In an open-label extension trial, tofersen showed significant reductions in SOD1 protein and neurofilament light over a 12-month period. It is now expected to be reviewed by the FDA by early Q2 2023.
After originally scheduling a PDUFA date of January 25, 2023, the FDA announced it has extended its review period for Biogen’s investigational agent tofersen, a drug designed to treat patients with a SOD1 mutation-mediated amyotrophic lateral sclerosis (ALS). The new updated PDUFA date is April 25, 2023.1
"We are committed to providing any details the agency needs to complete the review of tofersen,” Priya Singhal, MD, MPH, Head of Global Safety and Regulatory Sciences, and Interim Head of R&D, Biogen, said in a statement.1 "As the review continues, Biogen will maintain the early access program for tofersen."
There are currently no approved therapies for patients with SOD1 mutation, and only a handful of approved therapies for ALS in general. 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 as the basis for the NDA.
VALOR, a large-scale study that included 108 participants with SOD1 ALS, showcased tofersen’s impact on neurofilament light and SOD1 protein. Although it failed to meet its primary end point of statistically significant change from baseline in Revised ALS Functional Rating Scale (ALSFRS-R) after 28 weeks of treatment (difference, 1.2 points; P = .97), it continued to demonstrate positive effects across multiple secondary and exploratory end points that were observed over a 12-month treatment period.2
In September 2022, Biogen published the combined analysis of VALOR and its OLE in the New England Journal of Medicine. Here, 63 (88%) individuals were originally assigned to receive tofersen and 32 (89%) originally assigned to placebo, and, at the time of the most recent data cutoff (January 16, 2022), 49 participants (68%) in the early-start cohort and 18 (50%) in the delayed-start cohort remained in the OLE. At the 12-month time point, tofersen outperformed placebo on several outcomes, including clinical function, as assessed by ALSFRS-R score (difference, 3.5 points; 95% CI, 0.4-6.7) and respiratory, as measured by slow vital capacity (difference, 9.2% predicted; 95% CI, 1.7-16.6).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 hazard ratio (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.
At the time of the published results, principal investigator Timothy Miller, MD, PhD, codirector, ALS Center, Washington University School of Medicine in St. Louis, said in a statement, "I see 3 key take home points from these data. First, tofersen clearly leads to lowering of SOD1 protein, as would be expected. Second there is substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process. And third, there is a meaningful clinical benefit when looking at the later time points in the open label extension."3
Adverse events (AEs), mostly mild to moderate in severity, included mainly procedural pain, headache, pain in the arms or legs, falls, and back pain. Four (6%) participants who received tofersen in VALOR and 3 participants in the open-label extension (constituting 7% of all participants who received tofersen) had a total of 8 neurologic series AEs, including myelitis, chemical or aseptic meningitis, lumbar radiculopathy, increased intracranial pressure, and papilledema. In VALOR, 42 (58%) participants in the tofersen group and 2 (6%) participants in the placebo group had at least 1 cerebrospinal fluid (CSF) white cell count of more than 10 cells/m3, and approximately 40% of the participants had elevated CSF protein concentrations at baseline. Between the groups, the median CSF protein concentration has increased by 110 mg/L for those on tofersen and 15 mg/L for the placebo group.
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.