FDA Approves Tofersen as First SOD1-ALS Treatment

Angela Genge, MD, FRCPC

The FDA has approved Biogen’s investigational agent tofersen (Qalsody), a therapeutic designed to treat patients with SOD1 mutation-mediated amyotrophic lateral sclerosis (ALS), a genetic form of ALS for which there are no other approved products, under the accelerated approval pathway.¹

The decision was supported by the treatment's demonstrated reduction of plasma neurofilament light (NfL), a blood-based biomarker of axonal injury and neurodegeneration. The ALS treatment is administered intrathecally via lumbar puncture, with a recommended dosage of 100 mg/15 mL per administration. Patients receive 3 initial doses administered at 14-day intervals, followed by a maintenance dose every 28 days.

"I'm happy, overjoyed, relieved. I believe the FDA has done the right thing. This is a breakthrough therapy for an ultra-rare subset of ALS, those with familial genetically determined sod one ALS, and the FDA gave it accelerated approval on the full package and acknowledged that neurofilament as a biomarker readout can be used in SOD-1 ALS as a surrogate for efficacy," Angela Genge, MD, FRCPC, the director of the ALS Centre of Excellence for Research and Patient Care at McGill University, and an executive at the Clinical Research Unit at The Neuro (Montreal Neurological Institute-Hospital), told NeurologyLive^®. "And in the case of toferson, this is the key feature of the drug development program, and actually opens up the possibility that in other forms of ALS, we can now develop and validate and biomarkers—neurofilament and others—to enable us to get drugs through development and to approval in a more efficient manner and potentially using including smaller populations of patients only to allow trials to be run faster."

Tofersen, an antisense oligonucleotide, had its new drug application (NDA) accepted in July 2022, with data from a phase 1 study of healthy volunteers, a phase 1/2 dose-ascending study, the pivotal phase 3 VALOR study (NCT02623699), and its open-label extension (OLE), serving the basis for the NDA. In its response, FDA regulators voted that the effects seen from tofersen on surrogate biomarkers, specifically neurofilament light (NfL), was not sufficient to warrant FDA approval.

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More than a month before the PDUFA date, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee reviewed tofersen’s case as a potential therapy for SOD1-ALS, voting on 2 questions. The first asked whether reductions in NfL are reasonably likely to predict clinical benefit, for which they agreed, voting 9-0-0 (9 Yes; 0 No; 0 Abstain. The second vote, asking whether the data from VALOR and its OLE, along with results from the effects on relevant biomarkers, provide convincing evidence of the effectiveness of tofersen in SOD1-ALS, went differently, with the committee voting 3-5-1 (3 yes; 5 no; 1 abstain).²

Of note, the panel took issue with the use of “convincing,” instead preferring the use of “substantial evidence of effectiveness.” Among those who voted “No,” committee members pointed to weak statistical data in the pivotal trial, which did not meet its primary or secondary end points, as well as the differences between full versus accelerated approval. In a final discussion question, the committee was unanimous in that tofersen provides an acceptable risk-benefit profile in patients with SOD1-ALS.

In VALOR, tofersen failed to show statistically significant change in the primary end point of ALS Functional Rating Scale-Revised (ALSFRS-R; difference, 1.2 points; P = .97) relative to placebo; however, it did show positive effects in multiple secondary and exploratory end points, notably, 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.³

Survival data on tofersen showed that earlier initiation led to a lower risk of permanent ventilation (HR, 0.36; 95% CI, 0.137-0.941) and death (HR, 0.27; 95% CI, 0.084-0.890). Although the median time to death or permanent ventilation could not be estimated due to the limited number of events, the 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 a descriptive analysis, the disease duration in 16 participants of special interest with p.Ala5Val variant mutations who received tofersen was a median of 1.73 years, with 3 of these participants remaining in the trial at the time of the data cutoff.

“For more than a decade, Biogen has been steadfast in our commitment to pursuing treatments for ALS, and I want tothank the scientists as well as the entire ALS community who have all worked tirelessly to bring this first-of-its-kindtreatment to people with SOD1-ALS," Christopher A. Viehbacher, president and CEO of Biogen, said in a statement issued to NeurologyLive. "Today also marks a pivotal moment in ALS research as we gained, for the first time,consensus that neurofilament can be used as a surrogate marker reasonably likely to predict clinical benefit in SOD1-ALS.We believe this important scientific advancement will further accelerate innovative drug development for ALS.”

Tofersen was submitted under the accelerated approval pathway, which was built to facilitate drug development for serious or life-threatening conditions. By definition, an agent that goes through this pathway demonstrate an effect on a surrogate end point that is not itself a direct measure of the clinical benefit of interest, but is instead reasonably likely to predict clinical benefit. Typically, therapies for ALS are judged by ALSFRS-R; however, the FDA’s AdComm voted that NfL may be used as a surrogate end point. Previous research has suggested that elevated levels of NfL in the cerebrospinal fluid and plasma are associated with numerous degenerative neurological disorders beyond ALS and are a consequence of axonal damage.

After the decision, the NeurologyLive team spoke in-depth with Genge to acquire a greater understanding of the clinical implications of this decision, the context on the VALOR trial data, and more, in a special episode of the Mind Moments^® Podcast. Listen to the full episode, featuring Genge's commentary, below. (LISTEN TIME: 13 minutes)

REFERENCES
1. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. News release. FDA. April 25, 2023. Accessed April 25, 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene
2. FDA Briefing Document. Peripheral and Central Nervous System Drugs Advisory Committee. https://www.fda.gov/media/166326/download. Published online March 20, 2023. Accessed April 25, 2023.
3. 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.