Tofersen Treatment of  SOD-1 Familial Amyotrophic Lateral Sclerosis Reduced Clinical Decline and Improved Quality of Life, May Lower Risk of Death

Earlier treatment with tofersen (Biogen, Cambridge, MA) for amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 (SOD1) variants reduced functional and respiratory declines and improved quality of life. Additionally, those treated with tofersen for 52 vs 24 weeks, initiated 28 weeks earlier, had a 62% lower likelihood of death, permanent ventilation, or withdrawal due to disease progression (25.0% vs 36.1%; hazard ratio [HR], 0.38; 95% CI: 0.180, 0.821). Median times to death or permanent ventilation could not be estimated because the majority of participants survived.

Reduced functional decline was measured as an adjusted mean difference on the x-point ALS Functional Rating Scale Revised (ALSFRS-R) at week 52 was 3.5 (95% CI: 0.4-6.7; P=.0272). The adjusted mean difference in percent-predicted slow vital capacity at week 52 was 9.2 (95% CI: 1.7-16.6; P=.016) for those who received tofersen 28 weeks earlier. Those treated with tofersen in the placebo-controlled portion, maintained muscle strength measured with dynamometry at week 40. Similar plateauing and maintenance of muscle strength was seen in those initially treated with placebo at week 52.

On the ALS Assessment Questionnaire, individuals who received tofersen 28 weeks earlier had a slower rate of decline that resulted in a 10.3% difference at 52 weeks (P=.004). Those who received tofersen earlier had significantly better quality of life, as measured with the EuroQOL-5 Dimension 5-Level Questionnaire (adjusted mean difference 0.2 on scale of -.594 to 1.0; 95% CI: 0.13-0.32; P<.0001). 

Timothy Miller, MD, PhD, coprincipal investigator and ALS Center co-director at Washington University School of Medicine, St. Louis said, "These new 12-month data showed tofersen consistently slowed disease progression across endpoints and, if approved, may meaningfully change the lives of people living with SOD1-ALS.”
 
Tofersen is an antisense oligonucleotide (ASO) that binds SOD1 messenger RNA (mRNA) to reduce production of SOD1 protein. The clinical improvements seen with earlier tofersen treatment correlated with changes in biomarkers related to SOD-1 ALS pathogenesis. At 8 weeks of treatment, target engagement was observed as lowered cerebrospinal fluid (CSF) levels of SOD-1. At 12 weeks of treatment, plasma levels of neurofilament light (NfL) were also reduced, suggesting reductions in axonal injury and neurodegeneration. 

“The combination of these biomarker results and the clinical outcomes data provide additional evidence of tofersen's potential to effectively slow the relentless progression of SOD1-ALS," noted Merit Cudkowicz, MD, coprincipal investigator, director of the Healey & AMG Center for ALS, chair of Neurology at Massachusetts General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School.

Serious treatment-emergent adverse events included myelitis (2.0%), aseptic meningitis (2.0%), increased intracranial pressure (ICP; 1.0%), papilloedema (1.0%), lumbar radiculopathy (1.0%), and other neurologic disorder (1%) in the 104 participants treated with tofersen in both the placebo-controlled and open-label studies.   

This analysis is of integrated data from the 28-week placebo-controlled VALOR trial (NCT02623699) and its 24-week open-label extension and was presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS), 20th Meeting held June 1-3, 2022.