ALS clinical trials

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. No treatment is currently able to stop the disease process. In the absence of new active compounds there is an urgent need to develop new strategies based on the neuroprotective activity of available drugs. ALS is a heterogeneous disease. To build up these therapeutic trials, we need to have a better understanding of the prognostic factors in this disease. During the Phase IV Rilutek Trial in France, we developed in a large population of patients a prognostic score based on clinical parameters available at the bedside. The most significant variables are vital capacity, spasticity, fasciculations, swallowing, cough and creatininemia. This score proved to be very useful in daily use in the clinic and for planning disease management in ALS as in the design of therapeutic trials. In ALS clinical trials, efficacy can be evaluated using survival or functional parameters. In phase II trials, function remains the most commonly used. In phase III trials, the gold standard endpoint remains the survival rate at month 18. We analyzed the most recent ALS trials published in the literature. This review suggests that in these trials there is a discrepancy between drug effects on survival versus function. These results suggest that a reappraisal of strategies to identify therapeutic targets for ALS is required.

ObjectiveIntraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs.MethodsSurvival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20.ResultsSurvival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study.InterpretationComparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study.

Clinical trials in amyotrophic lateral sclerosis (ALS) have been conducted for over half a century now and have incorporated a wide variety of drugs. Most of these trials have had negative results and a cure remains elusive. The explosion in our understanding of molecular biology and parallel developments in clinical epidemiology have opened up a vast number of novel therapeutic strategies. However, advances in statistical analysis, computing, and global communications have also put greater pressure on scientific investigators to improve the design and implementation of clinical trials so that they permit rigorous testing of hypotheses within a solid ethical framework. This article documents the first published trial for all drugs tried clinically in the treatment of ALS, focusing in more detail on the large, multicenter trials of recent years, namely those involving riluzole, ciliary neurotrophic factor, insulin-like growth factor-I, brain-derived neurotrophic factor, and SR57746A. The problems in the design of trials in ALS are discussed, including the selection of end points and surrogate markers of disease progression, and the major parameters in ALS assessment are reviewed.

To study the attributes of quantitative strength testing using hand-held dynamometry (HHD) as an efficacy measure in 2 large phase 3 amyotrophic lateral sclerosis (ALS) trials. In the phase 3 trials of ceftriaxone and dexpramipexole, 513 and 943 patients, respectively, were enrolled in double-blind, randomized, placebo-controlled trials with planned follow-up of at least 1 year. Patients were studied every 3 months in the ceftriaxone study and every 2 months in the dexpramipexole study. Evaluators of HHD were trained and had to show evidence of adequate performance of strength testing; the testing paradigm involved testing 9 muscle groups in the upper and lower extremity bilaterally. Neither drug significantly affected any outcome measure. Strength measurements were evaluated by individual muscle and by megascores, which averaged scaled strength measures to produce an overall measure of muscle strength. A measure combining rate of decline with both within- and between-patient variabilities of measurement, the coefficient of variation for rate of change, was calculated, and showed that HHD overall performed slightly less well than Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) but better than vital capacity. Individual muscles were highly correlated to the identical muscles on the contralateral side, as well as to other muscles in the same body region. Strength decline was correlated both with ALSFRS-R and vital capacity. Quantitative strength testing using HHD is a reliable and reproducible measure of decline in ALS.

Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial. A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared. The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores. Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.

Introduction:Amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, is characterized by the progressive loss of cells in the brain and spinal cord that leads to debilitation and death in 3 – 5 years. Only one therapeutic drug, riluzole, has been approved for ALS and this drug improves survival by 2 – 3 months. The need for new therapeutics that can postpone or slow the progression of the motor deficits and prolong survival is still a strong unmet medical need.Areas covered:Although there are a number of drugs currently in clinical trials for ALS, this review provides an overview of the most promising biological targets and preclinical strategies that are currently being developed and deployed. The list of targets for ALS was compiled from a variety of websites including individual companies that have ALS programs and include those from the author's experience.Expert opinion:Progress is being made in the identification of possible new therapeutics for ALS with recent efforts in understanding the genetic causes of the disease, susceptibility factors and the development of additional preclinical animal models. However, many challenges remain in the identification of new ALS therapeutics including: the use of relevant biomarkers, the need for an earlier diagnosis of the disease and additional animal models. Multiple strategies need to be tested in the clinic in order to determine what will be effective in patients.

Objective To identify relevant concepts of measurement for people with amyotrophic lateral sclerosis (ALS) and to evaluate the face and content validity of clinical outcome assessments (COAs) that can be used to measure treatment benefits in ALS clinical trials. Methods A targeted literature review was conducted to explore patient experience (stage 1) and COAs used in ALS research (stage 2). s were screened against predefined eligibility criteria; full-text articles were reviewed for eligible abstracts and relevant data were extracted. Face and content validity of the identified COAs were assessed. Results Stage 1 searches identified 3,527 abstracts, of which 12 full-text articles, two summary reports, and one conference poster were included in this review. Twenty-five symptoms and 35 health-related quality of life (HRQoL) impacts were identified. Frequently reported symptoms included breathing and speech difficulties and muscle/limb weakness, each associated with a diverse range of impacts, including those related to emotional wellbeing, physical function, social and leisure activities, and activities of daily living. Stage 2 searches identified 119 COAs, of which 28 were reviewed. Many had acceptable face (13/28) and content validity (15/28), but 13 had not involved patients during development; only 10 were clearly worded and seven were lengthy, increasing patient burden risk. Conclusions This review identified wide-ranging symptoms and HRQoL impacts experienced by people with ALS, but detailed qualitative evidence is sparse. Multiple COAs were identified as potential measures in ALS clinical trials.

ObjectiveThe objective of this study was to evaluate the prognostic value of several muscle damage biomarkers.MethodsData from Piemonte and Valle d'Aosta Amyotrophic Lateral Sclerosis (PARALS) were considered for this study. Survival was defined as the time from diagnosis to death, tracheostomy, or the censoring date. Blood levels of potassium, creatinine, creatine kinase, phosphorus, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) diagnosis were evaluated as potential prognostic biomarkers. A Cox model was developed for each biomarker and adjusted for sex, onset age, onset site, and diagnostic delay. Significant findings from PARALS were evaluated in the Pooled Resource Open‐Access Amyotrophic Lateral Sclerosis Clinical Trials (PRO‐ACT) database. Additionally, a joint model was constructed to evaluate the prognostic role of phosphatemia slope over time using longitudinal data from PRO‐ACT.ResultsA total of 1,444 and 1,023 patients were included in the PARALS and PRO‐ACT cohorts, respectively. Only creatinine (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.50–0.85) and phosphorus (HR = 1.14, 95% CI = 1.04–1.24) showed a significant association with survival in the PARALS cohort. These findings were further validated in the PRO‐ACT cohort (creatinine HR = 0.21, 95% CI = 0.13–0.35, p < 0.0001; phosphorus HR = 2.35, 95% CI = 1.13–4.88, p = 0.02). Longitudinal data from the PRO‐ACT database showed that an increase of 0.1 mmol/l per month in phosphate levels was also associated with a HR of 8.26 (95% CI = 1.07–96.6, p = 0.044).InterpretationCreatininemia was confirmed as a prognostic marker in amyotrophic lateral sclerosis (ALS). Additionally, both phosphatemia levels at diagnosis and its rate of change over time were identified as a potential prognostic marker for ALS. As with other blood biomarkers, phosphate levels are cost‐effective and minimally invasive to measure, supporting their potential use in clinical trials. ANN NEUROL 2025;98:286–293

IntroductionRecent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.MethodsA literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.ResultsThe search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.ConclusionBCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.

The current state of amyotrophic lateral sclerosis (ALS) trial design is best understood within the context of ALS research over the past quarter century. Before the early 1990s, trials in ALS were typically small and clinical trial methodology was less rigorous than it is today. With the discovery of the SOD1 gene mutation in the early 1990s, a new era of excitement and innovation for ALS research began. Since then, the number of ALS trials has steadily increased and trial design and methodology has become increasingly sophisticated.

ObjectivesTo investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS).MethodsWe studied 192 patients with ALS and...

A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. Despite several genetic breakthroughs, the actual cause and mechanism of neurodegeneration in ALS remains a mystery. Nevertheless, recent scientific and clinical advances have led to the development of new therapeutic strategies for this progressive, fatal disorder. We review the progress of the most recent clinical trials in ALS, taking into account some of the hurdles encountered by these studies. We also discuss the potential role of retroviral infection as a cause or contributor to ALS, which is one of the most recent hypotheses for the pathogenesis of the disease. The genetic background of ALS is summarized and special attention is given to the newly identified ALS gene ALS2, and to those that are currently being investigated. The last part of this review is dedicated to the mutation in superoxide dismutase-1 (SOD1). The hypothesized deleterious mechanisms of mutant SOD1 are discussed, as well as the possibilities that the mutant protein activates the apoptotic cell death process and that these molecular alterations can be exploited to devise experimental neuroprotective therapies.

Amyotrophic Lateral Sclerosis (ALS) is a motor neurodegenerative disorder whose cellular hallmarks are the progressive death of motor neurons (MNs) located in the anterior horn of the spinal cord, brainstem and motor cortex, and the formation of intracellular protein aggregates. Over the course of the disease, progressive paralysis takes place, leading to patient death within 3–5 years after the diagnosis. Despite decades of intensive research, only a few therapeutic options exist, with a limited benefit on the disease progression. Preclinical animal models have been very useful to decipher some aspects of the mechanisms underlying ALS. However, discoveries made using transgenic animal models have failed to translate into clinically meaningful therapeutic strategies. Thus, there is an urgent need to find solutions to discover drugs that could impact on the course of the disease, with the ultimate goal to extend the life of patients and improve their quality of life. Induced pluripotent stem cells (iPSCs), similarly to embryonic stem cells (ESCs), have the capacity to differentiate into all three embryonic germ layers, which offers the unprecedented opportunity to access patient-specific central nervous system cells in an inexhaustible manner. Human MNs generated from ALS patient iPSCs are an exciting tool for disease modelling and drug discovery projects, since they display ALS-specific phenotypes. Here, we attempted to review almost 2 decades of research in the field, first highlighting the steps required to efficiently generate MNs from human ESCs and iPSCs. Then, we address relevant ALS studies which employed human ESCs and iPSC-derived MNs that led to the identification of compounds currently being tested in clinical trials for ALS. Finally, we discuss the potential and caveats of using patient iPSC-derived MNs as a platform for drug screening, and anticipate ongoing and future challenges in ALS drug discovery.

Aaron Gitler: yeast, proteins, and pioneering brain research