Tofersen’s Clinical Benefits for ALS Linked to NfL Levels: Trial Data
Patients with early drop in NfL levels showed slower functional declines
Early declines in neurofilament light chain (NfL), a biomarker of nerve cell damage, after treatment with tofersen may predict a slower disease progression over time in people with SOD1-associated amyotrophic lateral sclerosis (ALS).
Patients who received tofersen early also experienced a significantly slower worsening of clinical function than patients who started treatment six months later — with the difference between the groups reaching 3.5 points in the ALS Functional Rating Scale-Revised (ALSFRS-R) scale after one year.
That’s according to data from the Phase 3 portion of the VALOR Phase 1/2/3 trial (NCT02623699) and its ongoing open-label extension (NCT03070119), which were presented by Biogen, tofersen’s developer, at the annual meeting of the Northeast Amyotrophic Lateral Sclerosis (NEALS) Consortium.
Data from VALOR and its extension also supported Biogen’s application to the U.S. Food and Drug Administration seeking regulatory approval of tofersen for ALS. That application is currently under review, and a decision is expected by April 25, 2023.
Tofersen works to prevent mutated SOD1 gene from producing abnormal protein
In about 20% of people with familial ALS and 2% with sporadic ALS, mutations in the SOD1 gene lead to the production of a toxic form of the SOD1 protein that accumulates in nerve cells and disrupts their function.
Tofersen is an antisense oligonucleotide that essentially works to prevent the mutated SOD1 gene from giving rise to an abnormal protein, thereby blocking the protein’s production and accumulation.
The VALOR clinical trial was designed to test tofersen in people with ALS due to SOD1 mutations. Phase 3 enrolled 108 adults who were randomly assigned to receive 100 mg of tofersen (72 patients) or a placebo (36 patients), administered directly into the spinal canal in eight injections over six months. A total of 60 patients in this part were estimated to have fast-progressing disease.
Those who completed the six-month randomized trial had the option to enter the open-label extension and receive the treatment for up to seven more years. A total of 95 patients chose to join this extension study.
Earlier initiation of tofersen reduced decline in clinical function, respiratory function, strength, and quality of life
Levels of SOD1 protein and NfL significantly reduced in patients on tofersen
Top-line data showed that VALOR failed to meet its main goal of significantly slowing disease progression — as measured by changes in the ALSFRS-R scores — in the group of fast-progressing patients after six months.
But patients on tofersen demonstrated significant reductions in the levels of SOD1 protein and NfL compared with the placebo group.
Those who started tofersen in the randomized part had a significantly slower disease progression compared with patients who initiated the treatment in the extension, according to data presented at the NEALS meeting by Timothy Miller, MD, PhD, co-director of the ALS Center at Washington University School of Medicine in St. Louis.
Specifically, early starters lost an average of 3.5 fewer points on the ALSFRS-R after a year compared with patients who started treatment later. They also experienced significant slower declines in respiratory function and muscle strength, and reported less fatigue and better quality of life than the control group, over the same period.
Early survival data suggested a lower risk of death or permanent ventilation with an earlier start to tofersen treatment. However, most patients were still alive at the time of assessment and firm conclusions cannot yet be drawn.
Miller’s talk, titled “Evaluating Efficacy and Safety of Tofersen in Adults With SOD1-ALS: Results From the Phase 3 VALOR Trial and Open-Label Extension,” reported on data collected up to a cut-off date of Jan. 16.
Overall, “earlier initiation of tofersen reduced decline in clinical function, respiratory function, strength, and quality of life,” Miller stated in the presentation.
Patients treated with toferson from the beginning also continued to experience larger reductions in SOD1 protein and NfL levels.
In a poster, titled “Statistical Model of the Relationship of Neurofilament With Clinical Function in the VALOR Phase 3 Study of Tofersen in Adults with SOD1-ALS,” Miller showed that early drops in NfL during VALOR were associated with slower declines in clinical function among tofersen-treated patients.
The researchers developed a statistical model to determine if early changes in NfL levels could predict clinical function among patients on tofersen.
Early drop in NfL levels linked to slower declines in clinical function
They determined that every 10 picogram per milliliter drop in NfL blood levels up to day 113 (nearly four months after treatment initiation) predicted a 0.77 point slower reduction in ALSFRS-R scores up to day 197 (about 6.5 months).
This early NfL drop was also associated with slower declines in respiratory function, muscle strength, and patient-reported disease severity, although only the latter reached statistical significance.
Overall, the model estimated that if patients had received a placebo instead of tofersen in VALOR, they would have experienced a 3.83 point greater decline in ALSFRS-R scores, a 10.6% greater decline in lung function, and 0.12 points less decline on tests of muscle strength.
“The model suggests that early (day 113) reductions in plasma NfL with tofersen are associated with less decline in clinical function over time,” the researchers wrote.
Across VALOR and its extension, tofersen has been generally well-tolerated, although about 7% of patients experienced serious neurological side effects, such as spinal cord inflammation or meningitis.