EU Approves Biogen’s Tofersen as First Treatment for SOD1 ALS


Biogen's tofersen, an antisense oligonucleotide, remains the first and only marketed therapy to treat patients with SOD1-mutated amyotrophic lateral sclerosis.

Stephanie Fradette, PharmD, head of Neuromuscular Development Unit at Biogen

Stephanie Fradette, PharmD

Slightly more than a year after tofersen (Qalsody; Biogen) was approved in the US, Biogen has announced its EU approval for the treatment of SOD1-mutated amyotrophic lateral sclerosis (ALS). Approved under the accelerated approval pathway, it remains the first and only marketed therapy to treat this genetic form of the disease, which impacts approximately 2% of the patient population.1

The latest approval comes under exceptional circumstances, meaning that there is a positive benefit/risk profile; however, considering the rarity of the disease, it is unlikely that comprehensive data can be obtained under normal conditions of use. Tofersen, an antisense oligonucleotide, was approved based on data from the phase 3 VALOR trial (NCT02623699), the same double-blind, placebo-controlled trial that served as supportive evidence for its FDA approval.

"The European Commission’s approval of QALSODY is a testament to the unwavering dedication of the ALS community – people living with ALS and their loved ones, scientists, clinicians, and advocates – who have worked together over the past two decades to bring forward this important new treatment for the SOD1-ALS community," Stephanie Fradette, PharmD., head of Neuromuscular Development Unit at Biogen, said in a statement.1 "We are working with the medical community and local authorities to bring QALSODY to people living with SOD1-ALS across the region as quickly as possible."

VALOR, published in the New England Journal of Medicine, randomized patients with ALS to either tofersen 100 mg (n = 72) or placebo (n = 36) for 24 weeks. Although the therapy showed numerically greater results on the primary end point of ALS Functional Rating Scale (ALSFRS-R) in comparison with placebo, these data were not statistically significant (mean difference, 1.4; 95% CI, –1.3 to 4.1). For the first time ever, the agencies used neurofilament light (NfL), a marker of neuroaxonal damage, as a surrogate biomarker to predict clinical benefit.

All told, tofersen-treated patients showed a 55% reduction in NfL in comparison with placebo, which had increases of 12% (difference in geometric mean ratios: 60%; 95% CI, 51%-67%). In addition, the mean concentration of NfL in plasma was reduced by 60% in the tofersen-treated faster-progression subgroup and increased 20% with placebo (between-group difference in geometric mean ratio, 0.33; 95% CI, 0.25-0.45).

"QALSODY’s approval represents a paradigm shift in the treatment of SOD1-ALS, offering hope to patients and loved ones who have long awaited a breakthrough,” Philip Van Damme, MD, PhD, a professor of neurology and director of the Neuromuscular Reference Center at the University Hospital Leuven, said in a statement.1 "The European Academy of Neurology has confirmed new treatment guidelines for ALS that recognize QALSODY should be offered as first-line treatment for patients with SOD1-ALS."

READ MORE: ALS Candidate PrimeC Shows Greater Treatment Effect in High-Risk ALS

After completion of VALOR, 95 participants (88%) were enrolled in the nonrandomized open-label extension, with 63 (88%) originally assigned to receive tofersen and 32 (89%) originally assigned to receive placebo. At the time of the most recent data cutoff (January 16, 2022), 49 participants (68%) in the early-start cohort and 18 (50%) in the delayed-start cohort remained in the open-label extension. At 52 weeks, the change in ALSFRS-R score from the VALOR baseline was –6.0 points for early-start participants and –9.5 points for delayed-start participants (difference, 3.5 points; 95% CI, 0.4-6.7).2

In the open-label extension the change in the percentage of predicted slow vital capacity was –9.4% for early-start participants and –18.6% for delayed-start participants (difference, 9.2 percentage points; 95% CI, 1.7-16.6). The change in handheld dynamometry megascore from the VALOR baseline was −0.17 for early-start participants and −0.45 for delayed-start participants (difference, 0.28; 95% CI, 0.05 to 0.52). Although the median time to death or permanent ventilation could not be estimated due to the limited number of events, the hazard ratio (HR) for time to death or permanent ventilation for early-start participants vs delayed-started was 0.36 (95% CI, 0.14-0.94).

In addition to the ongoing open-label extension of VALOR, tofersen is being studied in the phase 3, randomized, placebo-controlled ATLAS study (NCT04856982) to assess whether the therapy can delay clinical onset when initiated in presymptomatic individuals with SOD1 genetic mutation and biomarker evidence of disease activity. The study, which anticipates to enroll approximately 150 participants, is expected to complete in 2027.

"At EUpALS, we are excited that people with SOD1-ALS in Europe will have access to QALSODY, the first treatment targeting a genetic cause of ALS. This is a major milestone for the ALS community, showing that ALS is a treatable disease,” Evy Reviers, chairwoman of the European Organization for Professionals and People Living with ALS (EUpALS).1 "As a representative of the European ALS community, I am excited to enter a new evolution in the common fight against ALS. We thank Biogen for the many years of scientific and clinical pioneering efforts that led to this medical success."

1. Biogen Receives European Commission Approval for QALSODY® (tofersen), the First Therapy to Treat a Rare, Genetic Form of ALS. News release. Biogen. May 30, 2024. Accessed June 5, 2024.,dismutase%201%20gene%20(SOD1%2DALS
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.
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