New ALS drug stabilizes decline with a trend toward improved strength, mobility for some
Long-term use of tofersen slows ALS disease progression in people with a genetic subtype, provides hope for treating other forms of ALS
Huy MachRickey Malloy (left), who receives tofersen treatment for SOD1-ALS at WashU Medicine, plays a round of golf with his wife, Jenny, and their son, Kash. Long-term use of tofersen, a new drug approved by the FDA for this rare genetic form of ALS, delays symptom progression and death and leads to stabilization or improvement in some, according to a study by WashU Medicine researchers and their collaborators.
Historically, people with amyotrophic lateral sclerosis (ALS) experience a relentless decline of neurological function that eventually robs them of the ability to move, speak, eat or breathe. Now, researchers from Washington University School of Medicine in St. Louis and collaborators report that long-term use of tofersen, a new drug approved by the Food and Drug Administration (FDA) for a genetic form of this deadly illness, delays symptom progression and death and in about one-quarter of participants leads to stabilization or improvement.
The new findings, published Dec. 22 in JAMA Neurology, provide long-term follow-up results from a phase 3 trial of tofersen and its open label extension, both co-led by WashU Medicine, that served as the basis for the FDA’s approval in 2023 of the drug for this rare form of ALS.
“Stopping disease progression and making improvements over three to five years is unheard of in this type of ALS,” said first author Timothy M. Miller, MD, PhD, the David Clayson Professor of Neurology at WashU Medicine and co-director of the WashU Medicine ALS Center. “Tofersen shows benefits compared with what we expect to see for these participants, with about 25% of participants experiencing improvement. These results provide hope that we can change the trajectory of this devastating disease, and we are optimistic we can do the same for other forms of ALS.”
Tofersen is designed to treat ALS caused by variants in a gene called SOD1, which accounts for about 2% of ALS cases. Earlier results of the phase 3 trial showed the drug reduced neurodegeneration and prompted the FDA to approve the drug in 2023 under an accelerated approval pathway. The drug, designed specifically for this type of ALS and based in part on research conducted at WashU Medicine, blocks production of the mutated SOD1 protein.
Now, new data on the long-term use of tofersen suggest that over about three years of treatment, roughly one-quarter of participants in one study group experienced stabilization of symptoms and even functional improvement in grip strength and respiratory function.
People living with ALS discuss their experiences and hopes for the future. The full film ‘Another Tomorrow’ is coming in spring 2026. Credit: WashU Medicine
‘My goal is to stand on my tiptoes again’
In 2023, Rickey Malloy, then age 41 and a plumber for 20 years, learned he had SOD1-ALS, despite no family history of the disease. After more than a year of seeking answers from different specialists, he was referred to the WashU Medicine ALS Center, where he was diagnosed, and was prescribed tofersen, which at the time had just been approved by the FDA. The drug is administered monthly via injection directly into the fluid surrounding the spinal cord.
“I’ve been on the drug two years now, and I feel pretty good,” Malloy said. “I have far less muscle spasming and cramping in my legs — it’s helped tremendously. My physical therapy team has added more exercises and walking, and even stairs are getting easier. My goal is to be able to stand on my tiptoes again. I’m now building strength rather than just maintaining it.”
About 20,000 people in the U.S. are living with ALS, also known as Lou Gehrig’s disease. The disease kills the nerve cells that control the muscles needed to walk, talk, swallow and breathe. The average life expectancy for patients with SOD1-ALS is two to three years from the start of symptoms.
When compared with historical knowledge of ALS disease progression, the improvement in patients such as Malloy receiving tofersen is life-changing, according to Miller and co-author Robert Bucelli, MD, PhD, a professor of neurology and co-director of the WashU Medicine ALS Center.
“There’s variability in patient response to tofersen — it’s not a panacea for everyone,” Bucelli said. “But for those patients who do have a substantial response, the fact that they’re able to maintain the independence they had when they went on the drug is a miracle.”
Malloy has shown enough improvement that he recently underwent a total knee replacement surgery that he had been told, more than a year ago, he did not qualify for because his ALS had been too severe.
“Rick’s diagnosis journey was extremely difficult and remains one of the most challenging experiences we have faced,” said his wife, Jenny Malloy, noting that her husband saw many specialists over more than a year before they were referred to WashU Medicine. “Connecting with the team at WashU Medicine became the turning point we so desperately needed. We are incredibly grateful to the physicians and researchers who have dedicated their careers to finding a cure for ALS. Their relentless pursuit of answers has brought light to what once felt like a dark and uncertain path. This medication represents more than just treatment, it offers hope, progress and a renewed belief that a cure is possible.”
Stopping neurological decline
Tofersen is a type of drug called an antisense oligonucleotide, which interferes with the activity of a target protein, in this case, SOD1. Miller and his colleagues Don Cleveland, PhD, of the University of California, San Diego, and Richard Smith, MD, of the Center for Neurologic Study in San Diego, along with collaborators at the biotech company Ionis Pharmaceuticals, pioneered the development of antisense oligonucleotides as a potential treatment for SOD1-ALS. The same approach is being used to target other damaging proteins in other forms of ALS and other neurodegenerative diseases.
The biotech companies Biogen and Ionis Pharmaceuticals along with the Miller lab developed the SOD1 antisense oligonucleotide, named tofersen, also known by the brand name Qalsody. Biogen funded the clinical studies of the drug. The phase 3 clinical trial lasted six months and compared participants receiving tofersen with those receiving a placebo. At the end of the six-month period, all participants were given the opportunity to receive tofersen as part of an open-label extension. Forty-six of the original 108 clinical trial participants completed the study after 3.5 to 5.5 years of follow-up, depending on when they enrolled.
The researchers saw improvement in strength and function in about one-quarter of the participants in the early-start group who continued in the open-label extension and concluded that participants treated with tofersen overall had much slower ALS disease progression compared with typical ALS. Tofersen also prolonged survival compared with the expected natural course of the disease. Typically, patients with SOD1-ALS live a little more than two years after the start of symptoms, whereas at least half of the trial participants were alive at the end of the study nearly five years from its start.
Although none of the differences between the two groups — those who took tofersen for the first six months and those who took the placebo for six months and then switched to tofersen when the open-label extension began — reached statistical significance at three years, the numerical trends favored those who started the drug earlier. At the same time, the fact that participants in both groups are doing better than expected compared with knowledge of the typical natural course of the disease is further evidence of tofersen’s efficacy.
The lack of a statistically significant difference between the two groups at three years is likely due to the study’s design, which allowed all participants who started on placebo to receive tofersen at the six-month mark. The authors suggested this relatively minor difference in tofersen treatment length over the course of several years may make it difficult to see a difference between the early- and late-start groups even as they both experienced slower disease progression compared with the typical progression of SOD1-ALS.
The most common side effects included headache, procedural pain, fall, back pain and pain in the extremities. Nine participants (9%) had more serious neurological side effects, primarily inflammatory in nature, and these were treated successfully with additional therapies.
Huy MachA new multisite clinical trial to evaluate whether tofersen is effective in preventing or delaying SOD1-ALS is underway for people who are known to have SOD1 gene variants but are not yet showing symptoms of the disease. Bucelli is leading the trial at the WashU Medicine site.
“We are grateful to the many people who have helped make tofersen a successful, available treatment for SOD1-ALS: the funders, scientific colleagues, clinical trial investigators, other partners and especially the study participants who dedicated so much time and effort to this study,” Miller said.
For information about all ALS clinical trials at WashU Medicine, visit the ALS Center’s website.
