Qalsody shows long-term benefits in some SOD1-ALS patients: Study
Rare improvements seen in physical and lung function, muscle strength
- Qalsody shows long-term benefits for some SOD1-ALS patients.
- Early Qalsody treatment improved physical function, lung function, and muscle strength.
- Early initiation also delayed major disease milestones by years.
Some people with amyotrophic lateral sclerosis (ALS) who received Qalsody (tofersen) in the VALOR trial experienced improvements in physical function, lung function, and muscle strength over about three years of treatment, a new analysis found.
Gains were observed more often among those who started treatment in the main trial compared with those who initially received a placebo and then started the medication six months later in the extension portion. Still, such improvements far exceed the outcomes that have historically been observed in people with ALS caused by SOD1 mutations (SOD1-ALS), who typically experience a continuous decline in these measures.
“For people living with ALS, irreversible loss of muscle strength is a foundational symptom of the disease. In the Qalsody study, 27% of study participants in the early-start group experienced improvements in muscle strength over [about] 3 years,” Timothy Miller, MD, PhD, principal investigator of VALOR and director of the ALS Center at Washington University School of Medicine in St. Louis, said in a press release from Biogen, the therapy’s developer. “This just does not happen in ALS: In the past, conversations with people living with SOD1-ALS were about how best to manage the progression of the disease; today, these conversations include the potential for how to maximize improvement.”
The findings come from a combined analysis of the completed Phase 3 portion of the Phase 1/2/3 VALOR clinical trial (NCT02623699) and its open-label extension (OLE) study (NCT03070119), which together followed participants for more than 3.5 years.
The study, “Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis,” was published in the journal JAMA Neurology.
Qalsody designed to reduce production of toxic protein
Mutations in the SOD1 gene account for up to 20% of familial ALS cases and up to 2% of sporadic ALS patients. Such mutations lead to the production of an abnormal form of the SOD1 protein that’s prone to misfolding and forming toxic clumps inside nerve cells, causing their death.
Qalsody is an RNA-based medication designed to reduce the production of the toxic SOD1 protein in people with SOD1-ALS. It is administered by injection into the spinal canal monthly, following three initial loading doses given every other week.
Based on initial data from the VALOR trial, the therapy received conditional approval in the U.S. in early 2023. Continued approval is now contingent on confirmation of clinical benefit in follow-up studies.
The Phase 3 portion of VALOR involved 108 adults with SOD1-ALS who were randomly assigned to receive either Qalsody or a placebo for a period of six months. After that, 95 participants (88%) moved into the trial’s OLE portion, where all received Qalsody to assess its long-term safety and efficacy.
By the end of the OLE, participants had been followed for a median of 4.9 years, with a range of 3.6 to 5.4 years.
While results from the main trial showed that Qalsody did not significantly slow ALS progression compared with a placebo, combined data from VALOR and the OLE revealed that people who started Qalsody earlier experienced slower disease progression and a reduced risk of death after at least one year of follow-up.
Early initiation was also associated with a significantly slower decline in lung function, muscle strength, and patient-reported quality of life and general health, relative to delayed initiation.
Patients who started treatment earlier experienced slower declines
The newly published analysis now confirms and extends these findings over 148 weeks, or nearly three years, showing that patients who started treatment earlier continued to experience numerically slower decline across these clinical outcomes.
Data also showed that a subset of participants experienced improvements on some clinical measures — an outcome not previously described in the natural history of SOD1-ALS, according to the company.
Again, improvements were consistently more frequent with earlier treatment initiation. For example, 21% of early starters and 17.3% of late starters experienced improvements in physical function, defined as an increase in ALS Functional Rating Scale Revised scores. Lung function improved in 23.1% of early starters versus 15.8% of late starters, and muscle strength increased in 27.3% of early starters versus 10.7% of late starters.
The final VALOR/OLE data further emphasize that, with the right target paired with the right therapeutic approach, we have the potential to meaningfully impact the course of ALS and improve the outlook for people living with this devastating disease.
Improvements were also most frequently observed in people with slower-progressing disease.
“The final VALOR/OLE data further emphasize that, with the right target paired with the right therapeutic approach, we have the potential to meaningfully impact the course of ALS and improve the outlook for people living with this devastating disease,” said Stephanie Fradette, head of the neuromuscular development unit at Biogen.“We are excited to share this progress, which would not have been possible without the study participants and their caregivers, investigators and site staff, and all who have contributed to the development of Qalsody over many years.”
Biogen conducting Qalsody trial in SOD1-ALS patients without symptoms
Blood NfL levels, which formed the basis for Qalsody’s approval, were found to decline progressively after starting treatment, reaching maximal reductions by approximately 16 weeks and remaining stable thereafter. By week 148, NfL levels had dropped by about two-thirds in both early and late starters.
Data suggested that starting Qalsody just six months earlier could delay major disease milestones — such as death or the need for permanent ventilation — by years in some cases. For example, patients with faster-progressing disease who started Qalsody in the main trial saw a 3.4-year extension of survival without permanent ventilation relative to those who began treatment in the extension only.
Qalsody was generally well-tolerated. The most common adverse events included headache, pain related to the injections, falls, back pain, and pain in the extremities. Serious neurological adverse events were reported in nine participants (8.7%) and resolved with standard care.
Biogen is currently conducting a Phase 3 trial, called ATLAS (NCT04856982), to determine whether Qalsody can delay the onset of ALS in people who carry a SOD1 mutation but have not yet developed symptoms of the disease.
“These final results illustrate what is possible with early initiation of Qalsody,” said Merit Cudkowicz, MD, director of the Healey & AMG Center for ALS, co-founder of the Northeast ALS Consortium, and co-principal investigator of the VALOR trial. “In the faster-progressing participants, initiation of Qalsody just 6 months earlier was associated with a 3.4-year extension of event-free-survival. This makes all of us very excited about what we will learn from the presymptomatic ATLAS study, where there is a possibility we could delay the onset of disease.”
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