Biogen’s Qalsody (tofersen) has been approved by the US Food and Drug Administration (FDA) for treating a rare form of amyotrophic lateral sclerosis (ALS). This is a good news for the small number of patients, affected by a genetically defined form of ALS, expected to access the antisense drug. Moreover, as the first ALS drug approval based on a blood-based marker of neuronal damage, this event has a wider relevance. The drug actually failed to reach the primary endpoint of a phase 3 pivotal trial, however Qalsody’s approval is related to its efficacy in reducing plasma levels of neurofilament light chain (NfL), a biomarker of neuronal damage.
Biogen’s drug Qalsody is the first drug to gain approval for a genetically defined form of ALS
Qalsody is an antisense oligonucleotide (ASO) designed to bind to SOD1 mRNA in order to reduce a mutated form of superoxide dismutase 1 (SOD1). This enzyme is able to prevent oxidative damage and its mutation is associated to the formation of toxic protein aggregates and the enzyme’s loss of function, these events may both contribute to the disease pathology. The case for Qalsody’s approval relies on numerous independent studies demonstrating that high levels of NfL are associated with fast disease progression and early death. NfL is a cylindrical neurofilament present abundantly in the cytoplasm of neurons. Any form of neuronal damage results in NfL release into the cerebrospinal fluid and the plasma, which can be readily detected. Nevertheless, NfL is not diagnostic of ALS and it is a non-specific marker of neuronal damage that can be associated with a range of other neurodegenerative diseases as well as ALS.
Qalsody’s green light is tied to its effect in reducing plasma levels of neurofilament
In Biogen’s 28-week pivotal study, patients in the group receiving Qalsody had 15-25% higher NfL levels at baseline than those in the control arm and, thus, were likely to progress more rapidly without any intervention. However, the subjects who received the active drug responded to the treatment with an average 55% reduction from baseline NfL concentrations. On the other hand, those taking placebo have been subjected to an increase of 12%. The FDA come to the conclusion that these effects “are reasonably likely” to predict a clinical benefit in ALS patients. Further elucidations will be possible through an open-label extension of the original phase 3 study and an additional phase 3 study in pre-symptomatic people with SOD1 mutations, which aims to determine whether the drug can delay the onset of symptoms in this group.
By Ramona Stringhi, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan
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