The pivotal phase 3 trial MCI186-19 (Study 19) demonstrated the efficacy of intravenous edaravone in slowing functional decline in patients with amyotrophic lateral sclerosis (ALS), leading to United States Food and Drug Administration approval. Study 19 utilized a targeted enrollment enrichment strategy based on post hoc analyses from earlier trials, selecting patients with higher baseline function, more rapid disease progression, and better respiratory status. To evaluate the generalizability of Study 19 results, subsequent post hoc analyses assessed the efficacy of edaravone in broader ALS populations. One machine learning-based analysis retrospectively applied a validated model to Study 16 data, stratifying patients by predicted risk of respiratory decline. This detectable effect cluster analysis suggested that up to 70% of Study 16 participants may have benefited from edaravone. A second analysis investigated edaravone efficacy in patients from Study 19 with forced vital capacity (FVC) < 80% predicted (%p) at the start of treatment, since FVC ≥ 80%p was one of the Study 19 inclusion criteria. Both high- and low-FVC subgroups demonstrated reduced ALS functional rating scale-revised decline at 48 weeks when treated continuously with edaravone. These findings support the potential benefit of edaravone in a wider range of patients with ALS than those enrolled in Study 19, providing important insights into how clinical trial enrichment strategies may influence perceived efficacy, and underscoring the need for future prospective studies in more diverse ALS populations.

Randomized controlled trials remain the cornerstone of evidence generation in amyotrophic lateral sclerosis (ALS), yet their inherent challenges, including disease rarity, heterogeneity, and limited validated biomarkers, highlight the need for complementary clinical evidence. This exploratory, retrospective study assessed overall survival in patients with ALS treated with intravenous (IV) edaravone using data from a large United States administrative claims database of patients enrolled from August 2017 to March 2020. Patients receiving IV edaravone (n = 318) were propensity score matched 1:1 with controls not treated with IV edaravone (n = 318), adjusting for 11 covariates. Median overall survival was 29.5 versus 23.5 months for the edaravone-treated group compared to controls, with a 27% reduced risk of death observed in the treated cohort (p = 0.005). These findings, together with existing data from the pivotal phase 3 Study MCI186-19 of IV edaravone, contribute to the growing body of literature suggesting a dual benefit of edaravone on both function and survival in ALS, offering critical insights for clinicians, patients, and payers navigating ALS treatment decisions.

While randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of therapies in amyotrophic lateral sclerosis (ALS), post hoc analyses can provide critical insights into clinical effectiveness, treatment durability, and subpopulation responses. Several post hoc analyses of Study MCI186-19 (Study 19), the pivotal phase 3 RCT that supported the United States Food and Drug Administration approval of intravenous edaravone, have been performed to explore the broader clinical impact of this therapy. These analyses assessed the long-term treatment efficacy, changes in individual ALS Functional Rating Scale-Revised item scores, survival and additional milestone events, and the impact of edaravone in patient subgroups defined by disease progression trajectories using latent class analysis. Collectively, these findings reinforce the long-term clinical benefit of edaravone and demonstrate that edaravone may offer benefits across a spectrum of ALS disease trajectories, beyond those defined in the original study criteria. These studies help address questions not captured in the original RCT and may inform future trial design and treatment decisions.

INTRODUCTION:Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups. METHODS:Disease trajectories of MCI186-19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories. RESULTS:ALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186-19 double-blind period. Latent classes 2-4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects. CONCLUSIONS:This post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.

Introduction/AimsIntravenous (IV) edaravone is a US Food and Drug Administration-approved treatment for amyotrophic lateral sclerosis (ALS), shown in clinical trials to slow physical functional decline. In this study we compared the effect of IV edaravone (edaravone-first group) versus placebo followed by IV edaravone (placebo-first group) on survival and additional milestone events. MethodsThis work is a post hoc analysis of Study 19/MCI186-19, which was a randomized, placebo-controlled, phase 3 study investigating IV edaravone versus placebo. Study 19 and its 24-week extension have been described previously (NCT01492686). Edaravone-first versus placebo-first group time to events for specific milestone(s) were analyzed post hoc. Time-to-event composite endpoints were time to death; time to death, tracheostomy, or permanent assisted ventilation (PAV); and time to death, tracheostomy, PAV, or hospitalization. ResultsThe risk for death, tracheostomy, PAV, or hospitalization was 53% lower among patients in the edaravone-first vs placebo-first groups (hazard ratio = 0.47 [95% confidence interval 0.25 to 0.88], P = .02). The overall effect of IV edaravone on ALS progression could be seen in the significant separation of time-to-event curves for time to death, tracheostomy, PAV, or hospitalization. ALS survival composite endpoint analyses (ALS/SURV) suggested a treatment benefit (least-squares mean difference) for the edaravone-first versus the placebo-first group at week 24 (0.15 & PLUSMN; 0.05 [95% confidence interval 0.06 to 0.25], P < .01) and week 48 (0.11 & PLUSMN; 0.05 [95% confidence interval 0.02 to 0.21], P = .02). DiscussionThese analyses illustrate the value of timely and continued IV edaravone treatment, as earlier initiation was associated with a lower risk of death, tracheostomy, PAV, or hospitalization in patients with ALS.

Respiratory therapist(RT)internet-supervised At-Home Telespirometry(AHT)was validated in pilot 22/95=23% ALS Clinic population. Erect, supine Vital Capacity(eFVC, sFVC)were measured longitudinally using ZephyRx smartphone interface and database recording in-clinic-conventional(Viaire-Vyasis-)and at-home-portable(MIR-Spirobank-Smart-)spirometers. Bland-Altman(BA)analysis supported content validity-precision and 7-day-test-re-test-validity [mean difference=0.15L(conventional–portable;95%CI -0.40L, 0.70L); = 2.7% predicted (conventional-portable;95%CI -12.1%, 17.5%) ]meeting ATS-ERS performance standards. RT Internet-supervised AHT measured sFVC was more frequently obtained[35/52=67.3 %]in-home-vs-in-clinic sFVC[9/21=42.9 %](Chi-Square;P=0.0533). Monthly mean eFVC slope decline for the eFVC > 60 % predicted baseline cohort was – 1.24% predicted per month[95% CI -2.15 ,-0.33% predicted]statistically significantly(P=0.015)less compared with the – 5.86% predicted per month[95% CI -9.44, -2.29 % predicted]decline for the eFVC < 60 % predicted baseline cohort and in this cohort was associated with statistically significant decreased survival(P=0.0219). RT Internet-supervised AHT facilitated initiation of non-invasive ventilation(NIV)in 5/22[23%]patients including 3/4[75%] homebound subjects. RT Internet-supervised AHT can be deployed for ALS patients stratified according to baseline eFVC for earlier detection of eFVC and sFVC decreases between clinic visits. A prospective research study[NCT05106569]is ongoing to further define the capability of online deployment of Respiratory therapist(RT)internet-supervised AHT in the timely initiation of NIV use to improve ALS respiratory care in larger numbers of ALS subjects.

OBJECTIVE:To evaluate the impact of 1) updating the existing algorithm to improve case-finding sensitivity and 2) reclassifying the Registry's diagnostic status nomenclature into four new categories ("confirmed ALS," "likely ALS," "undetermined ALS," or "not ALS") versus the current three ("definite ALS," "possible ALS," or "not ALS") to be more inclusive and descriptive of cases and individuals.METHODS:A retrospective analysis of Registry data from 2011-2017 was conducted to follow "possible ALS" individuals over time to determine what qualifier caused them to convert, if at all and when, to Registry-eligible cases (i.e. "confirmed ALS" or "likely ALS").RESULTS:In 2011, 720 individuals were classified by the Registry algorithm as having "possible ALS". By 2017, 42% of these had converted to Registry-eligible ALS cases. Approximately 14% of those who were identified solely based on an ALS prescription drug never converted to Registry-eligible cases. This analysis indicates that "possible ALS" individuals with a single prescription for an ALS drug should be converted to Registry-eligible cases which would add between 300-500 cases per year on average.CONCLUSIONS:The Registry's existing algorithm likely results in the under-ascertainment of ALS cases. However, updating the algorithm with the inclusion of patients having been prescribed ALS-specific drugs, even with a single prescription, leads to improved epidemiologic estimates of ALS in the US. This and future algorithmic updates will help the Registry more accurately depict the true disease burden of ALS in the US.

The estimated prevalence of amyotrophic lateral sclerosis (ALS) is approximately 5.2-7.9 people per 100,000 in the United States,(1,2) with a worldwide ALS estimate of 4.42 per 1,000,000 population.(3) Patients with ALS have progressive arm and leg weakness, speech, swallowing, and respiratory impairments, and frequent cognitive/behavioral dysfunction. Median tracheostomy-free survival from onset of weakness is 34.7 months, but progression rates vary substantially between individuals.(4) Although pharmacologic treatment options remain limited, judicious use of noninvasive ventilation, adequate nutritional support, and multidisciplinary care serve as the background for a landscape that continues to evolve with increasing availability of neuroprotective treatments and targeted genetic therapies on both a clinical(5) and research basis.(6,7)

The estimated prevalence of amyotrophic lateral sclerosis (ALS) is approximately 5.2–7.9 people per 100,000 in the United States,1,2 with a worldwide ALS estimate of 4.42 per 1,000,000 population.3 Patients with ALS have progressive arm and leg weakness, speech, swallowing, and respiratory impairments, and frequent cognitive/behavioral dysfunction. Median tracheostomy-free survival from onset of weakness is 34.7 months, but progression rates vary substantially between individuals.4 Although pharmacologic treatment options remain limited, judicious use of noninvasive ventilation, adequate nutritional support, and multidisciplinary care serve as the background for a landscape that continues to evolve with increasing availability of neuroprotective treatments and targeted genetic therapies on both a clinical5 and research basis.6,7

Background Edaravone slowed the rate of functional decline in subjects with amyotrophic lateral sclerosis (ALS) in phase 3 study MCI186-19 (Study 19). One of the Study 19 inclusion criteria was forced vital capacity (FVC) ≥80% of predicted (≥80%p). Therefore, the study provided no information on edaravone efficacy in subjects with FVC <80%p. In Study 19, 24-week, double-blind treatment was followed by open-label treatment where all subjects received edaravone. At 24 weeks, some subjects had FVC <80%p (FVC24 <80%p). This allowed for post-hoc assessment of the effects of edaravone in subgroups of subjects with FVC24 ≥80%p vs <80%p. Objective To address the question of the efficacy of edaravone in ALS patients with FVC <80%p. Methods Post-hoc analysis of Study 19 comparing edaravone efficacy at week 48 in subjects with FVC24 ≥80%p vs <80%p. Results With edaravone treatment, subjects in both the FVC24 ≥80%p and the FVC24 <80%p subgroups experienced a reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) score loss vs placebo subjects through week 48. For the FVC24 ≥80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were −7.63 for edaravone-edaravone vs −9.69 for placebo-edaravone, a difference of 2.05 (P = .034; 95% CI: 0.16, 3.94). For the FVC24 <80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were −10.26 for edaravone-edaravone vs −15.20 for placebo-edaravone, a difference of 4.94 (P = .0038; 95% CI: 1.64, 8.25). Linear regression analysis indicated that, in the FVC24 <80%p subgroup, there was a notable change in the slope of the ALSFRS-R score-vs-time graph after the start of edaravone treatment. Conclusion ALS subjects in the Study 19 placebo arm had a slowing in disease progression, even when edaravone was added with an FVC of <80%p prior to starting edaravone. A randomized, placebo-controlled study is needed to validate these post-hoc findings.