ABSTRACT

This chapter considers the many areas of research necessary to advance our understanding of amyotrophic lateral sclerosis (ALS) and measure progress toward making it a more livable disease. It first considers the drug development ecosystem, identifies major challenges to developing and testing drug candidates, and makes the case for establishing a clinical trials network to accelerate the development of new therapies, both pharmacologic and supportive. The chapter highlights the need for disease biomarkers to enable earlier detection of ALS, increase recruitment for clinical trials, and assess therapeutic efficacy in clinical trials and the importance of identifying new targets for developing new drug and gene therapies. It also discusses the use of patient registries in informing care and research for various diseases and the importance of bolstering the capabilities of the existing National ALS Registry. The chapter discusses ways to expand the National ALS Registry and integrate it into a comprehensive data platform featuring other sources of data. The chapter then discusses nonpharmacological therapies that can help relieve and manage disease symptoms and make ALS a more livable disease and notes the need for studies to identify which therapies and combinations of therapies work best to prolong the duration and quality of life and to improve the quality of interventions involving these therapies.

Immediately preceding and during the time this study committee was working, the U.S. Food and Drug Administration (FDA) approved two new ALS drugs (AMX0035/Relyvrio and tofersen/Qalsody). However, in March 2024, while the committee was finishing its work on this report, the company developing AMX0035/Relyvrio, announced the latest results of a Phase 3 trial in which the drug performed no better than placebo. In April 2024, the company that developed Relyvrio announced the drug would be removed from the market in the United States and Canada. It is not within the statement of task for this study to suggest regulatory approval or disapproval of any specific new ALS drug applications FDA will consider. However, the committee saw a unique opportunity in the therapeutic development space to provide broader recommended actions for industry, ALS nonprofit organizations, public–private partnerships, researchers, and regulators to make use of the research and clinical trials network discussed in Chapter 4 to foster a more detailed understanding of the root causes of ALS, how they manifest themselves as disease symptoms, and how to use that new knowledge to accelerate the development of new therapies that can improve the lived experiences of individuals with ALS.

ALS DRUG DEVELOPMENT THROUGH THE YEARS

The history of drug development for ALS is filled with many failures and too few successful drugs. Even the four drugs (Qalsody/tofersen, Radicava/edaravone, Rilutek/riluzole, and Nuedexta) and two additional formulations of riluzole (Tiglutik/thickened riluzole and Exservan/riluzole oral film) FDA has approved for ALS are based on limited clinical benefit or likelihood of clinical benefit. And one ALS drug (Relyvrio) was being removed from the market as of April 2024 due to lack of clinical benefit. Over the past decade, numerous research advances have identified a wide range of potential therapeutic pathways and potential drug targets and genes associated with the disease. However, the heterogeneity and complex biological pathways of ALS have slowed the development of biomarker research. Diagnostic delay and inadequate eligibility criteria affect the ability of study populations to appropriately reflect the heterogeneity of ALS (Katyal and Govindarajan, 2017). In many disease spaces, gene variants associated with the disease have indicated potential targets for drug and biomarker development. However, both sporadic ALS and familial ALS are associated with mutations in at least one of more than 50 disease causative genes and 120 genetic variants that increase the risk or modify the ALS phenotype (Fang et al., 2022). Each of these could point to a therapeutic target, and many are being studied (Mead et al., 2023).

A 2023 review of ALS clinical trials identified more than 60 compounds with a variety of mechanisms of action targeting different biochemical and genetic processes that researchers have evaluated as potential treatments for ALS (Mead et al., 2023). Figure 5-1 show the major ALS pathophysiological targets currently being pursued.

FIGURE 5-1

ALS pathophysiology, genetic causes, and risk factors. SOURCE: Mead et al., 2023.

ALS CLINICAL TRIALS AND NATURAL HISTORY STUDIES

Since 1995, FDA has approved five drugs and two additional formulations of one of those drugs for treating ALS. In addition to these medications, several other candidates are in clinical trials. One estimate is that 53 drug development programs that include a focus on ALS were underway in 2022 (Mead et al., 2023). Industry, academia, the federal government, and nonprofit organizations are all involved in some manner in efforts to develop therapeutics for ALS, often in collaboration across sectors. Examples include:

• The Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) is funded by the National Institute of Neurological Disorders and Stroke (NINDS) and is designed to increase efficiency of clinical trials, expand the capability of NINDS to test promising new therapies, and respond quickly as opportunities arise to test promising new treatments for people with neurological disorders. NeuroNEXT has more than 10 clinical trial sites in the United States (NeuroNEXT, 2024).
• Northeast ALS Consortium (NEALS), founded in 1995, includes 156 trial-ready sites for ALS. NEALS has successfully partnered with industry and academic researchers to conduct nearly 80 high-quality ALS studies for more than 25 years. NEALS provides all sites with comprehensive training in outcome measures and site management so NEALS can quickly initiate new trials and produce high-quality data. NEALS has also established a repository of serum, plasma, cerebrospinal fluid, whole blood, extracted DNA, and urine samples from NEALS research studies (NEALS, 2024).
• The HEALEY ALS Platform Trial,¹ led by researchers at the Healey & AMG Center for ALS at Massachusetts General Hospital (MGH), is a collaboration involving the Healey Center for ALS; NEALS; Barrow Neurological Institute; Berry Consultants; 78 participating U.S. sites overseen by one, central, SMART-institutional review board;² ALS patient members serving on steering committees; several pharmaceutical and biotech industry collaborators; and numerous biomarker development research groups. The HEALEY ALS Platform Trial is an adaptive clinical trial that serves as a Phase 2/3 clinical efficacy trial that in its first 3 years has accepted eight experimental drug regimens for testing.³
• The ALS Therapy Development Institute (TDI) is a nonprofit biotechnology company that conducts preclinical, clinical, and translational research and has screened more than 400 potential treatments for ALS in preclinical models. As part of its efforts, ALS TDI established the ALS Research Collaborative (ARC) to collect natural history data from people with ALS and merge those data with genomics, proteomics, and metabolomics data to empower the larger research community through the ARC Data Commons.⁴ ALS TDI has also developed a potential therapeutic that in May 2022 successfully completed a Phase 2a clinical trial (ALS TDI, 2022).

In addition to networks that conduct clinical trials, other consortia generate data to inform the design of clinical trials and accelerate progress on finding potential therapeutics that would enter clinical trials. Examples include:

• The Access for All in ALS Clinical Research Consortium (ALL ALS) funded by NINDS in 2023 will provide a large scalable clinical research infrastructure and has the goal of facilitating research aimed at obtaining mechanistic insights into ALS heterogeneity and identifying therapeutic targets and biomarkers (see Chapter 1 for additional information).
• In September 2022, FDA and the National Institutes of Health (NIH) established the Critical Path for Rare Neurodegenerative Diseases (CP-RND), a public–private partnership that the Critical Path Institute (C-Path) will lead. This effort will involve members of ALS patient communities, pharmaceutical and biotechnology companies, regulators, and ALS advocacy organizations, who will work together to set the initiative’s priorities for patient-focused drug development (C-Path, 2024). (See Chapter 1 for additional information.)
• The Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT) is a data platform, created in partnership with NEALS, that houses the largest collection of ALS clinical trials datasets. PRO-ACT contains placebo data from 11,675 people with ALS who participated in clinical trials sponsored by industry, foundations, and academia (NCRI, 2024)
• AnswerALS enrolled 1,000 participants from eight sites across the nation who provided biospecimens that the AnswerALS research team used to generate induced pluripotent brain stem cells from each participant. Every sample went through genomic, proteomic, and transcriptomic analysis to produce a personalized data of ALS-specific information. In collaboration with experts in machine learning and big data informatics, this biological data will be mined to uncover ALS causes, subtypes, pathways gone awry, and drug targets. These data will serve as the foundation for new clinical trials, suggest new ways to subgroup patients to better discover successful drugs, and identify drug-responsive biomarkers or diagnostics (Answer ALS, 2024).
• The European Network to Cure ALS (ENCALS) is a network of European ALS centers with aims including the development of a European ALS research network with database and biobank, collaboration between funding agencies to sponsor investigator-initiated research projects, reaching consensus on a classification of ALS suitable for European research projects, and studying novel designs for the assessment of efficacy of new therapies for ALS (ENCALS, 2024).
• The Treatment Research Initiative to Cure ALS (TRICALS), another European research consortium, includes 48 research centers in 16 countries, people with ALS, and ALS foundations that collaborate with pharmaceutical and biotechnology companies. This consortium focuses on using data to identify and develop biomarkers for different types of ALS, improving the design of clinical trials, and establishing an international registry of individuals with ALS to enable easy access to clinical trials (TRICALS, 2024).

Each ALS research initiative or network is uniquely structured and funded to meet its mission. The committee considered some of the attributes of three ALS research networks and resources currently in operation or under development in the United States today (see Table 5-1) to better understand the gaps and opportunities in the ALS research ecosystem.

TABLE 5-1

Attributes of Three ALS Research Networks and Resources.

Although each of these networks provides a useful resource, the differences among them make it difficult to integrate results across them and to maximize each trial’s possibilities. Today, many industry-sponsored ALS trials are run out of NEALS which provides access to many sites and significant flexibility to the sponsor in deciding which therapeutic candidates to test and whether data will be shared once the trial is complete. NEALS can provide a large network of trial-ready sites and clinicians, community engagement and education and standardized clinical outcomes training, but it does not have the scalable trial infrastructure, harmonized data banks, and funding model that an expanded, supported, NIH network could offer. Also, the development of the ALS clinical trials workforce is hampered under the currently fragmented research networks. The committee believes a centralized ALS clinical trials network led by NIH would provide the best of each current network and harmonize approaches and support to see improvements in ALS trial success. Similarly structured cancer clinical trials networks, such as the National Cancer Institute’s National Clinical Trials Network, have shown to be high impact for the field and benefited from NIH leadership. The committee suggests that the following areas would be improved under an NIH-led ALS clinical trials network:

• Data sharing—currently not required for studies run outside of NIH. A centralized data sharing requirement, with accountability, would advance open science for ALS.
• Infrastructure—currently variable, requiring research teams to be assembled anew for each research study. Sustained research teams and tools would be better prepared to launch and run trials effectively.
• Equity—clinical trial opportunities are currently inequitably allocated across the ALS population and focused on large academic centers. A centralized clinical trial network would be designed to bring in new, rural sites and adopt remote monitoring to improve the clinical trial experience for more people with ALS.
• Community engagement—trainings, educational opportunities, and partnerships among persons with ALS lived experience and ALS researchers are critical to the success of drug development efforts. Centralized supports and best practices for these activities are needed so they can take place in greater numbers across the country.
• Governance—variable across networks today but a centralized network could apply a coherent approach to selecting compounds to be tested in the network and involve steering committees that include people with ALS lived experience.
• Innovation—complexity in ALS clinical trial and specialized expertise often required. Innovations that improve the experience for people with ALS and speed the testing of new therapies deserve widespread consideration and adoption.

DEVELOPING ALS BIOMARKERS AND OTHER CLINICAL ENDPOINTS TO SERVE AS INDICATORS OF DRUG EFFICACY

One challenge for drug development, recruitment for clinical trials, and disease diagnosis is the heterogeneity of ALS in terms of how and when symptoms develop, how quickly it progresses, its resemblance to other motor neuron and neurological diseases, and in the genes and proteins associated with developing ALS. For the most part, ALS is diagnosed based on the appearance of certain clinical features, which both slows the diagnostic process and can confound drug development and stratifying people with ALS for participating in clinical trials. To address this problem, researchers are searching for biomarkers—specific molecular, biochemical, genetic, and imaging characteristics that can serve as a more accurate indicator of early disease confirmation, track disease progression, and detect biological treatment responses in trials using surrogate biomarkers before clinical benefits appear (see Box 5-1). Blood tests and magnetic resonance imaging, for example, are common biomarkers for a variety of diseases.

BOX 5-1

Types of Biomarkers.

TDP-43, a protein that regulates how RNA is processed, is one focus of recent research efforts because TDP-43 dysfunction is linked to almost all individuals with ALS and about half of those with frontotemporal dementia (FTD) (NINDS, 2024). Recent research further advanced our understanding of how cryptic exons could be involved in the disease process and how diseases involving TDP-43 dysfunction could be identified before symptoms appear by testing an individual’s cerebrospinal fluid (NINDS, 2024; Seddighi et al., 2024).

Having clinically proven, easy-to-measure screening and diagnostic biomarkers that can confirm ALS at the earliest stages of disease onset can accelerate early recognition of the disease, diagnosis, and initiation of therapies and approved medications. As Chapter 2 notes, diagnosing ALS in its earliest manifestation would enable more individuals to meet inclusion criteria for participating in clinical trials. Validated diagnostic biomarkers would address diagnostic uncertainties, reduce the number of referrals to nonspecialists, and eliminate potential confounding factors that can produce misleading clinical trial results. For example, if a potential therapeutic agent targets a specific genetic mutation, the odds of a clinical trial achieving statistically significant results would increase if the patient population being studied was restricted to individuals with that specific mutation, rather than being open to anyone with ALS.

Ideally, one biomarker or a combination of several biomarkers would provide presymptomatic diagnosis of ALS, which would be valuable for individuals with a family history of ALS and could enable developing and using therapies that stop or even reverse the disease process before it damages too many nerve cells. Currently, FDA accepts slowing of disease-related decline, stabilization, and improvement of function in daily activities, as measured using either the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)⁵ or a scale of combined function and survival outcomes (Berry et al., 2013; Cedarbaum et al., 1999; Quintana et al., 2023), as a clinical trial endpoint indicative of drug efficacy (FDA, 2019).

TRADE-OFFS IN ALS DRUG DEVELOPMENT AND APPROVAL

As of December 2023, FDA had approved several drugs to treat ALS or its symptoms. Several of these approvals have not been without controversy, stemming in part from a belief that some drugs might have been approved too soon, without sufficient data on efficacy because of pressure from advocates and people with ALS regarding the urgent need for new medications and the desire to have anything to help people living with ALS with this devastating and fatal disease. Considering the appropriate balance between achieving confidence in an ALS drug’s benefits and accessing the drug as quickly as possible is a complex and often emotionally charged issue. Approving drugs despite considerable residual uncertainty complicates clinical decision making, as people with ALS and their physicians must weigh adverse effects and other burdens against uncertain benefits. Without compelling efficacy data, it will not be clear which patients should be prescribed which drugs, or how they should be used alone or in combination to maximize benefit. In addition, adverse effects such as nausea, diarrhea, or dry skin may sound minor compared to the risks associated with a fatal disease, but adverse effects that may be tolerable for a drug that works are intolerable for a drug that does not. When there is inadequate evidence of benefit, expanded access programs offer a mechanism for ineligible for clinical trials to receive treatment while definitive data are being collected.

Even after FDA approval, access to new drugs is uneven for persons living with ALS today. Not everyone living with ALS will receive new drugs. Reasons for this include:

• Their insurance company will not pay for the drug given unclear efficacy.
• The person with ALS who wants to take the drug does not satisfy the criteria set in clinical trials to support the drug.
• The drug is prohibitively expensive with or without insurance coverage.
• The drug is administered in a manner that is impossible or unappealing for the person living with ALS.
• The clinic or care setting for a person living with ALS cannot support administration of the drug or the process of requesting insurance approval.
• The person with ALS may be among the estimated half of persons living with ALS today not receiving care in a multidisciplinary setting and therefore are unconnected to the latest ALS interventions.

Throughout the phases of developing, approving, and accessing a new ALS drug there are many considerations and trade-offs that deserve attention and discussion among a wide range of individuals affected by ALS. The committee encourages ALS organizations to host conversations about these trade-offs and include nonprofit advocacy organizations, academic research groups, and regulators. Participants could include persons living with ALS; families affected by ALS in the past, present, or likely future; at-risk genetic carriers; ALS clinicians; drug developers; and others. The goals of these conversations could include learning about and discussing the trade-offs arising between the urgent need for effective therapeutic interventions; the importance of strong evidence of clinical benefit and safety; and the implications for FDA approval, patient autonomy, payer coverage, and future development of ALS drugs. The committee offers these ideas for launching these discussions on trade-offs in the drug development and approval process:

• NIH and NINDS could support research to further understand and address these trade-offs as they arise, specifically in the context of ALS, and to improve the use of the expanded access pathway to ease the tension in demanding earlier drug approvals.
• FDA could seek comment on these trade-offs to better understand and appreciate the diversity of views on their implications in the ALS community. Such input might help FDA with difficult decisions on what counts as clinically meaningful benefit and adequate evidence in making critical approval decisions.
• ALS organizations could offer educational resources and create opportunities for people living with ALS and their families to discuss the trade-offs that result from approval of medications with substantial ongoing uncertainty about benefits to better represent the full range of views on this important question.

The committee recognizes the robust work of the public–private partnerships launched under Section 3 of the ACT for ALS: (1) CP-RND, (2) AMP ALS, and (3) ALL ALS. While these initiatives were being designed and priorities being set at the time of this report’s writing, the committee offers the following recommendation for opportunities to be included in the developing priorities for ALS translational research:

Recommendation 5-2: Expand ALS translational research.

The ALS-focused public–private partnerships created under the Accelerating Access for Critical Therapies for ALS Act should consider additional translational research priorities that would accelerate therapeutic developments in ALS. The National Institutes of Health and the National Institute of Neurological Disorders and Stroke should prioritize ALS research including the following:

a.

Understand the staging of disease, for both familial and sporadic ALS, in particular the preclinical disease or prodromal state, to inform when to intervene with therapeutics.

b.

Create and sustain a comprehensive, robust, and indefinitely ongoing natural history study across diverse patient populations and different stages of disease that could serve as external and concurrent controls for some clinical trials. This could help reduce the number of placebo-controlled designs for early phase trials and longer treatment duration clinical trials.

c.

Develop additional validated biomarkers that would enable identifying and monitoring disease progression, including the early molecular and cellular changes hypothesized to occur before the appearance of clinical symptoms, and to monitor effects of therapeutic interventions (e.g., TDP-43 pathology).

d.

Advance the identification of new therapeutic targets derived from a better understanding of the pathophysiology of sporadic ALS, including an understanding of plateaus when ALS disease progression stops or slows significantly for a period of time.

e.

Advance novel drug delivery methods and ALS patient-friendly formulations that are safe, effective, and allow greater inter-dose intervals and flexibility for ALS individuals with dysphagia, intravenous access, or lumbar puncture difficulties.

f.

Engage diverse stakeholders and experts with a variety of viewpoints and support research regarding the trade-offs between having new products to try, even absent compelling evidence of meaningful benefit, and developing safe and effective drugs for treating and preventing ALS and to improve the use of the expanded access pathway to ease the tension in demanding earlier drug approvals.

ESTABLISHING A COMPREHENSIVE ALS REGISTRY

In the committee’s view, a robust registry of people with ALS is a necessary tool to measure progress toward making ALS a more livable disease. It would collect data on care, outcomes, and risk factors, providing a valuable population-level perspective on living with ALS. This data would be collected as a routine part of care. The committee considered how best to expand the Centers for Disease Control and Prevention’s (CDC’s) already-existing National ALS Registry to meet that goal.

ALS data collection today is fragmented and uncoordinated. Different types of data in various formats exist in registries, individual academic centers, researchers’ labs, and at the more than 50 ALS nonprofit organizations operating across the United States. These dispersed and fragmented efforts raise the costs for individual projects, limit their ability to test multiple hypotheses, and restrict their capability to track the size and health of the overall ALS population. Establishing a comprehensive ALS registry is a key opportunity to address this problem.

Patient registries can be a powerful source of real-world disease data. When properly designed and implemented, registries can provide an accurate picture of clinical practice, patient outcomes, safety, and disease epidemiology. Depending on their design, rare disease patient registries can help researchers follow the disease’s natural history, track progress at the population level, recruit people into clinical trials, and accomplish other key goals such as determining whether earlier diagnosis, new therapeutics, or improvements in the care process are improving outcomes for people with the disease as a whole (Mayberry and McCleary, 2016; McGettigan et al., 2019) (see Box 5-2 for the difference between a registry and natural history study). For example, a recent analysis of the Irish population-based ALS registry revealed that despite changes in ALS care over the past 25 years, widespread use of noninvasive ventilation, and aggressive secretion management, as well as the overall increased incidence and prevalence of ALS in Ireland, the survivability of ALS has not improved (McFarlane et al., 2023).

BOX 5-2

Registries and Natural History Studies.

A critical role of registries is to provide a population-level view of a disease. By doing so, registries can offer insights into the accessibility or quality of care, the distribution of known and potential risk factors, and overall progress in survivability These questions can be further disaggregated by race, ethnicity, income level, insurance status, and other demographic data to assess the resources and difficulties of different populations.

Registries also offer a potential avenue for recruiting people with a disease into clinical trials. Registry enrollment can help researchers identify large numbers of potential subjects to participate in clinical trials (Tan et al., 2015). The NIH-funded Rare Disease Clinical Research Network, for example, launched a contact registry specifically to connect patients and researchers to advance rare disease research. In addition, registries can show the community what research is ongoing. Many registries maintain a public list of research using their data (Mayberry and McCleary, 2016). Not only does this encourage people with the disease to participate in the registry, but it also serves as another method to connect interested members of the community with researchers. Demonstrating the effects of research can also encourage philanthropic funders to invest more in relevant grants or organizations. When possible, epidemiological data from a registry should be linked to other data sources, such as biorepositories.

The Existing National ALS Registry

The CDC National ALS Registry, launched in October 2010, is the primary nationwide effort to count ALS cases in the United States. (Box 5-3 describes the data the National ALS Registry collects, as well as important information that it does not collect.) Using the most recently available data, CDC estimated there were 29,824 people living with ALS in the United States in 2018 (Mehta et al., 2023). This estimate is based off a count of 21,665 definite cases identified via Medicare, Veterans Health Administration, and Veterans Benefits Administration databases, as well as an online portal for self-identification and statistical modeling (Mehta et al., 2023). Based on an estimate of new cases identified in 2018 in administrative databases and CDC’s patient portal, it is estimated that these methods missed approximately 27 percent of cases (Mehta et al., 2023).

BOX 5-3

National ALS Registry Data Needs.

CDC records demographic information for all registrants via self-enrollment or administrative data. Individuals with ALS provide other information, such as clinical characteristics and risk factor exposure, via optional National ALS Registry risk factor surveys. After initial enrollment, people with ALS in the registry are given the option via email to complete or update these surveys via the registry’s online portal. Enrollees are also asked to complete the disease progression survey, which asks enrollees to report their ALSFRS-R score every 3 months after enrollment, and again, completing this survey is optional. After 1 year of enrollment, enrollees are asked to update their functional rating every 6 months. Notification for other surveys is sent every 6 months.

NEW AND EMERGING NONPHARMACOLOGICAL TECHNOLOGIES

Technological advances in robotics, sensing technologies, virtual reality, and artificial intelligence have introduced many opportunities for technology-mediated tools that may provide support for persons with ALS and their families and improve their quality of life at home. For example, advances in telehealth technology have accelerated home monitoring opportunities, such as video conferencing to support virtual visits with clinicians, capturing vital signs, remotely assessing gait and balance, and capture activities of daily living and sleep quality. Online communities and caregiver support apps are already available and provide access to information, connection among peers, and creating virtual networks.

The committee notes that emerging technologies should be developed with engagement from end users, consideration of data privacy and security, attention to inclusive technologies that reduce health disparities, and using technology to facilitate and increase access to clinical trials for individuals living with ALS. This section also discusses reimbursement considerations related to emerging technologies.

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