Three years after Qalsody was approved by the FDA as the first drug to target a genetic cause of ALS, some patients are reporting not only disease stabilization but also improvement of symptoms.
Saskatchewan is known for its harsh winters. For Paula Trefiak, a ballet dancer and mother of three, the winter of 2016 was harsher than most. Trefiak was diagnosed with ALS in February and given two to five years to live.
Later that year, however, Trefiak got a glimmer of hope—a call from The Montreal Neurological Institute and Hospital, inviting her to participate in a clinical trial for a drug in development for her specific type of ALS that’s linked to a superoxide dismutase (SOD1) gene.
“I jumped at the opportunity,” she recalled. “By late that afternoon, it was a Friday, I had my flights already ready to go to Montreal.” She flew out on Sunday and received the first dose of tofersen, an antisense oligonucleotide (ASO) developed by Biogen and Ionis Pharmaceuticals, in a Phase 1b trial.
At first the drug appeared to disappoint. Trefiak was given the lowest dose of 20 mg and continued to decline. Then the trial ended, Trefiak stopped receiving the drug and her disease kept progressing. “I was having more issues with my ankles, a lot more issues stuttering, my lip was drooping a lot more. . . . gripping things was becoming an issue.”
Finally, in March 2018, Trefiak began taking a 100 mg dose of tofersen in an open label extension study, and things started to change. By the summer of that year, “I started to feel stronger,” she recalled. Her ankles were stronger; her shoulders—which would freeze when she tried to reach for something—weren’t freezing anymore; she could hold herself up longer in a ballet move called demi-pointe. Her overall quality of life improved.
“I started to notice I was having a better sleep,” Trefiak said. “I wasn’t constantly waking up in agony for hours on end with cramping.”
Today, more than 10 years after her diagnosis, Trefiak can still do all those things and more. “I can dance, I can swim again without drowning,” she said. Her forced vital capacity (FVC)—a key measure of disease progression in ALS—was down to 72% at its lowest, she said. In May, it was at 101%—well within normal range.
It’s a striking outcome for the brutal neurodegenerative disease with only a handful of drugs on the market. And Trefiak is not alone. At least one patient in the Phase 2 trial of AL-S’s AP-101 has also experienced a reversal of decline, Angela Genge, chief medical officer at AL-S Pharma and the top recruiter for Qalsody’s Phase 1, 2 and 3 trials, told BioSpace.
In a study of seven patients with SOD1-ALS treated with the therapy at Washington University in St. Louis from November 2021 to February 2024, all patients saw either disease stabilization or slight improvement in function as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), per the ALS Association.
On the basis of biomarker data from the Phase 3 Valor trial, tofersen won FDA approval in April 2023 for patients with SOD1-ALS. Health Canada greenlit the therapy under its Special Access Program two years later. The drug is marketed in both countries as Qalsody.
It’s been a tough slog for the ALS treatment space. Amylyx’s Relyvrio, approved in 2022, was voluntarily withdrawn from U.S. and Canadian markets in 2024 after failing to show significant benefit in a Phase 3 trial, and more late-stage trials have failed to show efficacy.
But Qalsody’s success offers hope that researchers are on to something by targeting SOD1. Qalsody is currently indicated only for patients with ALS who have an SOD1 mutation. Notably, pathological levels of misfolding also occur in at least a third of sporadic ALS cases, according to Genge. AL-S Pharma is developing an antibody targeting this mutated protein.
Researchers are hopeful that Qalsody can also help more patients than it’s currently indicated for. Most cases of ALS are sporadic, while 5 to 10% are familial, with approximately 2% linked to a SOD1 mutation. This subset of the disease affects less than 500 people in the U.S.
Genge believes targeting SOD1 can be a real gamechanger in the treatment of ALS.
“We’re looking at targeting a pathway [SOD1] that really seems to be fundamental,” she said.
SOD1 and beyond
The SOD1 gene encodes an enzyme that plays an important role in protecting cells from oxidative stress. Mutations in this gene can lead to a defective form of SOD1 protein, which has been implicated in ALS. Qalsody works by reducing the amount of toxic SOD1 in the body.
While the antisense therapy missed the primary endpoint of a statistically significant change from baseline to week 28 on ALSFRS-R in the Phase 3 VALOR study, the FDA granted an accelerated nod based on its ability to reduce neurofilament light chain, a biomarker of neurodegeneration that the agency deemed “reasonably likely” to predict clinical benefit.
WashU is running a Phase 2 study of the drug in patients with non-SOD1 ALS to test whether more patients could be helped.
“In other neurodegenerative diseases . . . there’s often a link between the genetic causes of disease and what we find in terms of the pathophysiology of the disease,” Timothy Miller, co-director of WashU’s ALS Center and the study’s lead investigator, told BioSpace. In terms of a connection between SOD1 and sporadic ALS, he said the data are “mixed.”
WashU’s study, per ClinicalTrials.gov, has a primary completion date of January 2027.
Meanwhile, AL-S Pharma is targeting misfolded mutant and wildtype SOD1 with AP-101. Unlike Qalsody, the antibody treatment does not affect the level of healthy SOD1, according to Genge. This is important, she said, because “SOD1 is an obligatory protein in our biology, and so we don’t know how low we can knock it before we start building long-term side effects.”
Notably, the company is testing AP-101 in both SOD1-ALS and sporadic forms of the disease.
AL-S Pharma presented data at the ENCALS 2026 Congress in June from a Phase 2 trial of patients with both familial and sporadic ALS. The results showed that early treatment with AP-101 prolonged survival and delayed the need for patients to use a ventilator as compared to patients who were given placebo for six months followed by six months of treatment with the candidate. The results were consistent across patients with both SOD1- and sporadic ALS with moderately to significantly elevated levels of misfolded SOD1, Genge said. A Phase 3 trial is set to kick off in early 2027.
It’s also becoming clear to drug developers that early treatment is key when it comes to neurodegenerative disease.
While speaking with BioSpace last month about Biogen and Ionis’ tau-targeted Alzheimer’s therapy diranersen, Ionis Head of Development Holly Kordasiewicz compared the ASO to the companies’ other partnered therapies, Qalsody, and Spinraza—also an ASO—for spinal muscular atrophy.
“Earlier intervention in any of these neurodegenerative diseases where you have a lifetime of pathology accumulation, like in SOD1-ALS or like in [Alzheimer’s disease], I think earlier is going to be better,” she said.
When children were dosed with Spinraza at birth, Ionis started to see them meet normal motor milestones, Kordasiewicz recalled. “With [Qalsody], there’s a portion of the patients who, if you go in early enough, it’s looking like there’s reports that they’re now doing better as well.”
Biogen is running the Phase 3 ATLAS trial studying Qalsody’s efficacy in presymptomatic individuals with a confirmed SOD1 mutation and elevated neurofilament. Primary completion is expected in August 2027.
Not a cure
Several members of Trefiak’s family have died from SOD1-ALS. Currently, Qalsody is keeping the disease at bay for her sister and two of her cousins—all of whom were showing early symptoms of ALS when they started on the drug.
“They haven’t had the reversal like I have, but at least they’re not deteriorating,” she said. “They’re maintaining their health, which is significant.”
Still, Qalsody is not a cure. Trefiak must undergo an intrathecal injection of Qalsody once every four weeks to maintain the stability of her disease.
“I’ve now had officially 120 lumbar punctures or treatments with this drug that have gone into my spine. I don’t know what that’s doing to my spine long term,” she said. Intrathecal-related side effects can include benign intracranial hypertension and spinal cord inflammation. “To get this drug fewer times per year would be great as well,” Trefiak added.
This is where a treatment like AP-101—if approved—could be especially valuable. As a human monoclonal antibody, AP-101 is delivered intravenously, so it is “very easy to give,” Genge said, adding that the drug is “very well tolerated.”
For now, Trefiak and her family remain grateful for Qalsody. Her 18-year-old son learned, three days after Qalsody’s approval in Canada, that he also carries the G37R-SOD1 mutation. “His first reaction,” she said, “was, ‘at least I now have a treatable disease.’ It’s wonderful that we finally have something that works for our family.”
