In a phase 3 study, tofersen failed to meet its primary end point of functional change, but did meet its target engagement of SOD1 protein and reductions in neurofilament light.
Days ahead of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee hearing on tofersen (Biogen), an investigational agent for SOD1 mutation-mediated amyotrophic lateral sclerosis (ALS), the agency expressed openness, with caution, to use neurofilament light (NfL) as a surrogate marker to predict clinical benefit of the therapy.1
Tofersen, an antisense oligonucleotide, was submitted under the accelerated approval pathway and is currently under review by the FDA, with an expected decision set to come on April 25, 2023. After originally scheduling a PDUFA date of January 25, 2023, the FDA extended the review period, and later announced an AdComm meeting would be scheduled for March 22, 2023, to discuss the agent’s potential.2
In the latest FDA briefing document, the agency laid out the agenda for the hearing, which includes conversations on efficacy and safety issues, risk mitigation, and a background on the condition, standard of care, NfL, and pertinent drug development and regulatory history, among others. The report acknowledged that tofersen failed to meet its primary end point of statistically significant difference in ALS Functional Rating Scale; however, that results indicated target engagement of the therapy and a reduction in NfL that "has been shown to be correlated with disease progression and prognosis in patients with ALS." The agency added, "there are also post hoc exploratory analyses of an open-label extension study that may be suggestive of a clinical benefit with a longer duration of treatment."1
The new drug application for the antisense oligonucleotide included 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. After 28 weeks of treatment, findings from VALOR showed no statistically significant change in ALSFRS-R (difference, 1.2 points; P = .97), but positive effects across multiple secondary and exploratory end points.3
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 neurofilament light, a marker of neuron injury, 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.
By definition, accelerated approval may be granted for a product for a serious or life-threatening disease or condition upon a determination that the product has 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 that clinical benefit.
It the report, the agency wrote "A surrogate endpoint 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."1
While Biogen is proposing the use of plasma NfL as a reasonably likely surrogate end point, the report stated that it would seek the input of the committee to discuss whether the available evidence supports the use of this biomarker as likely to predict clinical benefit in patients with SOD1-ALS. As the agency continues to review the application, tofersen will continue to be evaluated in the ongoing phase 3 ATLAS study (NCT04856982), which assesses whether the drug can delay clinical onset when initiated in presymptomatic individuals with a SOD1 genetic mutation and biomarker evidence of disease activity.
In addition to ATLAS, the company plans to leverage the results of the ongoing open-label extension study, in which all patients are continuing to receive treatment and remain blinded to their original treatment assignment from the double-blind portion. These patients will continue to be followed for data on survival.
The report added, “Given the exceedingly low prevalence of SOD1-ALS, the seriousness of the disease, and the substantial unmet need, we would also like input from the advisory committee members on whether the combination of the existing clinical data from the Phase 3 study and the currently available data from the extension study, accompanied by the reductions of SOD1 and NfL, provide convincing evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS.”1