FDA Approval of Amyotrophic Lateral Sclerosis (ALS) Drug Represents Progress, But We’re Not Done

Neurodegenerative diseases result in progressive damage to specific cells and connections in the brain and spinal cord, and they exact an incalculable toll on patients, as well as their families and caregivers. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that gradually robs people of their ability to walk, talk, move, swallow, and even to breathe on their own. The disease affects motor neurons in the brain and spinal cord that control voluntary muscle movements, with most people dying within 3-5 years of symptom onset.

The National Institute of Neurological Disorders and Stroke (NINDS) and other agencies are hard at work to improve understanding of this terrible disease so that effective treatments can be developed. On September 29, 2022, the U.S. Food and Drug Administration (FDA) approved Relyvrio for ALS. Relyvrio is a combination of two drugs, sodium phenylbutyrate and taurursodiol, that was shown to reduce the rate of decline on a clinical assessment of daily functioning and was associated with longer overall survival. With this FDA approval, Relyvrio joins Riluzole and Edaravone as therapeutic options for ALS patients. These options may slow disease progression and prolong life for a time, but they are not cures, motivating continued research toward the goal of developing a cure.

To support additional advances, the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) was signed into law by President Biden on December 23, 2021. Components of the bill include: an FDA action plan to advance innovation that promotes and accelerates drug development for the treatment of rare neurodegenerative diseases including ALS; an FDA Rare Neurodegenerative Disease Grant Program that will be administered by the FDA Office of Orphan Products Development; a Public-Private Partnership (PPP) for Neurodegenerative Diseases between NIH and FDA , which was launched on September 14, 2022 with the announcement of the Critical Path Institute as the convener;  and an NIH grant program to fund ALS research that uses FDA’s expanded access to experimental drugs pathway for individuals who are not otherwise eligible for clinical trials in ALS. Advancing research for this disease requires a continued collaboration and joint effort between our agencies.

The Public-Private Partnership is one example of NIH and FDA working together to make meaningful progress in ALS. In close coordination with the Critical Path Institute, the ultimate goal of the Partnership is to identify concrete strategies that will advance the understanding of neurodegenerative diseases and fostering the development of treatments for amyotrophic lateral sclerosis (ALS) and other rare neurodegenerative diseases. This goal can only be met by working closely with people affected by ALS, advocacy organizations, researchers, and clinicians and our expectation is that all of these stakeholders will be closely involved in this effort. 

As part of the NIH funding opportunity, NINDS will be supporting a study on trehalose delivered by intravenous injection, an investigational product currently being tested in HEALEY ALS Platform Trial (a placebo controlled, randomized ALS clinical trial that tests multiple regimens in parallel), which has clinical trial sites across the country. Trehalose is a type of sugar that is thought to target autophagy, the cells’ process of clearing out old and damaged proteins and other molecular components. Problems with autophagy, such as cells’ inability to clear out clumps of toxic proteins, are associated with a variety of neurological diseases. In ALS, clumps of a protein called TDP-43 are deposited in the motor neurons that then die. Some data suggest that trehalose may be neuroprotective by activating the cellular waste system. The study is led by Dr. Sabrina Paganoni, M.D., Ph.D., co-director of the Massachusetts General Hospital Neurological Clinical Research Institute, Dr. Paganoni and her colleagues plan to investigate the safety of the therapy, measure levels of biomarkers that indicate nerve cell degeneration, and monitor disease progression and survival rates.

These therapeutic developments begin with research on the biology underlying ALS. In FY2021, NIH funded $120 million of research on ALS. Current projects are studying all aspects of the disease, including the disease biology that may reveal potential therapeutic targets. Major advances have come from the study of genetic forms of ALS. NIH grantees also are examining ALS’s natural history, genetic and environmental causes and risk factors, and interventions to help improve quality of life. Some recent examples include several team science projects funded by the Accelerating Leading-edge Science in ALS (ALS2) initiative, which is part of the NIH Common Fund’s High-Risk, High-Reward (HRHR) research program. The projects leverage multi-disciplinary approaches to uncover molecular and cellular changes that occur in ALS, to develop novel therapeutic strategies, and to explore how environmental exposures may contribute to ALS risk. In addition, multiple ongoing studies examine the biologic features shared between ALS and frontotemporal dementia, a neurodegenerative disease that affects the brain but can also present as ALS. There is reason to suspect that new molecular targets and strategies for therapeutic intervention will be applicable to both diseases. Furthermore, projects funded through the NIH BRAIN Initiative are developing brain-computer interface technologies to improve or restore communication for people living with ALS.

To prepare for the future of ALS research, NINDS is leading a strategic planning effort to prioritize research that will lead to improvements in diagnosis, management, treatment, and identification of a cure. People affected by ALS, including people living with the disease, caregivers, and gene mutation carriers who are at high risk of developing ALS, are critical partners in this strategic planning effort. They see and experience this disease firsthand, making their perspectives essential. Earlier this year, we issued a Request for Information to hear from the entire ALS community, particularly people affected by the disease, advocates, clinicians, and researchers. We received more than 300 responses, a summary of which is now available(pdf, 180 KB). Using these responses as a starting point, working groups composed of people affected by the disease, researchers, and clinicians have been developing draft research priorities that will be discussed at a public workshop held virtually on October 26-27. (Register for the workshop). We want your input and will have many opportunities for public participants to submit questions or provide comments, so I encourage you to attend and engage in the discussion. We expect to revise and refine the draft priorities after the public workshop and will post the revised draft priorities online for one last opportunity for public comment before they are presented to the National Advisory Neurological Disorders and Stroke (NANDSC) Council for final approval at our February meeting. NIH and other federal agencies, academic and industry researchers, advocacy organizations, and people affected by ALS will all need to work together to implement the plan’s research priorities to move us toward discovering new therapies and improving the lives of people affected by ALS.

Although we are grateful for new treatment options for this devastating disease, we know that our work is not done. We hope that all our research efforts will not only increase our understanding of the mechanisms underlying ALS but bring us quickly to effective therapies for individuals suffering from the disease, and eventually a cure.

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