The committee all agreed that tofersen presents a favorable risk-benefit profile in this particularly challenging patient population.
In a meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee to review tofersen (Biogen), an investigational antisense oligonucleotide currently under review for SOD1 mutated-mediated amyotrophic lateral sclerosis (ALS), the committee voted unanimously that the reduction in plasma neurofilment light chain (NfL) concentration in tofersen-treated patients is reasonably likely to predict clinical benefit of tofersen; however, the committee did not vote in support of the clinical data providing substantial evidence of effectiveness relevant to full approval of tofersen. The PDUFA date for the therapy’s supplemental new drug application (sNDA) is April 25, 2023.1
There are currently no FDA-approved therapies to treat familial forms of ALS, including SOD1-ALS, which accounts for approximately 20% of familial cases.
"Certainly the data [are] not fully conclusive, but there are aspects that do suggest strong clinical evidence," committee member Michelle Mielke, PhD, commented after the vote on question 2. "My decision is weighed on the unment need as ALS is a very serious disease, and the fact that some people may be stalling in their progression or possibly improving is very promising"
The committee voted on 2 questions, the first of which asked whether the available evidence is sufficient to conclude that a reduction in plasma NfL concentration in tofersen-treated patients is reasonably likely to predict clinical benefit of tofersen for treatment of patients with SOD1-ALS. In response, the committee voted unanimously 9-0-0 (9 Yes; 0 No; 0 Abstain) demonstrating their confidence in the biomarker as a surrogate end point predictive of clinical benefit.
The second vote placed more emphasis on the available clinical data, asking, "Does the clinical data from the placebo-controlled study and available long-term extension study results, with additional supporting results from the effects on relevant biomarkers (ie, changes in plasma NfL concentration and/or reductions in SOD1), provide convincing evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS?" Notably, the panel took issue with the use of "convincing," instead preferring the use of "substantial evidence of effectiveness." In response, the committee voted 3-5-1 (3 Yes; 5 No; 1 Abstain).
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.
Tofersen had its sNDA submitted under the accelerated approval pathway supported by data from a phase 1 study of healthy volunteers, a phase 1/2 dose-ascending study (NCT03764488), the pivotal phase 3 VALOR study (NCT02623699), and its open-label extension. In VALOR, tofersen failed to reach statistical significance against placebo in the primary end point of change in ALS Functional Rating Scale-Revised (ALSFRS-R; difference, 1.2 points; P = .97), but did show positive effects on multiple secondary and exploratory end points, notably, reductions in SOD1 protein and NfL.2
In the early- and delayed-start tofersen groups, patients demonstrated reductions of 33% and 21% in SOD1 protein, the intended target for tofersen, and 51% and 41% in plasma NfL, respectively, at the 12-month time point. Early survival data suggested a lower risk of death or permanent ventilation (PV; HR, 0.36; 95% CI, 0.137-0.941) and death (HR, 0.27; 95% CI, 0.084-0.890) with earlier initiation of tofersen. 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.
It remains to be seen whether the FDA will approve tofersen on these findings alone, considering the agent failed to meet its primary end point of functional change. Additionally, the fact that it was accepted under the accelerated approval pathway—meant for serious or life-threatening diseases or conditions—may play a role in the final decision.
Notably, committee member David Weisman, MD, expressed concern over treatment access if the drug is approved under the accelerated pathway, noting that the "odds are extremely high that this drug works, but I worry about the consequences of accelerated approval where payors will not cover this drug and consider it experimental, and that would be a big problem clinically."
In the days leading up to the meeting, the FDA released a briefing document in which it hinted at the possibility of accepting NfL as a satisfactory surrogate biomarker to predict clinical benefit. The report read, "A surrogate end point is a marker, such as a laboratory measure, radiographic image, or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. To consider a drug for accelerated approval, a drug must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit; studies to demonstrate such an effect must be ‘adequate and well controlled.’ If approved under accelerated approval, additional studies may be required to confirm the anticipated clinical benefit."3
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. NfL levels in the plasma and the CSF, including neurofilament heavy chain and NfL, are significantly elevated in patients with ALS relative to other neurodegenerative diseases. These elevated NfL levels in serum have been reportedly observed as early as 1 year before symptom onset in SOD1-ALS.4
The report also took into consideration the treatment landscape for SOD1-ALS specifically, and the difficulties with conducting and recruiting studies for genetic forms of the disease. "Given the extremely rare nature of SOD1-ALS, and the very small pool of patients available for enrollment into a clinical study, a second adequate and well-controlled, double-blind, placebo-controlled study in symptomatic patients with SOD1-ALS does not appear to be feasible at this time."
The AdComm meeting also included a public comment period, during which 26 speakers shared their thoughts on the drug. Of those, 23 were patients, family members, or advocates who spoke in favor of the approval. In an especially impactful statement, several members of a single family who has lost 22 members due to SOD1-ALS shared their stories, including of those currently enrolled in tofersen studies.