There are currently no treatments to stop the progression of amyotrophic lateral sclerosis (ALS). However, there are now four drugs available that provide some benefits to people living with ALS. Three drugs have been approved in the US for use by all people with ALS: riluzole, edaravone (Radicava), and Relyvrio. An additional drug, tofersen (Qalsody), was approved in early 2023 for use by people with SOD1-related genetic ALS.
Riluzole, currently sold under the brand names Rilutek, Tiglutik, and Exservan became the first drug approved in the US for the treatment of ALS in 1995. These three brand names represent different formulations of the drug respectively as a tablet, a liquid suspension, or a film that can dissolve in the mouth. The drug reduces the level of glutamate, an amino acid that acts as a neurotransmitter in the brain and spinal cord, by blocking its release from nerve terminals. While glutamate is essential to neural function, above-normal levels of the amino acid have been observed in ALS.
Trial Results: There were two pivotal trials that led to the approval of riluzole, one with 155 participants, and the second with 959 participants. These trials showed a two to three-month survival benefit for people with ALS that received active drug. More recently, a 2020 publication evaluating real world evidence of Riluzole’s effectiveness indicated a median survival benefit for people taking riluzole could range from 6 to 19 months.
Edaravone, sold under the brand name Radicava, was approved for use in ALS in 2017. It had previously been used since the 1980s as a medication for stroke in Japan. For most of this time, it was available only as an intravenous infusion. However, in 2022 an oral formulation was approved for people with ALS in the US and Canada. Edaravone’s mechanism of action in ALS is not fully understood, but it is known to be an antioxidant and thus may reduce oxidative stress in motor neurons.
Trial Results: In the phase III clinical trial of 134 participants in Japan that led to the FDA approval of Radicava, researchers observed a reduction in participants’ rates of disease progression with a difference of 2.49 ALSFRS-r points between the active treatment and placebo groups over 24 weeks. The inclusion criteria for this pivotal trial was based on post-hoc analysis from a previous trial of the drug. Trial participants were required to have a FVC breathing score of at least 80%, less than 2 years duration of ALS symptoms, at least 2 points on each of the ALSFRS-r items, as well as a decline of 1-4 ALSFRS-r points over 3 months prior to randomization.
Relyvrio is a combination of two compounds – sodium phenylbutyrate (PB), a drug that is FDA-approved for urea cycle disorders, and taurursodiol (TURSO), a bile salt available as a supplement, but also approved for liver disorders outside the USA. Research has shown they may work together to reduce mitochondrial dysfunction and ER stress, cellular pathways linked to neuronal death in ALS.
It is available as a powder which is dissolved in water and either swallowed or placed in a feeding tube.
Trial Results: A phase II trial sponsored by Amylyx Pharmaceuticals in 137 people with ALS demonstrated evidence of a decline in the rate of progression, a difference of 2.32 ALSFRS-r points, between the active treatment and placebo groups over 24 weeks. A post-hoc analysis of the open label extension data, where participants could choose to receive active treatment following the placebo controlled part of the trial, showed a potential increase in survival of 5 months when comparing those that began active treatment from the start of the trial to those that received placebo. In 2022, the drug was approved for use in the US and received conditional approval in Canada, where it is sold under the brand name Albrioza. A phase III trial for this drug in Europe is fully enrolled as of February 2023.
Tofersen, sold under the brand name Qalsody, is an antisense oligonucleotide (ASO), a short strand of nucleic acids that can enter a cell and bind with mRNA strands, in this case effectively “turning down” a gene and disrupting the production of a specific protein. Tofersen binds to SOD1 mRNA, reducing the production of the SOD1 protein, which has now shown to be protective against SOD1 ALS. It is delivered through an intrathecal injection into the spinal cord.
Trial Results: Although the phase III trial with 108 participants did not meet its primary functional endpoint, this drug was approved for use by people with SOD1 ALS in early 2023 based on reductions in levels of neurofilament light chain (NfL), a blood-based biomarker that is related to neurodegeneration, in participants on active drug. This approval was secured through the FDA’s accelerated approval pathway, which allows the agency to approve treatments based on “surrogate endpoints” for severe diseases that lack treatments. A surrogate endpoint is a measure in a clinical trial that scientists believe is likely to predict a clinical benefit, even if a clinical benefit is not directly observed in the trial.
In addition to the reduction in NfL, in post hoc analyses of data from participants that continued to the open label extension (OLE), at 52 weeks, there was a slowing of loss of function, based on ALSFRS-r, for those that received active drug from the beginning of the trial compared to those that began on placebo. There was also less decline in breathing function and strength when comparing these groups at 52 weeks. Additionally, some participants stayed on OLE for 3-7 years, providing long term data on the drug’s performance in people with ALS.
An additional trial of Qalsody for clinically Presymptomatic carriers of some ALS-related SOD1 mutations is still recruiting as of June 2023.
ALS TDI: Our Work to Find More Treatments for Everyone with ALS
The approval of all these treatments – including two in the last year – is an immensely important step for the ALS community. However, at the ALS Therapy Development Institute (ALS TDI), we know it will take many more treatments to end ALS for everyone with the disease. That’s why every day we’re working to identify effective treatments for the disease. As the Drug Discovery Engine for ALS, it is our mission to continue this work until there are effective treatments for the disease.
To learn more about our research to end ALS, visit: https://www.als.net/als-research/
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