Theme 09 - CLINICAL TRIALS AND TRIAL DESIGN

G. Addy, D. Gelevski, M. Rohrer, J. Carey, J. Scalia, A. Kostov, M. Yerton, M. Doyle, N. Parikh, G. Kane, A. Ellrodt, K. Burke, E. Sinani, A. Sherman, H. Yu, J. Mock, A. Kalmes, G. Archambeau, K. Hanus, C. Baecher-Allan, M. Adler, B. Wainger, K. Nicholson, J. Berry, S. Luppino, S. Paganoni and M. Cudkowicz Massachusetts General Hospital Healey Center, Boston, MA, USA; Revalesio Corporation, Tacoma, WA, USA; Brigham and Women’s Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA

Background: RNS60 is an electrokinetically altered aqueous fluid composed of saline and oxygen that has demonstrated neuroprotective and anti-inflammatory effects in both in vitro and in vivo models of ALS and other neurodegenerative diseases. RNS60 has been tested in 7 clinical pharmacology studies, in which it was well tolerated, and is in Phase II clinical testing for the treatment of amyotrophic lateral sclerosis (ALS). It can be administered by IV infusion and inhalation (nebulization). We designed an intermediate-size Expanded Access Program (EAP) to treat up to sixty ALS patients with RNS60 for up to 3 years. EAPs provide a means for patients who do not qualify for controlled clinical trials to access experimental drugs. These are often patients in the advanced stages of their disease. The objectives of this ongoing EAP are to provide investigational treatment of RNS60 for people with ALS who do not qualify for a clinical trial, establish the feasibility of EAPs in people with ALS, and monitor the safety and tolerability of long-term RNS60 administration. Methods: Participants are treated with twice-daily inhalation of nebulized RNS60 at home for up to 3 years. In addition, two participants receive once-weekly IV RNS60 in addition to nebulized RNS60 and one participant exclusively receives weekly IV RNS60 infusions. Participant safety is monitored through the collection of safety labs and the assessment of adverse events (AEs). We also administered the ALS functional rating scale revised (ALSFRS-R), measured slow vital capacity (SVC), and collected patient-reported experience questionnaires. Blood samples are collected for the measurement of soluble biomarkers in plasma and for functional assessment of regulatory T cells (Tregs). Results: 49 participants with ALS have been enrolled and treated with RNS60. 28 participants have completed six months of RNS60 treatment, 12 participants have completed 12 months of treatment, 5 participants have completed 18 months of treatment, and 3 participants have completed 24 months of treatment. Average age at baseline was 60.8 and average ALSFRS-R at baseline was 19.7. 10 participants have died due to complications related to ALS disease progression. No serious adverse events (SAEs) related to RNS60 have occurred and no participants have withdrawn from the program due to drug-related adverse events. This EAP has been well-accepted by the participating ALS patients and their caregivers. Conclusions: This EAP demonstrates the feasibility of performing EAPs in ALS patients as a complimentary approach to controlled clinical trials that allow for the collection of longer-term safety data. Overall, tolerability for and compliance with RNS60 treatment was high, which demonstrates the feasibility of RNS60 treatment in a broad ALS population, particularly those in the advanced stages of ALS disease progression. baseline in supine SVC at 12 weeks) nor the key secondary endpoint (combined assessment of function and survival (CAFS), including the revised ALS functional rating scale (ALSFRS-R) of the trial were met. Participants completing the REFALS study were provided an option to continue treatment with levosimendan in an open-label extension, the REFALS-ES study, evaluating the long-term safety and efficacy of oral levosimendan in ALS. Results of the REFALS-ES study are presented here. Methods: REFALS-ES included participants completing 48 weeks of treatment according to the REFALS study protocol, who were able to swallow the study treatment capsules and had not developed any new (or significant worsening of existing) illness, such as serious cardiovascular disease. The participants were treated with oral levosimendan 0.5-2 mg daily and followed up with clinic or remote visits at least every 3 months and reassessment 2 weeks after each dose change. The efficacy assessments included sitting and supine SVC, ALSFRS-R, need for respiratory support, and Borg Category Ratio 10 (CR 10) scale on dyspnea. Safety was assessed by adverse events (AEs), vital signs, 12-lead electrocardiogram and suicidality. Results: A total of 227 REFALS participants entered the study and received oral levosimendan for a mean of 24 (range 0.3-61.0) weeks. At 6 months from baseline, the supine and sitting SVCs had declined by À3.3 and À3.2 %points, respectively, ALSFRS-R total score by À3.4 points, with similar changes in all the four subdomains (À0.8-0.9 points), and Borg CR 10 had increased by 1.1 and 0.8 points for supine and sitting, respectively. Non-invasive ventilation was started by 15% of the participants during the study. Treatment-emergent AEs (TEAEs) were recorded in 71%, serious TEAEs in 19%, discontinuations due to TEAEs in 7% and deaths in 8% of the participants. The most frequently reported TEAEs were fall, headache and tachycardia. Increase in pulse and heart rate was seen during treatment with levosimendan. Discussion: The study showed a decline in all the efficacy outcome measures, the magnitude of which was less than expected for the SVC, possible reflecting selection bias in participants completing the REFALS study. No new safety concerns were identified. Background: Radicava V R (edaravone injection) is a US Food and Drug Administration-approved treatment for ALS that slows the rate of physical functional decline (1,2). As intravenous (IV) administration can burden patients, orally administered treatments are needed. Objectives: To assess the pharmacokinetics (PK) and bioequivalence of an oral suspension formulation of edaravone (MT-1186) compared with the already approved intravenous edaravone.
Methods: Three open-label phase 1 clinical studies were conducted in healthy subjects or in patients with ALS with or without percutaneous endoscopic gastrostomy (PEG). Study J03 was a single-dose, crossover, bioequivalence study involving 42 healthy subjects who received 105 mg of oral edaravone and IV edaravone (60 mg/60 min) (3). Assessments included PK parameters, metabolic profiles, and elimination pathways for each formulation. The 24-h PK of a single dose of investigational oral edaravone was also assessed in 9 patients with ALS (Study J04) and in 6 patients with ALS who had PEG tubes (Study J05). Results: In healthy volunteers (Study J03), the geometric mean ratios and 90% confidence intervals (CIs) of area under the plasma concentration-time curve (AUC) and the geometric mean ratio and its lower limit 90% CI of maximum serum concentration (Cmax) of the 105-mg oral suspension compared with the 60-mg IV formulation met bioequivalence limits. Both formulations showed quite similar triphasic plasma concentration-time profiles of edaravone after reaching Cmax. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. One subject in each group experienced an adverse event (AE), both of which were mild in severity and were not judged to be related to edaravone by the investigator. In patients with ALS (Study J04), the investigational, oral edaravone was well absorbed after the oral administration and showed triphasic plasma concentration-time profiles of edaravone after reaching Cmax, as in the healthy subjects. The single dose of investigational, oral edaravone was well tolerated, with 1 treatment-emergent AE (TEAE) reported in 1 patient. The TEAE was mild in severity and was judged not to be reasonably related to the investigational product by the investigator. Similar results were obtained in the study with ALS patients who had PEG tubes (Study J05). Discussion: These studies provide clinical evidence for the bioequivalence and tolerability of the investigational, oral edaravone and will help support the development of MT-1186 for patients with ALS.

stephen_apple@mt-pharma-us.com
Background: The sudden onset of the COVID-19 pandemic profoundly affected clinical trial patient recruitment, enrollment, and retention. Most medical clinics underwent significant reductions in patient visits to accommodate social distancing and lockdown regulations. As a result, a variety of strategies were employed to mitigate the impact of COVID-19 on clinical trial management. Most trial strategies focused on continuing to evaluate safety, rather than complex biomarkers. The REFINE-ALS study focused on continuing to collect biofluids requiring complex processing for biomarker evaluation. Objective: The REFINE-ALS study will identify putative biomarkers to serve as quantifiable biological nonclinical measures of the pharmacodynamic effect of edaravone in ALS and evaluate its effectiveness in people with ALS in real-world settings. Key strategies used to mitigate COVID-19 challenges in REFINE-ALS are described. Methods: REFINE-ALS is a prospective, observational, longitudinal, multicenter US study that will enroll up to 300 adults with ALS who will initiate Radicava V R (edaravone injection) treatment. Selected biomarkers, including those for oxidative stress, inflammation, neuronal injury and death, and muscle injury, will be evaluated. Other clinical efficacy assessments include ALS Functional Rating Scale Revised, King's clinical staging, ALS Assessment Questionnaire long form, slow vital capacity (SVC), and time to specified states of disease progression or death. DNA samples will be collected for genomic sequencing. Adverse events related to the study will be reported. Results: Study enrollment began in October 2019, and within months, was affected by COVID-19. In the early months of 2020, most participating sites reported strict institutional restrictions on in-person visits for observational studies, requiring cessation of patient enrollment. Site activations slowed, some already-activated sites closed, patient recruitment slowed or halted, and most enrolled participants were unable to visit clinical sites. Moreover, global supply chain limitations caused delays in the availability of laboratory kits for sample collection, and closure of research laboratories prevented processing of specimens. Mitigation strategies were deployed through protocol amendments. Multiple home health agencies and home spirometry vendors were assessed to find the best solutions. Workflows were developed to perform and document at-home visits by trained healthcare clinicians to collect blood samples, perform clinical assessments, and measure SVC. Informational webinars for study investigators were held in autumn 2020 to inform sites of upcoming protocol changes, and remote-visit training for sites was conducted in early 2021. As of April 2021, 33 sites have been activated, including 32 US sites and 1 Canadian site. A total of 33 patients were enrolled as of June 2021. Discussion: The COVID-19 mitigation strategies employed in the REFINE-ALS study may be applicable to other clinical studies in ALS and may help improve clinical trial procedures in future studies.

jdberry@mgh.harvard.edu
Background: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is the most commonly used outcome measure in ALS clinical trials. Objectives: The objective of this study is to identify potential limitations in the ALSFRS-R from a patient and caregiver perspective.
Methods: This study was reviewed and waived by North Star Institutional Review Board. An online survey was conducted via SurveyMonkey from 15 June 2021 to 2 July 2021. Study enrollment was open to all patients diagnosed with ALS or caregivers of people who currently have or who passed away from ALS. Participants were presented with each of the 12 items in the ALSFRS-R and asked a series of questions about each item. A qualitative content analysis was conducted to capture overarching themes. Quantitative analysis was performed with SPSS version 27. Qualitative data were analyzed with NVivo. Results: A total of 103 people responded to the survey, of whom 67% are people with ALS and 33% are caregivers. Participants originated from 17 countries, of which 32 (31%) are from the United States. The mean age of the participants was 50, and 47% identified as male. The mean most recent ALSFRS-R score, if known, was 31.4 (SD 11.8; range 1-48). Forty-seven (46%) individuals expressed concerns about their ability to accurately answer at least one item of the scale. Most individuals had concerns about item 1 (speech), item 8 (walking), and item 5 (cutting food). The majority of comments fell into one of the following categories: language used in the question is of a literacy level too high for most people with ALS; language used is of appropriate literacy level but needs clarity; the question is answered differently depending on the situation or equipment used; it is difficult to distinguish the difference between choices on the scale; and the structure and/or underlying assumptions of the question makes it difficult to answer. Discussion: In this study, we found that nearly half of the patients indicated concerns that parts of the ALSFRS-R do not accurately reflect their ability. Though improving language may address some of these concerns, there is need to critically revise items to accurately capture the patient's functioning. Background: Patient-reported outcome measures are of increasing importance for ALS research. The Revised ALS Functional Rating Scale (ALSFRS-R) is a primary outcome measure in most clinical trials for people with ALS (PALS). Recent studies have highlighted limitations of the ALSFRS-Rit is not linearly weighted, many PALS show no change over 6 months, some scores can improve with changes in symptom management, and though it is scored ordinally, the clinical meaning of a one-point change varies by question. Given these limitations, the Rasch-Built Overall ALS Disability Scale (ROADS) was developed with a focus on psychometric performance in an effort to capture functional changes in ALS as an outcome measure for ALS trials. Objective: The data collected in this study will be used to (1) understand the characteristics of the self-reported version of the ALSFRS-R and ROADS to quantify clinical changes in ALS and (2) compare the longitudinal characteristics of these scales. Methods: PALS consented and enrolled for this survey study online. They were asked to complete self-reported ALSFRS-R and ROADS questionnaires at baseline, 3-, 6-, 9-and 12months. The study is ongoing. We report results of the baseline through 6-month follow-up. Results: As of now, 260 people consented to the study, 182 PALS completed baseline surveys, 145 completed the 3month surveys, and 120 have completed the 6-month surveys. At baseline, the ALSFRS-R (mean ¼31, sd ¼9) and ROADS normed score (mean ¼79, sd ¼16) demonstrate a high correlation (r ¼ 0.89; p < 0.001). For the 113 PALS with complete month 3 follow-up and 82 PALS with complete month 6 follow-up, comparing a worsening of symptoms of at least 1 point in ALSFRS-R and ROADS we see agreement of 73% (kappa ¼0.41, p < 0.001) at month 3 and 76% (kappa ¼0.43 p < 0.001) at month 6. Average change per month in total ALSFRS-R at 3 and 6 months were À0.67 (n ¼ 135, sd ¼1.23) points and À0.48 (n ¼ 95, sd ¼0.87) points, respectively. Average change per month in ROADS normed scores at 3 and 6 months were À0.99 (n ¼ 115, sd ¼3.17) and À1.03 (n ¼ 83, 1.83), respectively. Discussion/Conclusions: Initial findings suggest that selfreported ALSFRS-R and ROADS are significantly correlated cross-sectionally but more work is needed to describe and evaluate differences in changes over time. The ROADS may capture more linear changes over time.
katherine.burke@mgh.harvard.edu CLT-08 Can bias and discrimination impact the ALS/MND patient experience? C. Carter 1,2 1 Princeton University, Princeton, NJ, USA; 2 Yale School of Public Health, New Haven, CT, USA Background: ALS/MND presents a unique set of biomedical, social, and clinical research challenges, given that the condition has no known etiology or cure. Global research efforts have shown that prevalence studies, disease databases, and clinical trial enrollment within the ALS/MND space are significantly imbalanced by race and ethnicity which are largely subsumed by white participants. Within multi-national and global trials, the inclusion of Black people and people of color is often limited and not reflective of the local population where participants are enrolled. It has been documented across high-income western countries that histories of systemic inequality and structural discrimination impact healthcare access and medical treatment, which is why it is particularly important to understand how these social realities impact a rare disease like ALS/MND. Objective: To date, only two studies (1,2) have noted unique disparities that exist between Black and white persons with ALS/MND but none have sought to explain the reasons that disparities exist for Black persons with ALS (B-pALS). This study seeks to fill this gap. Methods: This study was an empirically driven ethnographic investigation over 24 months. Research methods included participant observation at three multi-disciplinary ALS clinics in the United States, 86 semi-structured interviews with Black and white American ALS patients, caregivers, clinical researchers and care providers, a survey tool, and content analysis of ALS resources. Results: Findings revealed four major themes central to the care experiences of B-pALS navigating US healthcare systems: (1) Clinicians held beliefs that supported racial science and believed biological differences existed between Black and white pALS. (2) All B-pals experienced structural and/or individual racism when interacting with clinical care providers.
(3) B-pALS did not receive a timely diagnosis, or a diagnosis at all, of ALS/MND. Diagnosis in B-pals took 13 months longer compared to white pALS. (4) Some B-pALS lived shorter lives, on average 6.5 months, with ALS from diagnosis to death than white pALS. Discussion: The four central themes identified in this investigation provide a framework for acknowledging and addressing biases towards B-pALS and other people of color pALS. Many studies have revealed that experiences of bias and racism impact physical and mental health. Bias, discrimination, and racism in the ALS care space determinately impact diagnosis, treatment, life expectancy, and clinical research. More intentional work in this area will not only create more equitable care for all living with ALS but also improve clinical research trials towards a cure. While muscle strength loss is intrinsic to decline in function, the specific relationships of strength in individual muscles or muscle groups to functional state are not well described.
Objectives: To evaluate the relationship of alterations in individual or grouped muscle strength to changes in specific domains of the ALSFRS-R. Methods: FORTITUDE-ALS was a phase 2, double blind, placebo controlled 3-month trial of reldesemtiv in ALS. The ALSFRS-R was measured throughout the trial, and strength was measured using hand-held dynamometry (HHD) in 3 upper extremity muscles (first dorsal interosseous, wrist extensors and biceps) and 3 lower extremity muscles (tibialis anterior, quadriceps, and hip flexors) bilaterally. The ALSAQ-5 was also obtained. We correlated the change in the fine motor domain of the ALSFRS-R (FMD), the gross motor domain (GMD), as well as items 1 (standing) and 2 (using arms) of the ALSAQ-5 to individual upper and lower extremity muscle strength measurements, as well as averages of upper and lower extremity strength.
Results: The ALSAQ-5 item of activities of daily living and independence was well correlated with strength in all upper extremity muscles (Spearman's correlation coefficients (SCC) ranging 0.6-0.7), while ALSAQ-5 item of physical mobility had moderate correlation with lower extremity muscle strength (SCC: 0.4-0.6). The ALSFRS-R FMD had a strong association with First Dorsal Interosseus, Wrist Extensors and Elbow Flexion strength (SCC:0.6-0.7). In the legs, the gross motor domain also had a somewhat strong correlation with Ankle Dorsiflexion and Hip Flexion (SCC 0.6) but the correlation was moderate with Knee Extension (SCC: 0.5). Moderate correlations were also found between the fine and gross motor domains of the ALSFRS-R with SCC of 0.5. Discussion: Overall, strength and function as measured by both ALSFRS-R and ALSAQ-5 were better correlated in the upper extremity than in the lower extremity. In general, averaging upper and lower extremity muscle strength resulted in higher correlations than single muscle groups. Beyond being an objective and quantitative measure of ALS progression, strength as measured using HHD is moderately to strongly related to functional capacity in ALS. and Frontotemporal Dementia (FTD). The discovery that these diseases share a common cause has led to the realization that C9orf72-ALS/FTD is a single genetic disorder that manifests across a clinical spectrum. WVE-004 is an investigational stereopure oligonucleotide that is designed to target C9orf72 transcripts containing the hexanucleotide-repeat expansion and has potential as a disease-modifying therapy for patients with C9orf72-ALS/FTD. WVE-004 contains Wave's new PN chemistry, which has been shown to improve the pharmacological profile of oligonucleotides in preclinical studies. This adaptive Phase 1b/2a study of WVE-004, named FOCUS-C9, is a global, multicenter, randomized, double-blind, placebo-controlled trial that is planned to enroll approximately 50 patients who have a documented hexanucleotide-repeat expansion in C9orf72 and a diagnosis of ALS, FTD, or mixed phenotype. In FOCUS-C9, we will assess the safety and tolerability of single-and multiple-ascending doses of WVE-004 administered intrathecally (IT) by lumbar puncture. Secondary objectives include studying pharmacokinetics (PK) in plasma and cerebrospinal fluid (CSF) and poly glycine-proline (poly-GP) in CSF, a biomarker of pharmacodynamic (PD) effect. Exploratory objectives will consist of assessing changes in biomarkers of neurodegeneration, such as neurofilament light chain (NfL) in the CSF, as well as functional measures, such as ALSFRS-R (Revised ALS Functional Rating Scale), FVC (forced vital capacity), and FTLD-CDR (Frontotemporal Lobar Degeneration-Modified Clinical Dementia Rating). FOCUS-C9 is designed to be adaptive, using PK, PD, safety, and tolerability information to optimize dose level and frequency for each cohort in the single-and multiple-ascending dose phases of the trial. This first-in-human study will evaluate WVE-004 as a potential treatment for C9orf72-associated ALS and FTD.
kejebe@wavelifesci.com Introduction: ALS drug development is plagued by high clinical trial failure rates. Subgroup analysis is a key tool used to account for patient heterogeneity, but current methods fall short. DEC analysis systematically groups and analyzes patients based on predicted disease path, creating more homogeneous patient subgroups with reduced noise around the endpoint. Methods: To perform DEC Analysis, a multivariate, non-linear machine-learning model trained using PRO-ACT was used to rank order trial participants by predicted disease progression. Fifty initial subgroups were expanded by adjusting prediction thresholds in 2% nearest-neighbor increments until the FAS was reached. To analyze subgroups, a matrix was plotted in which each block had distinct upper and lower thresholds. A series of analyses were performed to assess variance (RMSE), treatment effect (TE), effect size, and P-value, thus developing a series of heat maps that revealed subgroups with favorable conditions for detecting a significant effect, whether through enhanced TE and/or lowered variance. The method was applied to the Ceftriaxone-ALS and Topiramate-ALS data sets available from the US NINDS.
Results: To focus on the development of DEC analysis, we used the 285 patients in the Ceftriaxone-ALS dataset who remained on study for 1 year. The 2:1 allocation of the full study was retained in this group and included 190 treated and 95 placebo patients, which allowed us to perform an exploratory analysis to generate a hypothesis for testing in a second analysis. We randomly separated the 190 treated patients into two groups, one for the exploratory analysis and a second for hypothesis testing. One-year predictions using our validated percent expected vital capacity model were made for all patients in the dataset. A broad central region, a hot-spot, where moderately progressing patients localized was detected and a subgroup, representing predicted 15-25% 1-year decline in percent expected vital capacity was selected to determine whether the subgroup could be detected in the test set. Examination of the test group confirmed the results of the exploratory analysis. In contrast to ceftriaxone, which had a slightly positive, non-significant TE, the topiramate trial reported a negative TE for the primary endpoint. DEC analysis using decline in ALSFRS-R as the endpoint was performed and failed to see any positive hotspots. Rather, the TE matrix showed broad zones of negative TEs. This experiment provides a strong negative control for DEC analysis.
Conclusions: DEC analysis organizes trial participants in an unbiased way into homogeneous subgroups: "Hot-spots" of detectable TEs that could form the basis for a subsequent successful trial are revealed. Numerous ways to implement this approach are envisioned: "rescue" of drugs that failed late-stage clinical development; all-comers trials to identify patients with detectable effects that can be seamlessly expanded into a fully powered trial. Background: IC14 is a chimeric, monoclonal, anti-CD14 antibody that decreases neuroinflammation by improving T-regulatory (T-reg) cell function. A previous trial of ten participants with ALS receiving four doses of IC14 over four days demonstrated initial safety. We designed an intermediate-size EAP of eight participants with ALS receiving IC14 to learn more about safety, pharmacokinetics (PK), and pharmacodynamics (PD). Methods: Participants receive intravenous infusions of IC14 every two weeks for 75 weeks. Due to the COVID-19 pandemic, some infusions were administered at home or at a local infusion center. We collected safety labs, amyotrophic lateral sclerosis function rating scale revised (ALSFRS-R), slow vital capacity (SVC), and physical, neurologic, and ophthalmologic exams. Whole blood and serum were collected to determine CD14 receptor occupancy (measured in real time), soluble CD14, and anti-drug antibodies (ADA). Ex-vivo T-reg function and characterization assays were collected starting with the fifth participant. Results: Average age was 60.2 (±7.7) years, with symptom onset to screening being 19.7 (±10.4) months. Average ALSFRS-R and SVC score at screening was 33.1 (±9.8) and 73.6% (±22.3), respectively. Participants received IC14 up to 59 weeks (average exposure: 40.7 weeks, range: 28-59 weeks). Three participants died due to disease progression. The most commonly reported adverse events (AEs) were falls (n ¼ 17) and headaches (n ¼ 10); all deemed unrelated to IC14. Treatment-emergent AES (TEASs) deemed probably related to IC14 were tongue paresthesias (n ¼ 1) and systemic exhaustion (n ¼ 1). There were eleven treatment unrelated serious adverse events (SAEs), the most common being: pneumonia (n ¼ 2) and worsening dysphagia (n ¼ 2). There were no significant changes in vital signs, exams, or safety labs. Monocyte CD14 receptor occupancy (% RO) increased for all participants after infusion with IC14. RO of greater than 80% was achieved in five participants after one (n ¼ 2), two (n ¼ 1), or three doses (n ¼ 2). One patient required a more frequent dosing regimen (every 10 days) to achieve >80% RO. We also observed an increase in T-reg suppression activity from baseline: 31.9-63.4% over six doses in one participant and 22.1-55.1% in twenty-six doses in another. There were no sustained ADA levels detected out to 41 weeks. Conclusion: In this intermediate-size EAP, chronic IC14 infusions were safe with no significant changes in laboratory tests, vital signs or ophthalmologic examinations when administered for up to 59 weeks. IC14 was successfully administered at home during the COVID-19 pandemic. TEAEs were uncommon, mild, and self-limited. Measuring RO in real time for each patient guided the adjustment of dosing frequency. Preliminary but encouraging data suggest an effect on T-reg function. Data collected in this EAP helped inform dosing frequency, however, additional studies will be required to determine a more general and optimal IC14 dose to achieve desired levels of RO (e.g. >90%).

dgelevski@mgh.harvard.edu
CLT-14 RESCUE-ALS Trial: a Phase 2, randomized, double-blind, placebocontrolled study of CNM-Au8 to slow disease progression in amyotrophic lateral sclerosis Background: RESCUE-ALS is a Phase 2 clinical trial investigating the novel cellular energetic catalyst, CNM-Au8, in patients with recently diagnosed sporadic ALS. CNM-Au8 is an aqueous suspension of highly faceted, clean-surfaced, gold nanocrystals shown to enhance neuronal metabolic energy, reduce oxidative stress, and improve protein homeostasis.
Objectives: To determine the therapeutic effects of orally administered CNM-Au8 as assessed by electromyography (motor unit number index (MUNIX)), a sensitive, quantitative measure of motor unit loss, in a cohort of sporadic ALS patients after 36 weeks of treatment.
Analyses of the change in the MUNIX(4)sum score from baseline to either week 12 or week 24 of the overall study population (active and placebo) significantly correlated with, and predicted, the change from baseline to end of study (week 36) for both the ALSFRS-R score as well as the FVC (% predicted). Unblinded efficacy (e.g., summated MUNIX score, FVC (% predicted), ALSFRS-R, NPi, SHi), and safety data will be presented. Discussion: As the first catalytic nanocrystal in development for the treatment of neurodegenerative diseases, CNM-Au8 has a unique multi-modal mechanism of action that addresses ALS disease-related cellular energetic failure, oxidative stress, and proteostasis dysregulation. Final results from this study will determine whether targeting the treatment of energetic failure with CNM-Au8 is a valid therapeutic approach to slow ALS disease progression. This study further supports the validation of neurophysiological endpoints as disease-relevant biomarkers of ALS disease progression.

robert@clene.com
CLT-15 Update of COURAGE-ALS: a Phase 3, double-blind, randomized, placebo-controlled, study to evaluate efficacy and safety of reldesemtiv in patients with ALS capacity (SVC) ! 60% of predicted. The primary analysis of the change in SVC from baseline to Week 12 did not reach statistical significance. However, positive trends were noted in SVC, ALSFRS-R, and muscle strength. Post hoc post-hoc analyses suggested that treatment effects were carried more strongly in patients with shorter symptom duration and faster pre-study ALSFRS-R progression rates. These observations informed the design of the ongoing phase 3 trial of reldesemtiv in ALS.
Objectives: To evaluate the effect of reldesemtiv versus placebo on functional outcomes and a joint rank test of function, respiratory insufficiency and survival in patients with ALS. Methods: Key inclusion criteria for the Phase 3 double-blind, randomized, placebo-controlled COURAGE-ALS trial (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS include symptom onset within 24 months, ALSFRS-R score of 44 and upright forced vital capacity (FVC) ! 65% of predicted for age, height and sex.
Approximately 555 participants will be randomized 2:1 to reldesemtiv 300 mg BID or placebo for 24 weeks; all patients then receive reldesemtiv for an additional 24 weeks. Stable doses of riluzole and or edaravone are permitted; patients are stratified accordingly. The primary endpoint is change from baseline in the ALSFRS-R total score at 24 weeks. Secondary endpoints include the combined assessment of ALSFRS-R total score, time to onset of respiratory insufficiency and survival time up to Week 24 using a joint rank test, change from baseline to 24 weeks in FVC, ALSAQ-40, and bilateral handgrip strength. To reduce patient burden, approximately half of the study visits will be performed remotely. COURAGE-ALS is currently being conducted in North America, Australia, and Europe. Results: Demographic features and baseline ALS related characteristics of the randomized cohort to date will be presented and compared to FORTITUDE-ALS. Discussion: COURAGE-ALS is an ongoing phase 3 trial of reldesemtiv in ALS incorporating inclusion criteria designed to enrich the patient population to those whose disease course trends toward moderate to more rapid progression rates to increase the sensitivity of detecting a treatment effect. We anticipate that this trial will provide clear evidence as to whether a fast skeletal troponin activator can have a meaningful role in the treatment of patients with ALS. Background: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by the loss of motor neurons. There have as yet been no fundamental curative medicines for ALS, and the development of an effective medicine is urgently required. Induced pluripotent cell (iPSC)based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular-targeted therapy of ALS. Bosutinib is a selective inhibitor of Src/c-Abl tyrosine kinase, and is approved for the treatment of chronic myelogenous leukemia (CML).
Methods: A Phase 1, open-label, multi-center, 3 þ 3 dose escalation study was conducted to evaluate the safety and tolerability of bosutinib for ALS patients. The preliminary efficacy of bosutinib was also evaluated using the clinical score of ALS Functional Rating Scale-Revised (ALSFRS-R), and predictive biomarkers were explored. The study consisted of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period, and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALSFRS-R score decreased by 1-3 points during the 12-week observation period received bosutinib for 12 weeks. Successive cohorts of patients received escalating doses of bosutinib starting from 100 mg QD (quaque die) up to 400 mg QD based on dose limiting toxicity (DLT) occurrence in the first 4 weeks of bosutinib treatment.
Results: A total of 20 participants were enrolled, 13 of whom received bosutinib treatment, and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but three DLTs (two cases of Grade 3 aspartate and alanine aminotransferase increase, one case of disseminated erythematous papular) were observed in the 400 mg QD cohort. The safety profile was consistent with what is known for CML treatment, and neither new safety signals nor ALS-specific adverse events were observed. Although the study was conducted with a small number of cases, bosutinib administration was found to halt progression in some of the participants, and 5 of 9 patients who had completed the administration of scheduled doses of bosutinib showed stable disease. Furthermore, a biomarker was found to enrich the target population showing a strong drug effect.
Conclusions: This study showed that bosutinib administration up to 300 mg QD was safe and well tolerated, with promising efficacy for motor symptoms in ALS. (Funded by AMED; ClinicalTrials.gov number, NCT04744532) Clinical data relating to phenotype, demographics, Edinburgh Cognitive Assessment Screen, ALS Functional Rating Scale and prior research involvement were extracted from CARE-MND and MND-SMART databases. Descriptive statistics will be used to summarise questionnaire responses, compare scores between variable groupings and report participants reaching pre-defined impairment thresholds for cognitive, behavioural and neuropsychiatric. To explore the association of covariates with trial engagement we will use logistic regression modelling. The binary outcomes of participation versus non-participation, and current participation versus withdrawal, will best explored using regression to evaluate the impact of the exploratory covariates on trial involvement. Results will be presented as odds ratios and with 95% confidence intervals.
Results: 158 pwMND consented to participate with 120 completing questionnaires, 10 individuals died prior to completing. 5% chose telephone appointments, remaining responses split equally between online and paper. Additional behavioural questionnaire completed by caregivers in 73% of respondents. Participants were 67% male, mean age 66 years (range 39-85) and 58% amyotrophic lateral sclerosis sub-type of MND. 40% of participants had participated in additional research projects prior to FIT-Participation-MND. 40% are in MND-SMART, expected to increase as more sites across Scotland become established. Discussion: This is the first study to prospectively explore pwMND's reasons for joining, and remaining, in a clinical trial.
Recruitment is now complete, with a quarter of the Scottish MND population completing questionnaires. After 12 months, we will assess how many people in this study were recruited into the trial and how many remain involved.  Discussion: This analysis effectively avoids confounding effects related to treatment switch-over (i.e. placebo patients switching to masitinib). NPP long-term OS analysis showed a significant survival advantage in favor of masitinib-treated patients as compared with masitinib-naïve patients. This benefit is consistent with results from long-term OS analysis of the overall study population, even in the absence of patient enrichment.

jesussmora@icloud.com
Background: An oral, fixed-dose coformulation of sodium phenylbutyrate (PB) and taurursodiol (TURSO) was designed to attenuate neuronal death by simultaneously targeting endoplasmic reticulum and mitochondrial dysfunction. The safety and efficacy of PB/TURSO were evaluated in adults with definite ALS (revised El Escorial criteria [rEEC]) 18 months from symptom onset with slow vital capacity (SVC) > 60% in the phase 2 CENTAUR trial comprising a 24week randomized period and up-to-132-week open-label extension period. PB/TURSO was associated with significantly slower functional decline in the randomized period of CENTAUR, and overall survival (OS) was significantly longer in those starting on PB/TURSO versus placebo at nearly 3 years after randomization. Similar adverse event (AE) rates were observed with PB/TURSO and placebo in the randomized period.
Objective: To describe the design of a phase 3 trial assessing safety and efficacy of PB/TURSO in a broader, international population of people with ALS. Methods: PHOENIX will be conducted in approximately 55 Treatment Research Initiative to Cure ALS (TRICALS) and Northeast ALS Consortium (NEALS) sites in Europe and the United States and include 600 participants (EU, n % 400; US, n % 200). Inclusion criteria expand on those in CENTAUR to enroll adults with clinically probable as well as definite ALS (rEEC), SVC !55%, and symptom onset <24 months prior to randomization. Participants will be randomized 3:2 to receive PB/TURSO (3 g PB/1 g TURSO per sachet) or matching placebo by mouth or feeding tube, 1 sachet per day for approximately 14-21 days and then, if tolerated, 1 sachet twice a day for the remainder of the 48-week study. Participants who complete the 48-week study will have the option to receive PB/TURSO after the trial if permitted by each region's regulatory guidance. This posttrial access to PB/TURSO will also be dependent on regulatory and reimbursement milestones. Results: Safety assessments will include incidence and severity of AEs and trial discontinuations. The primary efficacy outcome is a joint assessment of ALS Functional Rating Scale-Revised total score progression over 48 weeks and survival. Secondary efficacy outcomes include changes from baseline in SVC and patient-reported quality of life and health status outcomes (ALSAQ-40, EQ-5D, and EQ VAS); time to transition through King's and MiToS stages; ventilation-free survival rates; and OS, with all-cause mortality assessed beyond the planned 48-week follow-up. Exploratory outcomes include caregiver burden and measurement of plasma drug exposure and biomarkers of neuron damage and neuroinflammation. Discussion: Phase 3 PHOENIX trial of PB/TURSO in ALS will build on findings of the phase 2 CENTAUR trial by incorporating a larger, global, and more heterogeneous population of people with ALS followed for a longer duration. Early data relating to enrollment are expected to be available in late 2021.

Acknowledgements
This abstract was previously presented at ENCALS 2021. Background: ALS has a complex underlying pathophysiology in which multiple pathways are involved, such as dysregulation of microRNA metabolism, iron accumulation and neuroinflammation (1). Dysregulated microRNAs are found in ALS models' and in patient's microglia cells, motor neurons and skeletal muscles. microRNAs control multiple molecular mechanisms such as neuroinflammation, synaptic formation, neuronal activity and differentiation (1). Increasing evidence suggests that chronic neuroinflammation, characterized by microglia activation and secretion of proinflammatory cytokines as well as accumulation of brain iron, are hallmarks of ALS (1). Since the many pathological pathways of ALS are clearly convoluted and complex, a multi-factorial strategy is needed in order to target multiple pathways simultaneously and synergistically. PrimeC is a novel combined formulation composed of unique doses of Ciprofloxacin and Celecoxib, which aim to synergistically inhibit the progression of ALS by addressing these three aforementioned pathologies. In addition to being a broadly used fluoroquinolone antibiotic, ciprofloxacin is a potent iron chelator, as well as a regulator of Dicer activity, a key enzyme in the microRNA processing pathway. It can also indirectly hinder neuroinflammation (1). Celecoxib, an NSAID, regulates neuroinflammation mainly through COX-2 inhibition. Additionally, it has COX-2independent anti-inflammatory activities. Although celecoxib has not historically shown benefit for ALS patients when given at high doses as a single agent (2), preclinical studies in ALS models showed a synergistic effect when combined in low doses with ciprofloxacin (1). Objective: This study aimed to evaluate the safety and tolerability of PrimeC, and to examine its effects on ALSrelated biomarkers Methods: PrimeC has been evaluated clinically in a 12month, open-label, phase IIa study in 15 patients with ALS. Results: Results demonstrate that PrimeC was found to be safe and tolerable in the ALS patient population. These findings were reinforced by several virtual models (i.e Origent and ENCALS prediction models, and matched patients from the PRO-ACT database), which showed no safety concerns with regards to patient adverse events and survival. Additionally, the effect of PrimeC on serum neurofilament levels, as well as on neuronal extracellular vesicle (EVs) key ALS-related biomarkers was examined by extracting EVs from patient serum samples. Results exhibited significant change in exosomal-TDP-43 following PrimeC treatment, accompanied by a similar effect on the key autophagy marker LC3. Discussion: The present study demonstrates that PrimeC is safe and well-tolerated. Of significance, all patients completing the trial have opted to continue into an extension study with PrimeC. These safety findings in conjunction with the biological activity observed in biomarkers analysis, set the stage for a larger, placebo-controlled, pivotal study to examine the efficacy of PrimeC in ALS treatment.

Background: Radicava V R (edaravone) is a US Food and Drug
Administration-approved treatment for ALS that has been shown to slow the rate of physical functional decline (1,2) There is interest in a nonintravenous (non-IV) formulation of edaravone and an ongoing, multicenter phase 3 study is currently assessing the safety and tolerability of an investigational oral formulation of edaravone (MT-1186). Objective: To assess the long-term safety and tolerability of investigational oral edaravone in patients with ALS. Methods: This global, multicenter, open-label phase 3 study is evaluating the long-term safety and tolerability of investigational oral edaravone in patients with ALS. The study includes a screening period of up to 3 weeks, an open-label treatment period of 48 weeks, and a safety follow-up period of 2 weeks after the last dose. Entry criteria include males and females aged !18 years to 75 years, with an ALS diagnosis of definite ALS, probable ALS, probable laboratory-supported ALS, or possible ALS, according to El Escorial criteria; baseline forced vital capacity !70% predicted; disease duration 3 years; and functioning independently. Patients are receiving a 105-mg dose of investigational oral edaravone administered in treatment cycles that replicate the dosing of IV edaravone. This includes an initial treatment cycle with daily oral dosing for 14 days, followed by a 14-day drugfree period. Subsequent treatment cycles consist of daily oral dosing for 10 days of a 14-day period, followed by a 14-day drug-free period. Treatment cycles are every 4 weeks. In addition to the primary safety analysis, the study also includes exploratory end points, such as change from baseline in the revised ALS Functional Rating Scale (ALSFRS-R) score and time to death, tracheostomy, or permanent assisted mechanical ventilation. Results: A total of 185 patients were enrolled in the MT-1186-A01 study, with a mean age of 59.9 years. Fifty-eight percent of the patients are Caucasian and 35% are Japanese. The baseline mean score for the ALSFRS-R was 40. Additional baseline characteristics and interim data after 24 weeks of treatment will be included in the poster presentation. Background: Radicava V R (edaravone injection) is a US Food and Drug Administration-approved treatment for ALS that has been shown to slow the rate of physical functional decline (1,2). As intravenous administration can burden patients, orally administered treatments are needed. Some ALS patients may undergo a percutaneous endoscopic gastrostomy (PEG) for required nutritional and medical support due to dysphagia as ALS progresses. The possibility of administering drugs to ALS patients via a PEG tube should be considered. Objective: To assess the comparative bioavailability and pharmacokinetics (PK) of an investigational oral suspension formulation of edaravone (MT-1186) when administered with a nasogastric feeding tube as a model of administration via a PEG tube. Methods: Study Z-101 is a randomized, open-label, crossover-design, single-dose phase 1 study (3). The primary objective of the study is to investigate the comparative bioavailability of MT-1186 administered orally and via a nasogastric tube in healthy adult subjects. Administration via nasogastric feeding tube was used as a way of modeling a PEG tube because both are positioned in the stomach, are similar in composition, and are compatible with an oral suspension of edaravone, and because only administration via nasogastric feeding tube is feasible in healthy adults. Secondary objectives include assessing the safety, tolerability, and PK. Subjects will receive a single dose of MT-1186 and PK will be assessed over 48 h, followed by crossover to the other form of administration. Safety assessments were also conducted during the study.
Results: A total of 36 subjects were randomized to two groups of 18 subjects. Study results will be presented on the poster. Background: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an intracellular protein involved in regulating inflammation, cytokine release, and cell death. In amyotrophic lateral sclerosis (ALS) pathophysiology, RIPK1 critically mediates necroptosis and inflammatory pathways. SAR443820 is a selective, orally bioavailable, central nervous system penetrant, reversible inhibitor of RIPK1. By inhibiting necroptosis and inflammatory signalling through RIPK1, SAR443820 has the potential to modify the course of ALS. ACT16970 is a phase 2 study that will determine the efficacy and safety of SAR443820 in people with ALS. Objective: To present the study design of ACT16970 Methods: This is a multicenter, randomized, double-blind, placebo-controlled study followed by a long-term extension period. The study will include adults aged 18-80 years with diagnosis of possible, clinically probable, clinically probable laboratory-supported, or definite ALS, with disease duration 2 years and respiratory function SVC !60% at screening. The study will include approximately 230 participants.
ACT16970 includes a placebo-controlled period (Part A) and an open-label period (Part B). Part A is a 24-week, doubleblind, placebo-controlled treatment period where study participants will be randomized in 1:1 ratio to receive either oral SAR443820 or placebo. The primary endpoint of Part A is the rate of decline from baseline in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score over 24 weeks. Part B is a 2-year open-label, long-term extension that will begin at end of Week 24 and proceed through Week 128, where every participant will receive SAR443820. The primary goal of Part B is to assess the longterm efficacy and safety of SAR443820 in people with ALS. Discussion: ACT16970 study has been designed to assess the effect of SAR443820 compared to placebo in reducing ALS progression as measured by ALSFRS-R. The study is designed with both a randomized, placebo-controlled, double-blind part to generate well-controlled efficacy and safety data, as well as an open-label part to provide longer term efficacy and safety data. Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder caused by the selective death of motor neurons in the CNS leading ultimately to death within 2-5 years of diagnosis. There are currently no curative therapies for ALS and only two disease-modifying therapies have been approved: Riluzole and Radicava (edaravone). Much focus has been placed on uncovering the genetic mechanisms that cause ALS. Interestingly, many of the genes in which ALS-causing mutations have been identified code for RNA-binding proteins. It is therefore hypothesized that dysregulation of RNA activity may be involved in the pathogenesis of ALS. microRNAs (miRNAs), which are endogenous, non-protein coding, small RNAs that silence messenger RNA (mRNA) at the post-transcriptional level, are globally downregulated in motor neurons of people with sporadic and familial ALS, as well as in cultured neurons that express ALScausing mutant forms. Further evidence suggests that this global downregulation of miRNAs in ALS may be the result of impaired Dicer activity. Specifically, in cells transfected with ALS-causing mutant forms of TDP-43, FUS or SOD1, Dicer activity was shown to be significantly reduced. This reduction in Dicer activity could be partially rescued by the presence of enoxacin, a fluoroquinolone antibiotic originally approved for the treatment of genitourinary tract infections, that has since been identified to increase Dicer activity. In the SOD1G93A mouse model of ALS, enoxacin was shown to delay the deterioration of motor function, when assessed by multiple locomotive and neurological criteria. Additionally, in induced pluripotent stem cells (iPSCs)-derived motor neurons from people with ALS, enoxacin rescued expression of miRNAs that were downregulated relative to iPSC-derived motor neurons from healthy controls. Collectively, these preclinical data suggest that enoxacin has the potential to restore miRNA levels and thereby have a beneficial effect on disease pathogenesis in patients with ALS. This supports testing enoxacin as a disease-modifying therapeutic for ALS. Objectives: REALS-1 is a randomized, double-blind, parallel group, phase 1b/2 study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of three orally administered doses of enoxacin (200mg twice daily, 400mg twice daily and 600mg twice daily). Methods: 36 adult participants with ALS will be randomized 1:1:1 to each treatment arm. The primary outcomes are safety and tolerability as assessed by incidence of adverse events and serious adverse events. The secondary outcome is the PK profile of the three oral doses of enoxacin. Exploratory outcomes include examination of the PD profile of enoxacin, including effects on miRNA expression. This study will provide evidence around the safety, tolerability, and dosing of enoxacin as a potential therapy for ALS, and represents an important first step in the clinical development of enoxacin for ALS. The study opened for recruitment in March 2021. Background: MN-166 (ibudilast), an orally available, centrally active small molecule, inhibits macrophage migration inhibitory factor and phosphodiesterases 3,4, and 10, and has wellknown anti-inflammatory and neuroprotective properties. Notably, a recent in vitro study showed that ibudilast enhanced clearance of disease-linked TDP-43 and SOD1 protein aggregates, thus acting as an autophagy enhancer (1). A completed Phase 1b/2a trial in ALS participants suggested MN-166 slows disease progression more effectively than riluzole alone in certain subgroups of ALS patients and observed higher rates of stability or improvement in ALS functional activity in participants treated with MN-166. Objectives: The primary objective of the study is to evaluate the efficacy of MN-166 versus placebo on patient's functional activity measured by ALSFRS-R score and survival in ALS participants. Secondary objectives are to evaluate the efficacy on muscle strength measured by hand-held dynamometry, quality of life measured by ALSAQ-5, safety, and tolerability, and to characterize the pharmacokinetics (PK) of MN-166 using population PK modeling. Methods: This is a Phase 2b/3, multicenter, randomized, double-blind (12 months), placebo-controlled study followed by an open-label extension phase (6 months) compared to matching placebo in participants diagnosed with ALS. Participants who meet entry criteria will be randomly assigned 1:1 to 1 of two treatment groups, up to 100 mg/day MN-166 or matching placebo. We plan to enroll 230 participants at 30 sites in US, Canada, and Europe. (NCT04057898) Riluzole and edaravone are permitted medications while the participant is taking study drug.
Results: Approximately 20 sites in the US and Canada are actively enrolling participants. The COVID-19 pandemic prevented study enrollment in Europe, however, activity has resumed to open sites in some countries. Enrollment status and baseline characteristics of enrolled participants will be available at the time of final presentation. Discussion: Major ongoing activities of COMBAT-ALS will be reported. Please refer to the COMBAT-ALS webinar for more details on MN-166, patient support system (MedACT), and social media sites supporting the trial (2). Background: ALS is a devastating neurodegenerative disease. In the more than 150 years since it was first described, there are still no effective treatments or cures. One of the goals of I AM ALS is to remove barriers to therapies and improve ALS care and research from a multi-stakeholder perspective. Despite their expertise and contributions, people living with and impacted by ALS are still being blocked from attending scientific forums sponsored by organizations that are supposed to be serving the community. As such, ALS advocates turned to the HIV community to learn from how they demandedand receivedseats at the decision-making tables. Inspired by the Denver Principles, a landmark document drafted by HIV/AIDS activists in 1983, ALS advocates sought to create the first guidance document to outline people living with ALS' expectations regarding their inclusion in matters directly affecting them. The Morris Principles serve as a social contract that solidifies the necessary involvement of people living with ALS. Methods: Advocates met weekly via Zoom and corresponded via email from 5 March 2021 to 21 May 2021 to define and refine a document in an iterative process inspired by the Delphi consensus method. Results: Advocates identified five priority areas: (1) protecting "intellectual, physical and financial dignity"; (2) global stewardship of "our disease and respected partners in the science of treatments and cures"; (3) acting as trusted peers with clinicians, researchers, and policy makers; (4) fighting for "equity in decision-making"; and (5) leading to end ALS. Specific guidance was developed for targeted audiences: healthcare professionals; scientific and ALS research community; ALS policy community, legislators and regulators; and ALS nonprofits. This guidance document came to be named the Morris ALS Principles, as it was inspired by ALS advocate Sandy Morris. I AM ALS posted the Morris Principles on their website and allowed people to download a copy. I AM ALS and their community members then distributed the principles to ALS stakeholders. The Morris ALS Principles authors recommend the invocation of the principles in all interactions with stakeholders. The principal developers encourage all stakeholders to use the document when developing programs or initiatives and point out where the principles are not being adhered to. ALS advocates will work with and publicly cite offenders and upholders of the Morris ALS Principles, as well as proactively collaborate with organizations to confirm they are in adherence with the principles. Conclusion: The Morris ALS Principles provide a multi-stakeholder advocacy framework to create a more ethical and effective ALS landscape. We recommend that all stakeholders who work in the ALS space review, use, and enforce these principles. This will be a living document that will be maintained in the spirit of continuous improvement. Background: A diversity of prognostic, predictive, and pharmacodynamic biomarkers are proposed in ALS, but few have been validated. Radicava V R (edaravone injection) gained US FDA approval for treatment of ALS based on its ability to slow decline in physical function. The REFINE-ALS study combines standardized sample collection procedures with optimized biomarker assays to obtain real-world data on a variety of biomarkers in a broad group of people with ALS. Methods: This prospective, observational, longitudinal, multicenter US study will enroll up to 300 adult patients with ALS who initiate edaravone treatment as a part of their clinical care. Participation after the screening period will continue for approximately 24 weeks, 6 cycles of edaravone, administered according to the FDA-approved dosing regimen. Biomarker testing and other standard-of-care assessments will be performed at baseline and during on-and off-drug intervals of cycles 1, 3, and 6. Biomarkers of oxidative stress (3-nitrotyrosine, 4-hydroxynonenal, F2 isoprostanes, 8-hydroxy-2'-deoxyguanosine, and urate), inflammation (matrix metalloproteinase-9), neuronal injury and death (phosphorylated heavy and light chain neurofilaments, and urinary neurotrophin receptor p75), and muscle injury (creatinine), epigenetics (EpiSwitch TM ), and a biomarker discovery panel (SOMAscan V R ) are being evaluated. DNA samples are collected for genomic sequencing. Trained nurses collect blood and urine samples during study visits to the clinic or at the participant's home. Samples are processed and shipped for same-day delivery to a central collection company on either dry or wet ice as appropriate for the assays being conducted. Samples are stored centrally and later distributed to the specific specialty laboratories for each given assay. We are also exploring the best means for using banked samples from matched, untreated people with ALS for biomarker comparisons. Clinical efficacy assessments are performed at baseline and at the end of each treatment cycle. Adverse events related to the study are collected. Results: A total of 33 patients have been enrolled as of June 2021. Biosamples from the baseline visit and the first cycle of treatment from the first 16 participants were analyzed for all assays as a pilot evaluation of study and assay processes. Large fractions of the 3-nitrotyrosine and 4-hydroxynenal results were below the limit of detection, and these assays are being revised. All other assays provided reliable results. Greater than 7000 somamers from the SomaLogic platform passed quality control. Analysis pipelines were developed for data transfer and analysis to address within-cycle pharmacodynamic response and association with clinical outcomes. Discussion: The results of this study may help to identify biomarkers predictive of response to edaravone and biomarkers of pharmacodynamic response to edaravone that may elucidate biological mechanisms. The results will further evaluate the safety and efficacy of edaravone in treating patients with ALS in a real-world setting.
sally_nelson@mt-pharma-us.com Background: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative disorder characterized by progressive wasting and paralysis of voluntary muscles. Neuroinflammation is a key mediator of ALS disease progression. Reactive astrocytes and microglia as well as infiltrating lymphocytes, dendritic cells, monocytes and macrophages have been characterized in animal models of ALS and at autopsy in patients. CD40LG and the costimulatory pathway, which modulates signaling between antigen presenting cells and activated T cells, was identified in the spinal cord, sciatic nerve, and skeletal muscle in rodent models of ALS. The observations of costimulatory pathway activation seen in the murine ALS model were then confirmed in humans. Blocking CD40LG in a rodent model of ALS reduces macrophage attack on peripheral nerves, improves neuromuscular junction occupancy, reduces neuroinflammation, slows progression, and improves survival (1). CD40LG is a costimulatory type II membrane receptor for CD40. The binding of CD40LG on T helper cells to CD40 on antigen presenting cells induces multiple downstream immune and inflammatory responses, including B and T cell clonal expansion, antibody production and the production of pro-inflammatory cytokines and chemokines. AT-1501 is a humanized IgG1 antibody that blocks CD40LG signaling. AT-1501 has high affinity binding to human CD40LG and lacks Fc effector function eliminating risk of platelet activation and thromboembolisms. In a phase 1, single ascending dose study in healthy volunteers and adults with ALS, AT-1501   (2); however there remains a lack of knowledge on the lived experience during a Person with ALS's (PwALS) participation in a clinical trial. As the physical effects of ALS can already take a grand toll on a patient's daily functioning, it is essential to understand the factors that encourage a patient to participate in a research study. Objectives: To study PwALS's lived experience during their participation in a clinical trial.
Methods: This will be a qualitative study. Study participants with the defined criteria will be interviewed once.
Approximately 15-20 participants will be recruited. Those who are currently participating in a clinical trial for ALS will be eligible to participate. A semi-structured interview will be conducted with each participant.
Results: This is a work in progress. Interviews will be transcribed.  (1,2). There is interest in a non-intravenous (non-IV) formulation of edaravone and an ongoing, multicenter phase 3 study (MT-1186-A01) is currently assessing the safety and tolerability of an investigational oral formulation of edaravone (MT-1186).
Objective: To assess the long-term safety and tolerability of investigational oral edaravone in patients with ALS. In the case of necessary study drug dispensation, study staff ships the medication to participants, and used medication containers are shipped back to the site for purposes of drug accountability.
Conclusions: While COVID-19 has introduced numerous challenges to our site, our response has allowed us to continue providing access to medications and to monitor for safety in a way that protects both patients and study staff from risk. Sharing our experience may help other academic centers to establish EAPs. Furthermore, innovations in virtual visit follow-up and approaches to ease participant burden in our EAP programs may prove to be helpful for trials in ALS and other neurological disorders.
adwinter@mgh.harvard.edu CLT-36 Grip strength is more than a number: the relationship between grip strength and fine motor and arm function in FORTITUDE-ALS Background: FORTITUDE-ALS (NCT03160898) was a 12-week, Phase 2, double-blind trial of reldesemtiv in 458 patients with ALS randomized to 1 of 3 reldesemtiv doses or placebo. Outcome measures included ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength (GS), and ALSAQ-5. While GS is frequently performed as an outcome measure in ALS clinical trials and may be part of routine ALS care, the relationship of declining GS and the impact on fine motor function or on health-related quality of life for arm function has not been previously described.
Objectives: To investigate the relationship between GS and fine motor function as measured by the fine motor domain sub-score (FMDS) of the ALSFRS-R and GS and the patient's perception of difficulty using their arms and hands as measured by responses to Question 2 of the ALSAQ-5 (higher values reflect worse function). Fine motor domain questions include handwriting (HW), cutting food (CF) and dressing/hygiene (DH). Methods: ALSFRS-R, bilateral GS and the ALSAQ-5 were collected at Screening, Day 1, Weeks 2, 4, 8, 12 and follow-up. The average GS combined for both hands (GSbh) were summarized by ranges of the FMDS and the decline in FMDS for male, female and both sexes combined using descriptive statistics. The strength of correlations between GSbh and FMDS and between GSbh and Question 2 of the ALSAQ-5 were evaluated using Spearman's correlation.
Results: The Spearman correlation coefficient for the FMDS and GSbh was 0.723 (p < 0.0001). The Spearman correlation coefficient for Question 2 of the ALSAQ-5 and GSbh was -0.634 (p < 0.0001). Patients with a FMDS of 0-2 had a mean GSbh of 4.97 ± 7.02 lbs, FMDS of 3-5 had mean GSbh of 14.9 ± 11.4 lbs, FMDS of 6-8 had mean GSbh 31.9 ± 17.5 lbs and FMDS of 9-12 had a mean GSbh 53.2 ± 23.1 lbs for both sexes combined. Similar patterns were seen for females and males, with higher values seen for men. The mean GSbh score was numerically lower with each drop of one point on the individual items of the fine motor domain; this was true for males, females, and both sexes combined. For the 44 patients whose baseline FMDS was 12, DH scores declined before CF or HW scores. When comparing the GSbh for items scored 3, 2, or 1, in general higher GSbh results were found for DH > CF > HW.
Discussion: GSbh showed a strong correlation with the FMDS and a moderate correlation with patient perceived difficulty using their arms. These findings offer support that the GSbh has clinical and patient relevance as an outcome measure in ALS clinical trials.
awolff@cytokinetics.com Programme grants are large, complex pieces of research involving small teams working on different, linked projects, as part of the development of an intervention. Such research lends itself well to public involvement, with discrete, tangible elements providing an opportunity for considered and focused input. However, ensuring effective public involvement within such a broad and varied environment can be challenging, and requires appropriate planning.
The HighCALS programme has focused on the development of an intervention to support people with Motor Neurone Disease (MND) and their carers with nutritional management. The grant has a designated public involvement lead who is in regular contact with a carer co-applicant around progress and to seek appropriate input as the research has progressed. The grant also provides regular updates to, and seeks input from, a local MND patient and carer research group, the Sheffield Motor Neurone Disease Research Advisory Group. Their input contributed to the development of participant information materials for the early phase work and trial. Aside from this, the research team has established its own Public Involvement Network within the grant, aiming to extend the opportunity for involvement much wider than the local area, using promotion via social media and Motor Neurone Disease Association networks. People with MND may struggle to attend face-to-face meetings because of mobility or communication difficulties, for example. As such, the Network is focused on providing a flexible approach that allows input via other means, such as email and videoconferencing. This is particularly important in the current climate around COVID-19. The Network has had an integral role in the development of our intervention, OptiCALS, providing input into its content and format. As we now move into the trial phase of the programme, testing the intervention, regular progress updates will be provided to the Network aside from requests for input, so that people continue to feel engaged with its work. Newsletters will be used as one way of providing such updates, and will look to include member storiesit is hoped that this will help to develop an inclusive community, particularly for those unable to meet face-to-face.
We have worked to be as inclusive as possible, providing opportunities for people with MND and carers, considering their particular needs to facilitate engagement from a wider group of individuals. d.a.beever@sheffield.ac.uk Background: Despite being the most commonly used outcome measure in clinical trials, there is no consensus as to what represents a meaningful change in ALSFRS-R (1) score for patients. Objectives: We sought to estimate the minimal important difference (MID) for the ALSFRS-R in a prospective cohort of people with ALS. The MID will represent the smallest difference in ALSFRS-R score that is meaningful to patients in terms of a perceptible change in their condition. Methods: Anchor and distribution based methods were used to estimate the MID scores for patients with ALS in a longitudinal, observational study. ALSFRS-R data were collected at approximately 3 month intervals. Participants answered a global rating of change question (GRoC) to rate how their overall health-related quality of life compared to that at the previous visit. The data were grouped according to GRoC outcome at any given visit ("about the same", "better" or "worse"), with the change in ALSFRS-R scores between that and the previous visit then compared.