Tofersen is aimed at treatment of superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS). In people with this form of the disease, mutations in their SOD1 gene cause their bodies to create a toxic form of SOD1 protein. This toxic protein causes motor neurons to degenerate, resulting in progressive muscle weakness. Tofersen is designed to bind to SOD1 mRNA and reduce SOD1 protein production.
Biogen, which licensed the drug from Ionis Pharmaceuticals under a collaborative development and license agreement, is seeking approval of tofersen based on the use of neurofilament as a surrogate biomarker that is reasonably likely to predict clinical benefit.
The Cambridge, Massachusetts company's supplemental new drug application (sNDA) for tofersen was accepted for priority review by the US Food and Drug Administration (FDA) in July last year under the accelerated approval pathway. The agency is scheduled to make its final decision on the investigatational therapy on April 25.
The panel’s responses
The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee met yesterday to evaluate tofersen. The committee’s vote is not binding on the US regulator.
On the question: “Is the available evidence sufficient to conclude that a reduction in plasma neurofilament light chain (NfL) concentration in tofersen-treated patients is reasonably likely to predict clinical benefit of tofersen for treatment of patients with SOD1-ALS?” the Committee voted unanimously yes, for consideration of a potential accelerated approval.
On the second question: “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, i.e., changes in plasma NfL concentration and/or reductions in SOD1, provide substantial evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS?” the experts voted 3 (yes), 5 (no) and 1 (abstain), for consideration of a potential traditional approval.
Additionally, the committee discussed both of these topics and reached consensus that the benefit-risk profile was favorable based on the review of the totality of data for tofersen in people with SOD1-ALS.
Extended review period
In October last year, Biogen said the FDA had extended the review period for tofersen’s sNDA by three months, with the US agency asking the company for supplementary information.
The sNDA is supported by data from a phase 1 study of healthy volunteers, a phase 1/2 dose-ascending study, the pivotal phase 3 VALOR study, 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 but did show positive effects on multiple secondary and exploratory end points, notably, reductions in SOD1 protein and NfL.