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# FDA Approves Qalsody for SOD1-ALS Using Neurofilament Biomarker Despite Missed Primary Trial Endpoint
- URL: https://www.theamericanquorum.com/taq-historical-2023-04-29-healthcare/
- Published: 2023-04-30T03:59:00.000Z
- Updated: 2023-04-30T03:59:00.000Z
- Description: FDA granted accelerated approval to Qalsody for SOD1-linked ALS based on a major reduction in neurofilament light chain, even though the pivotal randomized trial missed its primary functional endpoint.
- Author: Kenneth R. Deans Jr.
- Tags: Healthcare, #Import 2026-09-01 00:51

The Food and Drug Administration on Tuesday granted accelerated approval to Qalsody, or tofersen, for adults with amyotrophic lateral sclerosis caused by mutations in the SOD1 gene, making it the first U.S.-approved therapy designed to target a genetic cause of ALS and an important test of biomarker-driven approval in neurodegenerative disease.

FDA’s [decision](https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene?ref=theamericanquorum.com) rests on reduction of plasma neurofilament light chain, or NfL, a marker of nerve-cell injury that the agency concluded is reasonably likely to predict clinical benefit. The approval is therefore conditional: continued marketing may depend on confirmatory evidence showing that the biomarker effect translates into meaningful slowing of disease.

## A narrow population with an unusually targeted treatment

ALS progressively destroys motor neurons, leading to weakness, loss of mobility, difficulty speaking and swallowing, respiratory failure and death. Most cases have no single identified genetic cause, but about 2% are associated with mutations in the superoxide dismutase 1 gene. FDA estimates fewer than 500 Americans have SOD1-ALS.

Qalsody is an antisense oligonucleotide administered by intrathecal injection. It is designed to bind SOD1 messenger RNA and reduce production of the SOD1 protein believed to contribute to motor-neuron toxicity in patients carrying pathogenic mutations. Biogen’s [approval announcement](https://www.globenewswire.com/news-release/2023/04/25/2654404/0/en/FDA-Grants-Accelerated-Approval-for-QALSODY-tofersen-for-SOD1-ALS-a-Major-Scientific-Advancement-as-the-First-Treatment-to-Target-a-Genetic-Cause-of-ALS.html?ref=theamericanquorum.com) describes three loading doses given 14 days apart followed by maintenance dosing every 28 days.

The medicine originated at Ionis Pharmaceuticals and was licensed to Biogen. Ionis’s [release](https://ir.ionis.com/news-releases/news-release-details/fda-approves-qalsodytm-tofersen-first-treatment-targeting?ref=theamericanquorum.com) emphasized that the approval validates both the SOD1 target and the use of an antisense approach to reduce production of a disease-linked protein.

## The clinical trial missed its primary endpoint

The regulatory decision is scientifically significant because the pivotal randomized trial did not meet its primary clinical endpoint. In the 28-week VALOR study, 108 participants were randomized 2:1 to receive tofersen or placebo. Among the primary analysis population, the difference in decline on the ALS Functional Rating Scale-Revised was not statistically significant.

The [New England Journal of Medicine](https://www.nejm.org/doi/full/10.1056/NEJMoa2204705?ref=theamericanquorum.com) publication reported that tofersen substantially reduced SOD1 concentrations in cerebrospinal fluid and lowered plasma neurofilament levels. Follow-up analyses from the open-label extension suggested that participants who began therapy earlier showed trends toward slower deterioration in function, respiratory strength and muscle strength than those who started later, but those analyses are exploratory and subject to confounding.

Biogen’s filing with the Securities and Exchange Commission, which included the [approval announcement](https://www.sec.gov/Archives/edgar/data/874015/000114036123020335/brhc20051944%5Fex99-1.htm?ref=theamericanquorum.com), states that the drug reduced plasma NfL by 55% in treated participants compared with a 12% increase in the placebo group in the overall intent-to-treat population. That biomarker result, rather than a statistically significant functional benefit in the randomized period, is the basis for accelerated approval.

## FDA accepts neurofilament as a surrogate marker

The accelerated-approval pathway allows FDA to approve treatments for serious conditions based on a surrogate endpoint that is reasonably likely to predict clinical benefit when there is an unmet medical need. The approach is intended to make promising therapies available sooner, but it shifts part of the evidentiary burden to post-approval confirmatory studies.

For ALS research, the important precedent is FDA’s acceptance of neurofilament reduction as such a surrogate in SOD1-ALS. Neurofilaments are structural proteins released when neurons are damaged. Elevated blood levels are associated with more active neurodegeneration and worse prognosis in several neurologic diseases. If lowering NfL reliably predicts a clinical benefit, future ALS trials could potentially use the biomarker to reach decisions faster than studies that depend only on survival or functional decline.

The ALS Association had urged accelerated approval after an FDA advisory committee voted unanimously in March that tofersen’s effect on neurofilament was reasonably likely to predict clinical benefit. Its [advisory-committee statement](https://www.als.org/stories-news/fda-committee-unanimously-recommends-accelerated-approval-tofersen?ref=theamericanquorum.com) described the potential importance of a biomarker pathway for a disease in which rapid progression can make traditional trials difficult.

## Safety and delivery remain substantial considerations

Qalsody is not a simple outpatient pill. It requires lumbar-puncture administration by clinicians experienced with intrathecal therapy. FDA lists common adverse reactions including pain, fatigue, joint pain, muscle pain and increased white blood cells in cerebrospinal fluid. More serious neurologic events reported in the development program include myelitis, radiculitis, papilledema, elevated intracranial pressure and aseptic meningitis.

The [ALS Association’s approval statement](https://www.als.org/stories-news/fda-approves-first-als-treatment-accelerated-approval?ref=theamericanquorum.com) welcomed the decision while underscoring how limited the eligible population is. Genetic testing becomes essential because Qalsody is designed specifically for people with SOD1 mutations and is not expected to treat the much larger population with other genetic forms or sporadic ALS.

Access will also depend on specialized treatment centers, insurance coverage and the logistics of repeated spinal injections. Biogen says the medicine should begin shipping to U.S. providers within about a week, but the pace of treatment will vary as institutions establish protocols.

## The confirmatory trial now carries unusual weight

Biogen is using the ongoing ATLAS study as the confirmatory trial required by the accelerated pathway. ATLAS enrolls people who carry SOD1 mutations and show biomarker evidence of disease activity but have not yet developed clinical ALS. The study is designed to test whether beginning tofersen before symptoms emerge can delay the onset of manifest disease.

That design reflects the biological logic of the treatment. If toxic SOD1 protein drives motor-neuron injury, reducing its production before extensive irreversible neuron loss could produce a larger clinical effect than beginning treatment after weakness has progressed. But that hypothesis remains to be proven.

Tuesday’s decision therefore represents both access and uncertainty. For the small group of patients with SOD1-ALS, a genetically targeted therapy is now available. For regulators and drug developers, the approval establishes neurofilament as a meaningful surrogate endpoint in this setting. The next question is whether the biomarker-driven decision will be confirmed by evidence that patients actually develop symptoms later, lose function more slowly or survive longer.