Tofersen's Biomarker Approval Masks a Critical Payer-Evidence Gap That Confirmatory Trials Must Close

Qalsody Reverses Decline in Some SOD1-ALS Patients

Biogen's Qalsody (tofersen), an antisense oligonucleotide, is showing promising results in some patients with SOD1-ALS, with reports of disease stabilization and even symptom improvement. Approved by the FDA in April 2023 based on biomarker data from the Phase 3 VALOR trial, and by Health Canada in 2025, Qalsody targets the genetic cause of ALS linked to the SOD1 gene. While it missed its primary endpoint in VALOR, its ability to reduce neurofilament light chain, a biomarker of neurodegeneration, led to accelerated approval. Patients like Paula Trefiak, who has been on the drug for years, have experienced significant improvements in quality of life and functional capacity, including an increase in forced vital capacity.

• Patient-Reported Improvements and Functional Gains: Patients with SOD1-ALS treated with Qalsody have reported significant clinical improvements, moving beyond disease stabilization to actual symptom reversal. For instance, Paula Trefiak, a long-term participant, experienced stronger ankles and shoulders, improved sleep, and an increase in her forced vital capacity (FVC) from 72% to 101% over 10 years. A small study at Washington University also noted stabilization or slight improvement in function for all seven SOD1-ALS patients.
• Regulatory Approval Based on Biomarker Data: Qalsody received accelerated FDA approval in April 2023 and Health Canada approval in 2025 for SOD1-ALS patients. This approval was granted despite missing the primary clinical endpoint (ALSFRS-R change) in the Phase 3 VALOR study. Instead, the FDA based its decision on Qalsody's ability to significantly reduce neurofilament light chain, a biomarker of neurodegeneration, which was deemed reasonably likely to predict clinical benefit.
• Expanding Therapeutic Horizons and Future Research: The success of Qalsody highlights the potential of targeting SOD1 in ALS, a pathway considered fundamental to the disease. While currently indicated only for SOD1-ALS (affecting less than 500 people in the U.S.), research is exploring its potential in non-SOD1 ALS cases. Additionally, other therapies like AL-S Pharma's AP-101, an antibody targeting misfolded SOD1, are in development, showing promise in both familial and sporadic ALS and emphasizing the importance of early intervention in neurodegenerative diseases.

Qalsody's Long-Term Impact: Reversing Decline in SOD1-ALS?

Published data on long-term outcomes for SOD1-ALS treatment is anchored primarily in the tofersen clinical program, comprising the VALOR phase 3 trial and its open-label extension (OLE). The OLE, completed in August 2024, accumulated up to 3.5 years of follow-up per participant (range: 192–276 weeks from VALOR initiation). Of the 108 participants enrolled in VALOR, 95 (88%) entered the OLE, and 46 completed it. Over 148 weeks, earlier initiation of tofersen relative to delayed initiation (approximately 6 months later) was associated with numerically less decline across all key endpoints: ALSFRS-R score (−9.9 vs. −13.5 points), slow vital capacity (−13.8% vs. −18.1%), handheld dynamometry megascore (−0.38 vs. −0.43 points), ALSAQ-5 quality-of-life score (17.0 vs. 22.5 points), and EQ-5D-5L score (−0.1 vs. −0.2 points). Tofersen also prolonged survival relative to the expected natural history of SOD1-ALS, reinforcing the clinical relevance of early intervention.

Biomarker data provide compelling evidence of sustained neurobiological effect. Tofersen produced durable reductions in neurofilament levels — established markers of axonal injury and neurodegeneration. Real-world studies reported mean serum NfL declines of −57.9% to −62%, CSF-NfL declines of −66% (range: −52% to −86%), and mean CSF pNfH reductions of −67.6%. The German early access program specifically documented median serum NfL declining from 78.0 pg/mL to 36.0 pg/mL (p = 0.02) and median CSF pNfH from 2,226 pg/mL to 1,151 pg/mL (p = 0.02) over 12 months, underscoring the reproducibility of these findings outside controlled trial settings.

Real-world observational data from single-center and multicenter cohorts further corroborate the durability of clinical response. One study reported apparent disease stabilization, with a mean ALSFRS-R change of 1.1 (SD = 0.7) and a notable mean improvement in functional independence as measured by FIM motor score of 5.13 points (SD = 3.85). The German multicenter cohort demonstrated a median ALSFRS-R progression rate of only 0.11 points lost per month during tofersen treatment. From a safety standpoint, the adverse event profile remained consistent with known ALS disease progression and procedural effects; all serious neurological adverse events were reversible, few resulted in treatment discontinuation, and no persistent symptoms were reported in real-world settings — supporting a favorable long-term benefit-risk profile.

VALOR Trial: Unpacking Qalsody's Biomarker-Driven Approval

The pivotal evidence base for tofersen in SOD1-ALS spans a Phase 3 randomized controlled trial (VALOR), an open-label extension, and complementary real-world and translational studies. Together, these investigations establish a multi-dimensional endpoint framework encompassing functional decline, respiratory capacity, neurofilament-based biomarkers, and patient-reported outcomes. The table below summarizes key design parameters and endpoints across the principal trials.

Beyond Qalsody: Emerging Therapies and Broader SOD1-ALS Targets

Recent research into SOD1-ALS has expanded well beyond antisense oligonucleotide strategies, with several mechanistically distinct therapeutic approaches now advancing through preclinical and early clinical stages. These emerging modalities target diverse biological nodes — from upstream gene silencing to downstream proteostasis and neuroinflammatory cascades — reflecting the complexity of mutant SOD1-driven motor neuron degeneration.

• siRNA-based gene silencing via ACO conjugation: A novel siRNA modality conjugated to an accessory oligonucleotide (ACO) has demonstrated superior efficacy compared to antisense oligonucleotides resembling tofersen in SOD1G93A mice, delaying disease progression, extending survival, and preventing declines in mobility, muscle strength, and coordination. The ACO chemistry confers favorable bioavailability and CNS delivery properties, and this siRNA-ACO conjugate is currently advancing in clinical trials.

• Asymmetry rule-based siRNA design: A functional siRNA design strategy incorporating a mismatch at position 1 of the 5' antisense strand has successfully converted previously inactive siRNAs into functional silencing agents capable of suppressing mutant SOD1 alleles regardless of target position, broadening the design space for allele-selective gene silencing.

• HspB8-mediated proteostasis and autophagic clearance: HspB8, a small heat shock protein, selectively reduces mutant SOD1 aggregation and enhances its solubility and clearance without altering wild-type SOD1 turnover. It operates through the HspB8/Bag3/Hsc70/CHIP multiheteromeric complex to activate autophagic removal of misfolded proteins — importantly, retaining activity even when proteasomal function is impaired — and also demonstrates activity against truncated TDP-43.

• Anti-neuroinflammatory intervention via bee venom: In hSOD1G93A mice, bee venom administration reduced microglial marker expression and phospho-p38 MAPK levels in the spinal cord and brainstem, suppressed caspase-3 activity, and blocked mitochondrial structural defects, extending median survival by 18% (139 ± 3.5 days vs. 117 ± 3.1 days in controls) alongside improved motor activity.

• CIIA-mediated modulation of ASK1 cytotoxic signaling: CIIA has been identified as a negative modulator of ASK1-mediated cytotoxic signaling in SOD1G93A models, with its targeting shown to prevent downstream mitochondrial dysfunction and caspase activation, positioning the ASK1 pathway as a tractable signaling node in mutant SOD1 pathology.

Qalsody's Breakthrough: Validating Biomarkers in Neurodegeneration

The journey of Qalsody (tofersen) from clinical trials to patient impact marks a significant moment for the neurodegenerative disease landscape, particularly for those living with SOD1-ALS. Its accelerated approval, driven by compelling reductions in neurofilament light chain (NfL) levels, underscores a growing acceptance of biomarkers as critical indicators of therapeutic effect, even when initial functional endpoints are not met. This paradigm shift is crucial for conditions like ALS, where disease progression is rapid and traditional clinical endpoints can be challenging to achieve in short-term studies.

Long-term data from the VALOR trial's open-label extension have been instrumental, demonstrating that earlier initiation of tofersen is associated with a slowed decline in functional and respiratory measures, improved quality of life, and prolonged survival. These findings, coupled with individual patient reports of disease stabilization and even functional recovery, paint a picture of genuine disease modification—a profound achievement in a field historically dominated by symptomatic treatments. This success validates the antisense oligonucleotide (ASO) approach for targeting specific genetic drivers of neurological disease, opening doors for similar strategies in other rare genetic conditions.

However, the path forward is not without its considerations. The initial miss of the primary functional endpoint in the VALOR trial highlights the ongoing challenge of translating biomarker improvements into immediate, statistically significant clinical benefits. Furthermore, while NfL is a powerful biomarker, the literature indicates a lack of standardization and proportional bias across different NfL immunoassays. This analytical variability will be important to address for consistent clinical application and interpretation. Given that SOD1 mutations are rare, affecting only a small percentage of ALS patients, the commercial strategy for Qalsody will need to be highly focused, emphasizing early genetic diagnosis and patient identification. Ultimately, Qalsody's story is a testament to the potential of precision medicine and biomarker-guided development, offering a beacon of hope and a blueprint for future innovations in neurodegenerative care.