF-neurofilament thresholds of prognostic and stratification value with regards to response to therapy in neuromuscular and neurodegenerative diseases pending. ### Funding Statement This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND http://www.neurodegenerationresearchneurodegenerati onresearch.eu/ (UK, Medical Research Council (MR/L501529/1 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1). AA-C is an NIHR Senior Investigator. AA-C receives salary support from the National Institute for Health and Care Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. The work leading up to this publication was funded by the European Community's Health Seventh Framework Program (FP7/2007-2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 772376-EScORIAL. This study represents independent research part funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. AI is funded by South London and Maudsley NHS Foundation Trust, MND Scotland, Motor Neurone Disease Association, National Institute for Health and Care Research, Spastic Paraplegia Foundation, Rosetrees Trust, Darby Rimmer MND Foundation, the Medical Research Council (UKRI), LifeArc, and Alzheimer's Research UK. Project MinE Belgium was supported by a grant from IWT (n 140935), the ALS Liga Belgie, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. AAK is funded by The Motor Neurone Disease Association (MNDA), NIHR Maudsley Biomedical Research Centre and ALS Association Milton Safenowitz Research Fellowship, the Darby Rimmer MND Foundation, LifeArc, and the Dementia Consortium. AAK is supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the Medical Research Council. VS Receives or has received research supports from the Italian Ministry of Health, AriSLA, E-Rare Joint Transnational Call, and the ERN Euro-NMD. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The datasets used in your study were individual-level data all individual-level data had been de-identified. All data used in this study are publicly available. The ALS genome data and GWAS data used in this study are from Project MinE and can be accessed via online application (www.projectmine.com). Other data utilized in this study include the following: the Wellcome Trust Case Control Consortium (https://www.wtccc.org.uk/) and dbGaP datasets (phs000101.v3.p1, phs000101.v3.p1, phs000101.v3.p1, phs000101.v3.p1, phs000126.v1.p1, phs000196.v1.p1, phs000344.v1.p1, phs000344.v1.p1, phs000344.v1.p1). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data used in this study are publicly available. The ALS genome data and GWAS data used in this study are from Project MinE and can be accessed via online application (www.projectmine.com). Other data utilized in this study include the following: the Wellcome Trust Case Control Consortium (https://www.wtccc.org.uk/) and dbGaP datasets (phs000101.v3.p1, phs000101.v3.p1, phs000101.v3.p1, phs000101.v3.p1, phs000126.v1.p1, phs000196.v1.p1, phs000344.v1.p1, phs000344.v1.p1, phs000344.v1.p1).

INTRODUCTION/AIMS:Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease (FEWDON-MND) is characterized by motor weakness predominantly affecting finger extension, accompanied by downbeat nystagmus. To date, only 11 patients have been reported. The present study adds a further three and aims to provide a more detailed description of the electrodiagnostic features of these patients. METHODS:We present the clinical and electrophysiological features of three French patients from specialized motor neuron centers and review the electrophysiological findings of previously reported patients. RESULTS:These three patients presented with pure motor weakness affecting finger extension and downbeat nystagmus. They exhibited a slowly progressive disease course without respiratory involvement. Nerve conduction studies showed decreased compound muscle action potential amplitudes in the extensor indicis muscles. Abnormal spontaneous activity on needle electromyography (EMG) was rare in two patients, absent in one, and otherwise limited to weak muscles. Additionally, chronic motor axon loss features suggestive of motor neuronopathy were seen in our patients. Importantly, they were also detected in distant asymptomatic muscles. DISCUSSION:The three patients reported here confirm the typical phenotype of FEWDON-MND, characterized by slowly progressive distal motor weakness initially affecting finger extension, associated with downbeat nystagmus. Although chronic motor axon loss features have been found in all reported patients, our three patients show that active denervation can be absent or rare. Thus, finger drop and diffuse chronic neurogenic changes on EMG should lead clinicians to look for downbeat nystagmus and to consider FEWDON-MND.

Genetic testing in amyotrophic lateral sclerosis (ALS) often reveals variants of uncertain significance (VUS), which are frequently omitted from diagnostic reports or reported with limited clinical interpretation. To address this gap, we developed a rapid functional assessment pipeline in collaboration with FILSLAN, the French ALS care network, combining in vitro and in vivo neurogenetic assays. We illustrate this approach through the reclassification of the SOD1 p.Val120Leu variant, identified in an ALS patient, as pathogenic. Functional studies demonstrated that this variant leads to cytoplasmic aggregation, reduced neurite outgrowth, and abnormal motor behavior in zebrafish. These results support the systematic use of functional assays to clarify the pathogenicity of uncertain variants, thereby improving diagnostic accuracy, preventing misdiagnosis, and enabling timely therapeutic interventions in ALS.

Amyotrophic lateral sclerosis is a rare neurodegenerative disease that requires multidisciplinary care, resulting in extensive healthcare resource utilization. No study has explored the prevalence of amyotrophic lateral sclerosis or characterized associated healthcare resource utilization in France, despite its high burden on people living with amyotrophic lateral sclerosis, caregivers and the healthcare system. Herein, we conducted a France-wide retrospective study to describe the epidemiology, disease course and economic burden of amyotrophic lateral sclerosis. People living with amyotrophic lateral sclerosis were identified from the French population from 2012 to 2019 using the French national health data system. A milestone and symptom-based staging algorithm was developed to categorize the incident cohort into early, mid and late stages. Data were extracted on epidemiology, demographic and clinical characteristics and clinical treatments. Healthcare resource utilization and costs were analysed for amyotrophic lateral sclerosis cases and matched non-amyotrophic lateral sclerosis controls and at disease stages. Events of interests were identified, and a competing risk analysis was conducted. Comparative statistics were performed using paired t-test, ANOVA and χ2 test. We identified 18 289 incident amyotrophic lateral sclerosis cases, 56.1% of whom were male. The average age at diagnosis was 68.4 (± 12.5) years. In 2019, the estimated incidence and prevalence were 3.5/100 000 person-years and 11.0/100 000 persons, respectively. All-cause hospitalizations were higher among people at mid stage (1.66 person-years) and late stage (2.82 person-years) than among people at early stage (1.46 person-years) and for the amyotrophic lateral sclerosis cases (1.98 person-years) than for the matched non-amyotrophic lateral sclerosis controls (0.45 person-years). Home hospitalization and rehabilitation admission were more prevalent among people in later stages. The rate of out-patient and ambulatory consultations to all specialties was 13.8 person-years for people at early and mid stages and 11.1 person-years for people at late stage and 13.0 and 8.7 person-years for the amyotrophic lateral sclerosis cases and the matched non-amyotrophic lateral sclerosis controls, respectively. Direct costs increased as the disease progressed and were also higher for the amyotrophic lateral sclerosis cases than for the matched non-amyotrophic lateral sclerosis controls. Amyotrophic lateral sclerosis imposes a significant health burden through incremental healthcare resource utilization across all stages that increases with disease progression. Out-patient and ambulatory resource consumption decreased as the disease progressed to a more severe form, accompanied by a corresponding increase in in-patient services. These findings shed light on the complex needs of people living with amyotrophic lateral sclerosis and the continued need for more efficacious treatments.

Objective: To describe the development of a methodology to characterize hospitalizations and their relationship to amyotrophic lateral sclerosis (ALS) and provide results using this process in a phase 3 trial of reldesemtiv in ALS. Methods: ALS clinical trialists assisted in developing a classification system to determine if a hospitalization was related to ALS (HR-ALS), unrelated (HU-ALS), or if the relationship was indeterminate (HI-ALS) and this was applied by the investigators to hospitalizations in COURAGE-ALS. Time to first hospitalization and number of hospitalizations were compared between those assigned reldesemtiv or placebo for up to 48 weeks. Demographic and clinical features were evaluated for prediction of hospitalization risk; this analysis was limited to those participants who completed the first 24-week double-blind placebo-controlled portion of the trial. Results: COURAGE-ALS terminated early due to futility. Time to first hospitalization was similar in the reldesemtiv compared to placebo arms as was the incidence, with 86 of the participants (17.6% of those originally assigned placebo and 18.0% originally on reldesemtiv) experiencing an event. The largest percentage of events was classified as HR-ALS for both placebo (64%, 18/28) and reldesemtiv (76%, 44/58). In a multivariate model, only bulbar or respiratory onset disease was a significant risk factor for hospitalization. Conclusion: While most hospitalizations in COURAGE-ALS were HR-ALS, HU-ALS and HI-ALS also occurred. When using hospitalization as an endpoint in an ALS clinical trial, recording its relationship to ALS provides additional details to characterize disease burden and clinical meaningfulness of the endpoint.

Introduction/AimsEdaravone intravenous (IV) and oral suspension have been shown to have similar pharmacokinetics, safety, and slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Study MT-1186-A01 indicated that edaravone oral suspension was well-tolerated over 48 weeks, with no new safety concerns identified relative to existing safety data of IV edaravone, including Study MCI186-19. The aim of this study was to assess the long-term safety and tolerability of edaravone oral suspension in patients with ALS.MethodsStudy MT-1186-A03 (NCT04577404) was a phase 3, open-label, multi-center, extension study that evaluated the long-term safety of edaravone oral suspension over an additional 96 weeks in patients with ALS who have completed the initial 48 weeks of Study MT-1186-A01, for a total of up to 144 weeks of treatment. Patients received a 105-mg dose of edaravone administered in treatment cycles identical to the approved edaravone on/off dosing schedule. Patients had definite, probable, probable-laboratory-supported, or possible ALS.ResultsIn Study MT-1186-A03, edaravone oral suspension was well tolerated with no new safety concerns. The most common treatment-emergent adverse events (TEAEs) were fall, muscular weakness, dyspnea, constipation, and dysphagia. These TEAEs were consistent with the safety profile for edaravone from previous clinical trials.DiscussionThese results help establish the long-term safety and tolerability profile of edaravone oral suspension.

Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression. To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS. A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale–Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted. Oral reldesemtiv, 300 mg, or placebo twice daily. The primary end point was change in ALSFRS-R total score from baseline to week 24. Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was −1.1 (0.53; 95% CI, −2.17 to −0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11). This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS. ClinicalTrials.gov Identifier: NCT04944784

INTRODUCTION:The presymptomatic phase of frontotemporal dementia and amyotrophic lateral sclerosis associated with C9orf72 repeat expansion features widespread structural brain changes. We aimed at fulfilling the unmet need of quantitative magnetic resonance imaging (MRI)-derived measures suitable for disease tracking. METHODS:We compared the profile of longitudinal gray (GM) and white matter (WM) changes in 66 presymptomatic carriers and 52 controls over 3-year follow-up and appraised their annualized rate of change (ARC). RESULTS:Both putamen (p < 0.01) and left insula (p = 0.005) volumes declined the most in carriers over 40, with an ARC up to four-fold higher than in controls. Increases in mean diffusivity occurred first in the left uncinate fasciculus, followed by thalamo-cortical bundles (p < 0.05), associated with higher neurofilament levels. DISCUSSION:Our study highlighted the GM and WM structures showing the greatest longitudinal decline during the preclinical stage, whose ARC may serve as an MRI-derived biomarker for longitudinal surveillance and therapeutic outcome. CLINICAL TRIAL REGISTRATION:NCT02590276 and NCT05358431. HIGHLIGHTS:We studied longitudinal multimodal MRI changes in presymptomatic C9orf72 disease. Carriers displayed faster atrophy in putamen, insula and cerebellar regions. Mean diffusivity increased mainly in uncinate and thalamo-cortical tracts. These differences were even more significant in older (> 40) participants. We proposed targeted annualized rate of change as a quantitative biomarker.

Importance Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression. Objective To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS. Design, Setting, and Participants A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted. Interventions Oral reldesemtiv, 300 mg, or placebo twice daily. Main Outcomes and Measures The primary end point was change in ALSFRS-R total score from baseline to week 24. Results Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11). Conclusions and Relevance This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.