Amyotrophic Lateral Sclerosis Clinical Trials Research Articles

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.

Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger containing (PIKfyve) inhibitor with favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis models. In this amyotrophic lateral sclerosis clinical trial, the safety, tolerability, CNS penetrance, and modulation of pharmacodynamic target engagement biomarkers were evaluated. This Phase 2a, randomized, double-blind, placebo-controlled, biomarker-endpoint clinical trial was conducted in four USA centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansion were randomly assigned (2:1) to receive twice-daily oral treatment of 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent adverse or serious adverse events attributable to study drug, and tolerability as trial completion on treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition (soluble glycoprotein nonmetastatic melanoma protein B [sGPNMB] upregulation) and disease-specific CNS target engagement (poly[GP]). Between Dec 16, 2021, and Jul 7, 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance (N=9 [90%] apilimod dimesylate; N=5 [100%] placebo). At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/mL (SD: 0.937). At Week 12, apilimod dimesylate increased plasma sGPNMB by > 2.5-fold (p < 0.001) indicating PIKfyve inhibition and lowered CSF poly(GP) protein levels by 73% (p < 0.001) indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker endpoints in this Phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to have the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis.

To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00-1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09-1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07-0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (-4.2 forced vital capacity%/month, 95% CI -6.3 to -2.2, p < 0.0001) and faster weight loss (-0.15 kg/month, 95% CI -0.25 to -0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024.

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.

Giving Breath to Motor Neurons: Noninvasive Mechanical Ventilation Slows Disease Progression in Amyotrophic Lateral Sclerosis.

Noninvasive mechanical ventilation (NIMV) improves amyotrophic lateral sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. Here, we test whether NIMV use changed the rate of functional decline among ALS patients. In this retrospective observational study, we included 448 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation adjusting for covariates. Functional decline was based on the nonrespiratory items of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). NIMV initiation resulted in a slower functional decline (mean improvement = 0.16 points per month, 95% confidence interval = 0.12-0.19, p < 0.001), with consistent effects observed across various demographic factors, including sex, age at diagnosis, and disease duration before NIMV initiation. This finding was replicated using the PRO-ACT (Pooled Resource Open-Access ALS Clinical Trials) dataset. The favorable impact of NIMV on ALSFRS-R progression was evident independently of disease stages. Notably, NIMV benefits were not dose-dependent but were particularly prominent for nighttime respiratory support. NIMV significantly influences the rate of motor progression in ALS, and this effect is not determined by the nonlinearity of ALSFRS-R trajectory. The functional decline slowed following NIMV initiation, independently of the site of disease onset or disease severity at the time of NIMV initiation. Our findings underscore the importance of timely NIMV initiation for all ALS patients and highlight the need to consider NIMV-induced slowing of disease progression when evaluating clinical trial outcomes. ANN NEUROL 2024.

Mismatch between clinically defined classification of ALS stage and the burden of cerebral pathology.

This study aimed to investigate the clinical stratification of amyotrophic lateral sclerosis (ALS) patients in relation to in vivo cerebral degeneration. One hundred forty-nine ALS patients and one hundred forty-four healthy controls (HCs) were recruited from the Canadian ALS Neuroimaging Consortium (CALSNIC). Texture analysis was performed on T1-weighted scans to extract the texture feature "autocorrelation" (autoc), an imaging biomarker of cerebral degeneration. Patients were stratified at baseline into early and advanced disease stages based on criteria adapted from ALS clinical trials and the King's College staging system, as well as into slow and fast progressors (disease progression rates, DPR). Patients had increased autoc in the internal capsule. These changes extended beyond the internal capsule in early-stage patients (clinical trial-based criteria), fast progressors, and in advanced-stage patients (King's staging criteria). Longitudinal increases in autoc were observed in the postcentral gyrus, corticospinal tract, posterior cingulate cortex, and putamen; whereas decreases were observed in corpus callosum, caudate, central opercular cortex, and frontotemporal areas. Both longitudinal increases and decreases of autoc were observed in non-overlapping regions within insula and precentral gyrus. Within-criteria comparisons of autoc revealed more pronounced changes at baseline and longitudinally in early- (clinical trial-based criteria) and advanced-stage (King's staging criteria) patients and fast progressors. In summary, comparative patterns of baseline and longitudinal progression in cerebral degeneration are dependent on sub-group selection criteria, with clinical trial-based stratification insufficiently characterizing disease stage based on pathological cerebral burden.

Predicting amyotrophic lateral sclerosis (ALS) progression with machine learning

ObjectiveTo predict ALS progression with varying observation and prediction window lengths, using machine learning (ML).MethodsWe used demographic, clinical, and laboratory parameters from 5030 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to model ALS disease progression as fast (at least 1.5 points decline in ALS Functional Rating Scale-Revised (ALSFRS-R) per month) or non-fast, using Extreme Gradient Boosting (XGBoost) and Bayesian Long Short Term Memory (BLSTM). XGBoost identified predictors of progression while BLSTM provided a confidence level for each prediction.ResultsML models achieved area under receiver-operating-characteristics curve (AUROC) of 0.570-0.748 and were non-inferior to clinician assessments. Performance was similar with observation lengths of a single visit, 3, 6, or 12 months and on a holdout validation dataset, but was better for longer prediction lengths. 21 important predictors were identified, with the top 3 being days since disease onset, past ALSFRS-R and forced vital capacity. Nonstandard predictors included phosphorus, chloride and albumin. BLSTM demonstrated higher performance for the samples about which it was most confident. Patient screening by models may reduce hypothetical Phase II/III clinical trial sizes by 18.3%.ConclusionSimilar accuracies across ML models using different observation lengths suggest that a clinical trial observation period could be shortened to a single visit and clinical trial sizes reduced. Confidence levels provided by BLSTM gave additional information on the trustworthiness of predictions, which could aid decision-making. The identified predictors of ALS progression are potential biomarkers and therapeutic targets for further research.

Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial

Objective To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial. Methods In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5). Muscle strength was measured quantitatively with hand-held dynamometry, and grip strength with a dedicated dynamometer. The relationship between strength and ALSFRS-R fine and gross motor domain scores, or responses to ALSAQ-5 questions on hand function and walking, was assessed with Spearman’s rank correlation. The relationship between mean upper- or lower-extremity muscle strength and specific ALSFRS-R domains was modeled using principal-components analysis. Results Upper-extremity muscle strength and hand grip were highly correlated with ALSFRS-R fine motor scores and the ALSAQ-5 hand function question. Similarly, lower-extremity strength correlated well with ALSFRS-R gross motor domain and the ALSAQ-5 walking question. For SVC, correlation was poor with the ALSFRS-R respiratory domain, but stronger with the total score, potentially reflecting the insensitivity of the respiratory questions in the scale. Upper- and lower-extremity strength were both strong predictors of ALSFRS-R domain scores. Conclusions In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS.

The natural history of ALS: Baseline characteristics from a multicenter clinical cohort

Background Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. Methods The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant’s electronic health record. Participant burden is therefore minimal. Results Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. Conclusions ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants. Key Messages What is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population. What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures. How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

Multimodal MRI improves diagnostic accuracy and sensitivity to longitudinal change in amyotrophic lateral sclerosis

BackgroundRecent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord.MethodsWe acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section.ResultsWe demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics.ConclusionsOur findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials.

Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS.

Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity or prognosis. The use of composite score risks declaring treatments ineffective if not all dimensions of ALS disease progression are affected equally. We aimed to develop the ALS Impairment Multidomain Scale (AIMS) to comprehensively characterize disease progression and increase the likelihood of identifying effective treatments. The Revised ALS Functional Rating Scale (ALSFRS-R) and a preliminary questionnaire, based on literature review and patient input, were completed online by patients from the Netherlands ALS registry at bimonthly intervals over a period of 12 months. A 2-week test-retest, factor analysis, Rasch analysis, and a signal-to-noise optimization strategy were performed to create a multidomain scale. Reliability, longitudinal decline, and associations with survival were evaluated. The sample size required to detect a 35% reduction in progression rate over 6 or 12 months was assessed for a clinical trial that defines the ALSFRS-R or AIMS subscales as a primary endpoint family. The preliminary questionnaire, consisting of 110 questions, was completed by 367 patients. Three unidimensional subscales were identified, and a multidomain scale was constructed with 7 bulbar, 11 motor, and 5 respiratory questions. Subscales fulfilled Rasch model requirements, with excellent test-retest reliability of 0.91-0.94 and a strong relationship with survival (p < 0.001). Compared with the ALSFRS-R, signal-to-noise ratios were higher as patients declined more uniformly per subscale. Consequently, the estimated sample size reductions achieved with the AIMS compared with those achieved with the ALSFRS-R were 16.3% and 25.9% for 6-month and 12-month clinical trials, respectively. We developed the AIMS, consisting of unidimensional bulbar, motor, and respiratory subscales, which may characterize disease severity better than a total score. AIMS subscales have high test-retest reliability, are optimized to measure disease progression, and are strongly related to survival time. The AIMS can be easily administered and may increase the likelihood of identifying effective treatments in ALS clinical trials.

Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord. The causes of ALS are not fully understood. About 10% of ALS cases were associated with genetic factors. Since the discovery of the first familial ALS pathogenic gene SOD1 in 1993 and with the technology advancement, now over 40 ALS genes have been found. Recent studies have identified ALS related genes including ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7. These genetic discoveries contribute to a better understanding of ALS and show the potential to aid the development of better ALS treatments. Besides, several genes appear to be associated with other neurological disorders, such as CCNF and ANXA11 linked to FTD. With the deepening understanding of the classic ALS genes, rapid progress has been made in gene therapies. In this review, we summarize the latest progress on classical ALS genes and clinical trials for these gene therapies, as well as recent findings on newly discovered ALS genes.

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.

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

<h3>Objective:</h3> To assess the potential effect of placebo-to-active crossover on intent-to-treat (ITT) overall survival results from the CENTAUR trial evaluating an oral, fixed-dose sodium phenylbutyrate and taurursodiol combination (PB&amp;TURSO) in amyotrophic lateral sclerosis (ALS), a post hoc analysis was performed utilizing an external, propensity score–matched (PSM), PB&amp;TURSO-naïve cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database as a historical control comparator. <h3>Background:</h3> CENTAUR encompassed a 6-month randomized placebo-controlled phase and a long-term open-label extension (OLE) phase. ITT analysis at trial conclusion (maximum postrandomization follow-up, 44 months) showed a 4.8-month longer median survival time in those originally randomized to PB&amp;TURSO (23.5 mo) versus placebo (18.7 mo; hazard ratio [HR]=0.64; 95% CI, 0.42–1.00; <i>P</i>=.048). Notably, 71% of placebo-randomized participants entered the OLE phase and crossed over to active treatment. Such placebo-to-active crossover may lead to underestimation of survival benefit of investigational therapies in trials incorporating this design. Comparison with an external control group may provide additional context beyond observed survival outcomes in this setting. <h3>Design/Methods:</h3> PRO-ACT participants were control subjects from historical trials who met major enrollment criteria from CENTAUR and had known mortality information. PB&amp;TURSO-randomized participants from CENTAUR (n=89) and historical control participants (n=85) were propensity score matched using covariates of prognostic significance. Survival probability through the date of final participant visit in CENTAUR was compared between groups using a Cox proportional hazards model. <h3>Results:</h3> PSM covariates were generally well balanced between groups. Median survival duration was 10.39 months longer in PB&amp;TURSO-randomized participants from CENTAUR (23.54 months) versus historical controls (13.15 months; HR=0.48; 95% CI, 0.31–0.72; <i>P</i>=.00048). <h3>Conclusions:</h3> The results of this analysis suggest a greater survival benefit with PB&amp;TURSO than seen on ITT analysis in CENTAUR. The survival benefit attributed to PB&amp;TURSO in this analysis aligns with prior analyses using statistical models controlling for placebo-to-active crossover in CENTAUR. <b>Disclosure:</b> Dr. Paganoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Paganoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jannsen. Dr. Paganoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Paganoni has received personal compensation in the range of $0-$499 for serving as a Consultant for Sola. Dr. Paganoni has received personal compensation in the range of $0-$499 for serving as a Consultant for Frequency Therapeutics. The institution of Dr. Paganoni has received research support from Amylyx. The institution of Dr. Paganoni has received research support from Revalesio. The institution of Dr. Paganoni has received research support from Alector. The institution of Dr. Paganoni has received research support from UCB. The institution of Dr. Paganoni has received research support from Biohaven. The institution of Dr. Paganoni has received research support from Clene. The institution of Dr. Paganoni has received research support from Prilenia. The institution of Dr. Paganoni has received research support from Seelos. The institution of Dr. Paganoni has received research support from Calico. The institution of Dr. Paganoni has received research support from Denali. The institution of Dr. Paganoni has received research support from Anelixis. The institution of Dr. Paganoni has received research support from Cytokinetics. Dr. Quintana has nothing to disclose. Dr. Yuehui has received personal compensation for serving as an employee of Amylyx. Dr. Yuehui has stock in Amylyx. Dr. Timmons has received personal compensation for serving as an employee of Amylyx Pharmaceuticals. Dr. Cudkowicz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for biogen. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for cytokinetics. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for als pharma. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RRD. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for immunitypharm. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for denali. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for wave. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for transposon. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quralis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regeneron. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for LIlly. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Cudkowicz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Faze. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AB sciences. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MTPC. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neurosense. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for vectorY. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for Arrowhead. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Servier. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eledon. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Locust Walk. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pasithea. Dr. Cudkowicz has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Praxis Precision Medicine. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology . An immediate family member of Dr. Cudkowicz has stock in Sqz. The institution of Dr. Cudkowicz has received research support from NINDS. The institution of Dr. Cudkowicz has received research support from ALSA . The institution of Dr. Cudkowicz has received research support from ALSFAC. The institution of Dr. Cudkowicz has received research support from UCB ra. The institution of Dr. Cudkowicz has received research support from Biohaven. The institution of Dr. Cudkowicz has received research support from Clene nanomedicine. The institution of Dr. Cudkowicz has received research support from prilenia. The institution of Dr. Cudkowicz has received research support from ALS one. The institution of Dr. Cudkowicz has received research support from Seelos. The institution of Dr. Cudkowicz has received research support from Calico. Dr. Cudkowicz has received publishing royalties from a publication relating to health care.

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.

Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: Propensity-score-matched control, surveillance study.

Neuronata-R® (lenzumestrocel) is an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product, which was conditionally approved by the Korean Ministry of Food and Drug Safety (KMFDS, Republic of Korea) in 2013 for the treatment of amyotrophic lateral sclerosis (ALS). In the present study, we aimed to investigate the long-term survival benefits of treatment with intrathecal lenzumestrocel. A total of 157 participants who received lenzumestrocel and whose symptom duration was less than 2 years were included in the analysis (BM-MSC group). The survival data of placebo participants from the Pooled-Resource Open-Access ALS Clinical Trials (PROACT) database were used as the external control, and propensity score matching (PSM) was used to reduce confounding biases in baseline characteristics. Adverse events were recorded during the entire follow-up period after the first treatment. Survival probability was significantly higher in the BM-MSC group compared to the external control group from the PROACT database (log-rank, p < 0.001). Multivariate Cox proportional hazard analysis showed a significantly lower hazard ratio for death in the BM-MSC group and indicated that multiple injections were more effective. Additionally, there were no serious adverse drug reactions found during the safety assessment, lasting a year after the first administration. The results of the present study showed that lenzumestrocel treatment had a long-term survival benefit in real-world ALS patients.

Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.

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.

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.

Progress, development and challenges in amyotrophic lateral sclerosis clinical trials

Introduction Amyotrophic Lateral Sclerosis (ALS) brings unique challenges to a clinical trial setting, due in part to relatively low disease prevalence coupled with a poor prognosis, in addition to the complexities linked to disease heterogeneity. As critical understanding of the disease develops, particularly in relation to clinical phenotype and the mechanisms of disease progression, so too new concepts evolve in relation to clinical trials, including the advent of precision therapy, targeted to subgroups of ALS patients. Areas covered Individualized, or precision medicine in ALS recognizes the heterogenous nature of the disease and utilizes information such as the clinical phenotype of the disease, clinical biomarkers, and genotyping to promote a tailored approach to treatment. Separate to these considerations, the present review will discuss clinical trial design and how this can be improved to better match patient and investigator needs in ALS clinical trials. Expert opinion Precision therapy will promote a more focused treatment approach, with the goal of improving clinical outcomes for ALS patients. An increased community awareness of ALS, coupled with significant industry and philanthropic funding for ALS research is accelerating this process.