Real-World Study Highlights Positive Treatment Benefits of Tofersen on ALS Disease Progression, Function

Sean E. Smith, MD, MPHS

A small-scale, single-center observational study showed that treatment with tofersen (Qalsody; Biogen), an FDA-approved medication for patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations, can lead to meaningful preservation of function and slowing of motor decline. In addition, the study revealed robust, significant, and sustained reductions in serum and cerebrospinal fluid neurofilaments (NfL), further supporting the role of neurofilaments as therapeutic biomarkers.¹

Tofersen, an antisense oligonucleotide that binds to and facilitates RNase-mediated degradation of SOD1 messenger RNA, was approved in April 2023 as the first and only treatment for SOD1 mutation-mediated ALS, a genetic form of the disease. The study, an investigator-initiated investigational trial, comprised of 7 patients who had a confirmed, pathogenic, mutation in SOD1 and received 100 mg of tofersen via intrathecal administration. The dosing regimen included 3 loading doses at 14-day intervals followed by monthly maintenance doses, the same regimen suggested in the current prescribing label for tofersen.

Led by Sean E. Smith, MD, MPHS, a board-certified physiatrist at the ALS Center, Washington University School of Medicine in St. Louis, treated patients demonstrated robust and sustained declines in serum NfL (–57.9%; range, –6 to –67) and CSF pNFH (–67.6%; range, –3286 to –349). This was notable considering tofersen was granted accelerated approval based on reductions in neurofilament levels, a surrogate biomarker deemed reasonably likely to predict clinical benefit.

"Our understanding of neurologic and functional recovery in SOD1 ALS on tofersen is just coming into existence and it is important to think how to best optimize ALS recovery and capture meaningful changes," Smith et al concluded.¹ "Future research is warranted to evaluate the benefit of neuromuscular rehabilitation in the setting of ALS recovery."

Using available data (n = 6), all patients demonstrated some sort of stabilization or slight functional improvement on ALS Functional Rating Scale-Revised (ALSFRS) total score (mean, 1.1 [SD, 0.7), considered the gold standard for ALS functional evaluation. Based on the most recent assessments, the mean ALSFRS-R was 36.2 (SD, 11.5) compared with the mean expected ALSFRS-R of 28.7 (SD, 10.7) if patients had gone without tofersen therapy, with an estimated 52% slowing of disease progression.

READ MORE: Early Immunotherapy May Be Crucial to Prevent Axonal Damage in CIDP, Study Suggests

Muscle strength, measured through handheld dynamometry (HHD) total score, was improved in 5 of the 6 patients with available data (delta HHD total score: 11.2%; range, –13.4 to 46.1). In addition, using functional independence measure (FIM), treated patients gained, on average, 5.13 points (SD, 3.85) in functional independence through tofersen. Notably, 4 patients who had longitudinal functional assessments performed independent of the study team by board-certified physical therapists showed improved mobility and gait performance assessed by 10-minute walk test, timed-up-and-go, and 30-s Sit to Stand.

In terms of safety, most adverse events (AEs) with tofersen were mild to moderate, aligning with ALS progression or lumbar puncture side effects. Common events included procedural pain, back pain, myalgias, and headache. CSF protein levels increased by 118.96% on average, with lymphocytic pleocytosis observed in all patients but without clinical correlation. According to the study authors, the cause of elevated CSF protein and white cell counts remains unclear, consistent with findings in prior tofersen trials.

One year into tofersen therapy, Patient 1 experienced a significant strength decline during a clinical visit, despite not noticing changes herself. An MRI revealed diffuse enhancement of the conus medullaris and cauda equina nerve roots, coinciding with elevated CSF cell counts and three unique CSF oligoclonal bands. Despite these findings, the patient remained asymptomatic, with motor deficits resolving on follow-up. She chose to continue tofersen and has now completed three years of therapy without further issues.

Tofersen was approved based on a handful of lower-stage studies, as well as the pivotal phase 3 VALOR study (NCT026223699) and its open-label extension (OLE). In VALOR, tofersen failed to show statistically significant change in the primary end point of ALSFRS-R (difference, 1.2 points; P = .97) relative to placebo; however, it did show positive effects in multiple secondary and exploratory end points, notable reductions in SOD1 protein and NfL. SOD1 protein, the target engagement for tofersen, was reduced by 33% and 21% among patients in the early- and delayed-start tofersen groups, respectively, after 12 months of treatment. These groups also saw reductions of 51% and 41%, respectively, in NfL at the same time point as well.²

REFERENCES
1. Smith SE, McCoy-Gross K, Malcolm A, et al. tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a “real-world” setting. Annals of Clinical and Translational Neurol. Published online January 9, 2025. doi:10.1002/acn3.52264
2. Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387:1099-1110. doi:10.1056/NEJMoa2204705.