ALS Drug Development Guidances and Trial Guidelines: Consensus and Opportunities for Alignment

The US Food and Drug Administration (FDA) developed a draft guidance for drug development in amyotrophic lateral sclerosis (ALS) that was issued in February 2018. The FDA draft guidance considered the recommendations developed by the ALS community that incorporated the views of a large group of clinical investigators, industry representatives, advocacy groups, patients, and caregivers. This external input from the ALS community reviewed the current state of clinical research in ALS, made suggestions over a wide range of drug development topics, and served as an educational tool to provide the agency with additional inputs about ALS, the state of the science, and the community\u27s views on key topics. In parallel to this effort, there was an independent effort to revise and update the ALS Clinical Trial Guidelines. We discuss the areas of agreement of these 3 documents and the areas that provide opportunities to improve the efficiency of drug development in ALS. It is likely that further research into biomarkers, efficacy endpoints, and predictive algorithms will provide greater alignment among community stakeholders and increase clarity on drug development efforts going forward. Continued patient engagement and inclusion of patient experience data in every aspect of the drug development process will further facilitate the approval of new treatments

Profile of Medical Care Costs in Patients With Amyotrophic Lateral Sclerosis in the Medicare Programme and Under Commercial Insurance

Objective: To determine amyotrophic lateral sclerosis (ALS)-associated costs incurred by patients covered by Medicare and/or commercial insurance before, during and after diagnosis and provide cost details. Methods: Costs were calculated from the Medicare Standard Analytical File 5% sample claims data from Parts A and B from 2009, 2010 and 2011 for ALS Medicare patients aged ‰¥70 years (monthly costs) and ‰¥65 years (costs associated with disability milestones). Commercial insurance patients aged 18€“63 years were selected based on the data provided in the Coordination of Benefits field from Truven MarketScan® in 2008€“2010. Results: Monthly costs increased nine months before diagnosis, peaked during the index month (Medicare: $10,398; commercial:$9354) and decreased but remained high post-index. Costs generally shifted from outpatient to inpatient and private nursing after diagnosis; prescriptions and durable medical equipment costs were much higher for commercial patients post-diagnosis. Patients appeared to progress to disability milestones more rapidly as their disease progressed in severity (14.4 months to non-invasive ventilation [NIV] vs. 16.6 months to hospice), and their costs increased accordingly (NIV: $58,973 vs. hospice:$76,179). Conclusions: For newly diagnosed ALS patients in the U.S., medical costs are substantial and increase rapidly and substantially with each disability milestone

ALS Longitudinal Studies With Frequent Data Collection at Home: Study Design and Baseline Data

Objective: To design an ALS clinical study in which patients are remotely recruited, screened, enrolled and then assessed via daily data collection at home by themselves or caregivers. Methods: This observational, natural-history study included two academic medical centers, one providing overall clinical management and the other overseeing computing and web-services design and management. Both healthy and ALS subjects were recruited on the Internet via advertisement on governmental and foundation websites as well as through Facebook and Google paid advertisements. Individuals underwent screening and enrollment remotely, including signing an electronic informed consent form. Participants were then provided self-measurement equipment and instructed on their use through a series of web-based videos. The equipment included a handgrip dynamometer, spirometer with smartphone connection, electrical impedance myography device, and an activity tracker. ALS Functional Rating Scale-Revised data were also collected. Subjects were asked to collect data daily for three months and twice-weekly for the subsequent six months. Results: One hundred and eleven ALS patients and 30 healthy individuals enrolled in the study from across 41 states (74 men, 62 women). Baseline median ALSFRS-R score was 33. Seventy two percent of the ALS patients sent equipment and 88% of the healthy subjects sent equipment were able to complete a first set of measurements. Expected baseline differences between the ALS patients and healthy participants were identified for all measures. Conclusions: It is possible to design and institute an at-home based study in ALS patients, using a number of state-of-the-art approaches, including web-based consenting and training and Internet-connected measurement devices

Harmonized standard operating procedures for administering the ALS functional rating scale-revised

The ALS Functional Rating Scale-Revised is the most commonly used primary outcome measure in current ALS clinical trials. While rigorous training and certification is generally recognized as critical to reliable performance, differences have existed between training in the two groups responsible for most training in ALS outcome measures. We present a harmonized standard operating procedure which is intended to further reduce response variability by the use of identical training in North America and Europe

Respiratory Measures in Amyotrophic Lateral Sclerosis

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that causes skeletal muscle weakness, including muscles involved with respiration. Death often results from respiratory failure within 3€“5 years. Monitoring respiratory status is therefore critical to ALS management, as respiratory/pulmonary function tests (PFTs) are used to make decisions including when to initiate noninvasive ventilation. Understanding the different respiratory and PFTs as they relate to disease progression and survival may help determine which tests are most suitable. Methods: This review describes the tests used to assess respiratory muscle and pulmonary function in patients with ALS and the correlations between different respiratory measures and clinical outcomes measures. Results: The most commonly used measurement, forced vital capacity (VC), has been shown to correlate with clinical milestones including survival, but also requires good motor coordination and facial strength to form a tight seal around a mouthpiece. Other tests such as slow VC, sniff inspiratory pressure, or transdiaphragmatic pressure with magnetic stimulation are also associated with distinct advantages and disadvantages. Conclusions: Therefore, how and when to use different tests remains unclear. Understanding how each test relates to disease progression and survival may help determine which is best suited for specific clinical decisions

A Phase III Trial of Tirasemtiv as a Potential Treatment for Amyotrophic Lateral Sclerosis

Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: ˆ’16.8, ˆ’11.9) in the placebo group and 13.4% (95% CI: ˆ’15.3, ˆ’11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. Conclusions: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898)

MiToS and King\u27s 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\u27s 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 RESULTS: The full analysis set consisted of 456 patients randomized 3:1 ( CONCLUSION: This exploratory analysis showed the feasibility of MiToS and King\u27s staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials