Trials In Amyotrophic Lateral Sclerosis Research Articles

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A systematic Review.

More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found. To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses. 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5% . The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.

Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.

Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms.

Magnetic resonance imaging can detect neurodegenerative iron accumulation in the motor cortex, called the motor band sign. This study aims to evaluate its sensitivity/specificity and correlations to symptomatology, biomarkers, and clinical outcome in amyotrophic lateral sclerosis. This prospective study consecutively enrolled 114 persons with amyotrophic lateral sclerosis and 79 mimics referred to Karolinska University Hospital, and also 31 healthy controls. All underwent 3-Tesla brain susceptibility-weighted imaging. Three raters independently assessed motor cortex susceptibility with total and regional motor band scores. Survival was evaluated at a median of 34.2 months after the imaging. The motor band sign identified amyotrophic lateral sclerosis with a sensitivity of 59.6% and a specificity of 91.1% versus mimics and 96.8% versus controls. Higher motor band scores were more common with genetic risk factors (p = 0.032), especially with C9orf72 mutation, and were associated with higher neurofilament light levels (std. β 0.22, p = 0.019). Regional scores correlated strongly with focal symptoms (medial region vs. gross motor dysfunction, std. β -0.64, p = 0.001; intermediate region vs. fine motor dysfunction, std. β -0.51, p = 0.031; lateral region vs. bulbar symptoms std. β -0.71, p < 0.001). There were no associations with cognition, progression rate, or survival. In a real-life clinical setting, the motor band sign has high specificity but relatively low sensitivity for identifying amyotrophic lateral sclerosis. Associations with genetic risk factors, neurofilament levels and somatotopic correspondence to focal motor weakness suggest that the motor band sign could be a suitable biomarker for diagnostics and clinical trials in amyotrophic lateral sclerosis.

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.

Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.

Evolution of the Amyotrophic Lateral Sclerosis Diagnostic Criteria Towards the Gold Coast Criteria

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons (LMNs). Careful history taking, neurological examination, and electromyography are used to confirm its clinical diagnosis. The El Escorial, revised El Escorial and Awaji criteria have proposed varying degrees of diagnostic probability for ALS. However, such categories may cause uncertainty among patients regarding the certainty of diagnosis. Cases labeled as “possible ALS” also risk exclusion from clinical trials. To clarify and simplify the diagnostic criteria of ALS, the previous diagnostic categories of possible, probable, and definite were abandoned in the newly suggested criteria, Gold Coast criteria. The simplified criteria offer practical utility for precise diagnosis of LMN-predominant ALS and clinical trial recruitment going forward.

Tauro-Urso-Deoxycholic Acid Trials in Amyotrophic Lateral Sclerosis: What is Achieved and What to Expect.

Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable and devastating disease. We review the available evidence on the efficacy and safety of TUDCA, administered alone or in combination, by analyzing and comparing published and ongoing studies on amyotrophic lateral sclerosis. Two independent phase II studies (using TUDCA solo or combined with sodium phenylbutyrate) showed similar efficacy in slowing disease progression measured by functional scales. One open-labelfollow-up TUDCA+sodium phenylbutyrate study suggested a benefit on survival. Two subsequent phase III studies with TUDCA (solo or combined with sodium phenylbutyrate) have been initiated and are currently ongoing. Their completion is expected by the end of 2023 and beginning of 2024. Evidence collected by phase II studies indicates that there are no safety concerns in patients with amyotrophic lateral sclerosis. The efficacy shown in phase II studies was considered sufficient to grant approval in some countries but not in others, owing to discrepant views on the strength of evidence. It will be necessary to wait for the results of ongoing phase III studies to attain a full appreciation of these data.

Database Evaluation for Muscle and Nerve Diseases - DEMAND: An academic neuromuscular coding system

Background: A database which documents the diagnosis of neuromuscular patients is useful for determining the types of patients referred to academic centers and for identifying participants for clinical trials and other studies. The ICD-9 or ICD-10 numeric systems are insufficiently detailed for this purpose. Objective: To develop a database for neuromuscular diagnoses Methods: We developed a detailed diagnostic coding system for neuromuscular diseases called DEMAND: Database Evaluation for Muscle and Nerve Diseases that has been adopted by neuromuscular clinics at University of Texas Health Science Center San Antonio (UTHSCSA), Ohio State University (OSU), University of Kansas Medical Center (KUMC), and University of Texas Southwestern (UTSW). At the initial visit, patients are assigned a diagnostic code which can be revised later if appropriate. Fields include patient’s name, date of birth, and diagnostic code. The neuromuscular database consisted of 457 codes. Each code has a prefix (MUS or PNS) followed by a three-digit number. Depending on whether muscle or nerve is primarily involved, there are eight broad groups: motor neuron disease (MUS codes 100-139); neuromuscular junction disorders (MUS 200-217); acquired and hereditary myopathies (MUS 300-600s); acquired and hereditary polyneuropathies (PNS 100-400); mononeuropathies (PNS 500s); plexopathies (PNS 600s); radiculopathies (PNS 700s); and mononeuritis multiplex (PNS 800s). Results: During a period of 10 years, 17,163 of patients were entered (1,752 at UTHSCSA, 1,840 at OSU, 3,699 at KUMC, 9,872 at UTSW). The number of patients in several broad categories are: 3,080 motor neuron disease; 1,575 neuromuscular junction disease; 1,851 muscular dystrophies; 633 inflammatory myopathies; 1,090 hereditary neuropathies; 1,001 immune-mediated polyneuropathies; 620 metabolic/toxic polyneuropathies; 535 mononeuropathies; 296 plexopathies; and 769 radiculopathies. Conclusion: A detailed diagnostic neuromuscular database can be utilized at multiple academic centers. The database should be simple without too many fields to complete, to ensure compliance during busy clinic operations. This database has been very useful in identifying groups of patients for retrospective, observational studies and for prospective treatment studies including trials for Amyotrophic Lateral Sclerosis (ALS), Muscular Dystrophies (MD), Myasthenia Gravis (MG), and retrospective studies of Primary Lateral Sclerosis (PLS), chronic inflammatory demyelinating neuropathy (CIDP), etc.

At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment in motor function. Promising drug development efforts have accelerated in amyotrophic lateral sclerosis, but are constrained by a lack of objective, sensitive, and accessible outcome measures. Here we investigate the use of wearable sensors, worn on four limbs at home during natural behavior, to quantify motor function and disease progression in 376 individuals with amyotrophic lateral sclerosis. We use an analysis approach that automatically detects and characterizes submovements from passively collected accelerometer data and produces a machine-learned severity score for each limb that is independent of clinical ratings. We show that this approach produces scores that progress faster than the gold standard Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (−0.86 ± 0.70 SD/year versus −0.73 ± 0.74 SD/year), resulting in smaller clinical trial sample size estimates (N = 76 versus N = 121). This method offers an ecologically valid and scalable measure for potential use in amyotrophic lateral sclerosis trials and clinical care.

IPSC-based research in ALS precision medicine

Clinical trials in amyotrophic lateral sclerosis (ALS) are challenged by the lack of pre-clinical models and biomarkers of disease onset and progression. In this issue, Morimoto etal. use induced pluripotent stem cell (iPSC)-derived motor neurons from patients with ALS to study therapeutic mechanisms of ropinirole in a clinical trial and identify treatment responders.

P.048 Monitoring and managing gastrointestinal events with sodium phenylbutyrate and ursodoxicoltaurine for the treatment of Amyotrophic Lateral Sclerosis

Background: Sodium phenylbutyrate and ursodoxicoltaurine/taurursodiol (PB&amp;TURSO) is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in Canada and the U.S. In the CENTAUR trial, a phase 2 U.S. multicenter trial in ALS, PB&amp;TURSO was generally well-tolerated. The most common adverse reactions were gastrointestinal (GI) and occurred most often during the first three weeks of therapy. Although the occurrence of GI events in people living with ALS (PLWALS) and treated with PB&amp;TURSO are recognisable and generally manageable, many of the symptoms are often not managed proactively. We sought to develop an evidence-based tool to help guide clinicians on managing diarrhea and abdominal pain in PLWALS and treated with PB&amp;TURSO. Methods: Three ALS specialized neurologists and one gastroenterologist combined their clinical experience, research, and each Medications respective product monograph, to develop a patient-centric GI tool. Results: A guide to monitoring and managing potential GI events with PB&amp;TURSO was developed. The tool provides clinicians a proactive, step-by-step guide to help manage diarrhea and abdominal pain in PLWALS treated with PB&amp;TURSO. Conclusions: The GI tool has the potential to improve monitoring, recognition, and treatment of GI events in PLWALS treated with PB&amp;TURSO. Proactively managing GI events may aid medication adherence and improve patient quality of life.

First-in-Human Study of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SAR443820, a Central Nervous System Penetrant RIPK1 Inhibitor in Healthy Participants (S46.005)

<h3>Objective:</h3> To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of SAR443820 in first-in-human, Phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (SAD; Part-1a) and multiple-ascending dose (MAD; Part-2) studies in healthy participants. Part-1b was a separate open-label single-dose study for assessing SAR443820 levels in cerebrospinal fluid (CSF). <h3>Background:</h3> Receptor-interacting serine/threonine protein kinase-1 (RIPK1), which regulates inflammatory signaling and necroptotic cell death, is implicated in several neurodegenerative diseases. SAR443820, a central nervous system (CNS) penetrant oral RIPK1 inhibitor, is being developed in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). <h3>Design/Methods:</h3> In Part-1a, 4 cohorts (n=8 each; 6 SAR443820, 2 placebo) received single-ascending doses of SAR443820 (up to 4-fold the lowest dose) or placebo. Part-1b included 2 single-dose cohorts (n=6 each) receiving the lowest and 4-fold the lowest doses of SAR443820. In Part-2, 4 cohorts (n=10 each; 8 SAR443820, 2 placebo) received 14-day SAR443820 or placebo in multiple-ascending doses. <h3>Results:</h3> Overall, SAR443820 was well-tolerated with no treatment-related serious adverse events (AEs) or permanent treatment discontinuation. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in hematology, chemistry, vital signs, or electrocardiogram parameters. There were no major deviations from dose proportionality for maximum concentration (C_max) and area under the curve (AUC) over the range of SAR443820 doses. Mean plasma half-lives ranged between 6–8h and 7–9h in SAD and MAD cohorts, respectively. Mean CSF-to-unbound plasma concentration ratio suggested high CNS-penetrance. Concentration-QTcF analyses did not indicate any potential for SAR443820 to cause relevant change in QTcF. Maximum median inhibition of phosphorylated-Ser166-RIPK1 levels across all SAR443820 groups reflected a marked target engagement. <h3>Conclusions:</h3> The first-in-human study demonstrated that single and repeated SAR443820 doses were generally safe and well-tolerated, with favorable pharmacokinetics, high CNS-penetrance, and robust RIPK1-target engagement, supporting further development in actively recruiting Phase 2 trials in ALS (Himalaya; NCT05237284) and MS (K2; ACT16753). <b>Disclosure:</b> Mrs. HINCELIN-MERY has nothing to disclose. Pascale Lewanczyk has nothing to disclose. Mrs. Cantalloube has received personal compensation for serving as an employee of Sanofi. Mr. Nicolas has nothing to disclose. Myriam Benamor has nothing to disclose. Dr. Pomponio has received personal compensation for serving as an employee of Sanofi. Dr. Pomponio has stock in sanofi. Dr. KRUPKA has nothing to disclose. Dimitry Ofengeim has received personal compensation for serving as an employee of Sanofi. Dimitry Ofengeim has received stock or an ownership interest from Sanofi. Dimitry Ofengeim has received personal compensation in the range of $500-$4,999 for serving as a Study Section Reveiwer with NIH. Dr. Eastenson has nothing to disclose. Dr. Xiong has received personal compensation for serving as an employee of Sanofi. Dr. Atassi has received personal compensation for serving as an employee of Sanofi. Dr. Atassi has stock in Sanofi.

Analysis of Amyotrophic Lateral Sclerosis (ALS) Clinical Trials Posted on www.clinicaltrials.gov from 1999–2022. (P10-8.011)

<h3>Objective:</h3> To create a database of Amyotrophic Lateral Sclerosis (ALS) clinical trials on www.clinicaltrials.gov and analyze trends over the past three decades. <h3>Background:</h3> ALS is a progressive neurodegenerative disease of the brain and spinal cord neurons with a typical lifespan of 3–5 years from symptom onset. Clinical trials have evolved over the past three decades as more awareness and research funding have been dedicated to understanding and treating ALS, partially due to the ALS Ice Bucket Challenge in 2014. A review of the evolution of study design and parameters over time provides insights into the future of clinical trials and is reflective of improvements in the science. <h3>Design/Methods:</h3> “ALS” and “Amyotrophic Lateral Sclerosis” were searched on www.clinicaltrial.gov in August 2022. A database was created to capture information on trials: year posted, study type, primary endpoints, and inclusion criteria. <h3>Results:</h3> The term ALS had 777 results and Amyotrophic Lateral Sclerosis had 891 results, for a total of 954 unique clinical trials from 1999 to 2022. Two hundred and seventy-three trials were removed due to non-ALS trials (other neurological disorders, drug name with ALS, or advanced life support) and 681 were analyzed. Thirty-four countries were represented with the United States (n=288, 43%), France (n=71, 11%), and Italy (n=28, 4.1%) having the highest number. The largest number of new trials posted in one year was in 2021 with 81. Forty-eight percent of studies are completed, and 146 (21%) are actively recruiting. Length of time to primary endpoint ranged between one day to ten years. 40% of studies did not specify ALS diagnostic criteria for eligibility and 4% required genetic testing. <h3>Conclusions:</h3> Analyzing current and past trends of ALS clinical trials will help guide future trial designs in the hopes to optimize ALS outcomes and trials. <b>Disclosure:</b> Dr. Zelikovich has nothing to disclose. Eric Anderson has nothing to disclose. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NeuroAlert. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Merck Manual. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Wave Life Sciences. Dr. Andrews has received personal compensation in the range of $0-$499 for serving as a Consultant for Cytokinetics. Dr. Andrews has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AL-S Pharma.

Development and Evaluation of a Simulation-Based Algorithm to Optimize the Planning of Interim Analyses for Clinical Trials in ALS.

Late-phase clinical trials for neurodegenerative diseases have a low probability of success. In this study, we introduce an algorithm that optimizes the planning of interim analyses for clinical trials in amyotrophic lateral sclerosis (ALS) to better use the time and resources available and minimize the exposure of patients to ineffective or harmful drugs. A simulation-based algorithm was developed to determine the optimal interim analysis scheme by integrating prior knowledge about the success rate of ALS clinical trials with drug-specific information obtained in early-phase studies. Interim analysis schemes were optimized by varying the number and timing of interim analyses, together with their decision rules about when to stop a trial. The algorithm was applied retrospectively to 3 clinical trials that investigated the efficacy of diaphragm pacing or ceftriaxone on survival in patients with ALS. Outcomes were additionally compared with conventional interim designs. We evaluated 183-1,351 unique interim analysis schemes for each trial. Application of the optimal designs correctly established lack of efficacy, would have concluded all studies 1.2-19.4 months earlier (reduction of 4.6%-57.7% in trial duration), and could have reduced the number of randomized patients by 1.7%-58.1%. By means of simulation, we illustrate the efficiency for other treatment scenarios. The optimized interim analysis schemes outperformed conventional interim designs in most scenarios. Our algorithm uses prior knowledge to determine the uncertainty of the expected treatment effect in ALS clinical trials and optimizes the planning of interim analyses. Improving futility monitoring in ALS could minimize the exposure of patients to ineffective or harmful treatments and result in significant ethical and efficiency gains.

Cox regression and survival analysis from the tauro-urso-deoxycholic trial in amyotrophic lateral sclerosis.

Recent phase II pilot clinical trials suggested that tauro-urso-deoxycholic acid (TUDCA) might slow functional decline and increase survival in patients with amyotrophic lateral sclerosis (ALS). We performed a multivariate analysis of the original TUDCA cohort to better define the treatment effect and allow comparability with other trials. Linear regression slope analysis showed statistical differences in the decline rate, favoring the active treatment arm (p-value < 0.01; -0.262 for the TUDCA group and -0.388 for the placebo group). Mean survival time, estimated by the Kaplan-Meier analysis, showed a 1-month difference, favoring active treatment (log-rank test p-value = 0.092). Cox regression analysis demonstrated that placebo treatment was associated with a higher risk of death (p-value = 0.055). These data further support the disease-modifying effect of TUDCA monotherapy and raise the question of what could be the additional effect of combining TUDCA with sodium phenylbutyrate.

Effect of mesenchymal stromal cell transplantation on long-term survival in amyotrophic lateral sclerosis

Background aimsThanks to their immunomodulatory, tissue-protective and regenerative properties, mesenchymal stromal cells (MSCs) are a promising approach for amyotrophic lateral sclerosis (ALS); however, trials are limited and few follow-up studies have been published. This post-hoc analysis aims to describe the potential long-term effects of MSCs in ALS, analyzing data from two phase 1 clinical trials in ALS patients conducted by our group in 2002 and 2006. MethodsWe conducted two consecutive phase 1 prospective, open, pilot clinical trials, enrolling a total of 19 ALS patients. We followed patients for the duration of the disease. For each patient, we used the European Network to Cure ALS (ENCALS) survival prediction model to retrospectively calculate the expected survival at diagnosis. We then compared the predicted disease duration with the observed survival, analyzing patients at a single-patient level. ResultsUsing the ENCALS model, we predicted short survival in one patient, intermediate survival in three patients, long survival in three patients and very long survival in 12 patients. The difference between predicted and observed survival for the whole group was significant and demonstrated a mean predicted survival of 70.79 months (standard deviation [SD], 27.53) and a mean observed survival of 118.8 months (SD, 89.26) (P = 0.016). Based on the monthly ALS Functional Rating Scale–Revised progression rate (median, 0.64/month), we considered 10 of 19 patients slow progressors and nine of 19 patients fast progressors. Of the slow progressors, eight of 10 (80%) had significantly increased disease duration compared with predicted, and only two (20%) had decreased estimated disease duration. By contrast, five of nine (55%) fast progressors had increased disease duration, whereas four (45%) had decreased disease duration. To date, four patients are still alive. ConclusionsThe current study represents the first very long-term analysis of survival as an effect of MSC focal transplantation in the central nervous system of ALS patients, demonstrating that MSC transplantation could potentially slow down ALS progression and improve survival. Due to the interindividual variability in clinical course, at the current state of our knowledge, we cannot generalize the results, but these data provide new insights for planning the next generation of efficacy MSC clinical trials in ALS.

Wearable device and smartphone data quantify ALS progression and may provide novel outcome measures

Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer the self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2–4 weeks. Each participant used a wrist-worn activity monitor (ActiGraph Insight Watch) or an ankle-worn activity monitor (Modus StepWatch) continuously. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcome measure development.

Promising application of a new ulnar nerve compound muscle action potential measurement montage in amyotrophic lateral sclerosis: a prospective cross-sectional study.

Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional "belly-tendon" montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles. A new method of ulnar nerve compound muscle action potential measurement was developed in 2020, which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist. This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential. In this prospective cross-sectional study, we included 64 patients with amyotrophic lateral sclerosis and 64 age- and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital. The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage. In the controls, no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings. In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy, the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2 (P < 0.01). Using the new method, damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method, in particular for patients in early stage amyotrophic lateral sclerosis. In addition, the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position, and that this method is more suitable for monitoring disease progression than the traditional montage. This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.

Identification of potential pathways and biomarkers linked to progression in ALS.

To identify potential diagnostic and prognostic biomarkers for clinical management and clinical trials in amyotrophic lateral sclerosis. We analysed proteomics data of ALS patient-induced pluripotent stem cell-derived motor neurons available through the AnswerALS consortium. After stratifying patients using clinical ALSFRS-R and ALS-CBS scales, we identified differentially expressed proteins indicative of ALS disease severity and progression rate as candidate ALS-related and prognostic biomarkers. Pathway analysis for identified proteins was performed using STITCH. Protein sets were correlated with the effects of drugs using the Connectivity Map tool to identify compounds likely to affect similar pathways. RNAi screening was performed in a Drosophila TDP-43 ALS model to validate pathological relevance. A statistical classification machine learning model was constructed using ridge regression that uses proteomics data to differentiate ALS patients from controls. We identified 76, 21, 71 and 1 candidate ALS-related biomarkers and 22, 41, 27 and 64 candidate prognostic biomarkers from patients stratified by ALSFRS-R baseline, ALSFRS-R progression slope, ALS-CBS baseline and ALS-CBS progression slope, respectively. Nineteen proteins enhanced or suppressed pathogenic eye phenotypes in the ALS fly model. Nutraceuticals, dopamine pathway modulators, statins, anti-inflammatories and antimicrobials were predicted starting points for drug repurposing using the connectivity map tool. Ten diagnostic biomarker proteins were predicted by machine learning to identify ALS patients with high accuracy and sensitivity. This study showcases the powerful approach of iPSC-motor neuron proteomics combined with machine learning and biological confirmation in the prediction of novel mechanisms and diagnostic and predictive biomarkers in ALS.

MiToS and King’s staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial

Objective To evaluate the Milano-Torino staging (MiToS) and King’s staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS. Methods This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King’s stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage. Results The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n = 342, placebo n = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King’s stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King’s stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King’s. Conclusion This exploratory analysis showed the feasibility of MiToS and King’s staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.