medwireNews: Data from the open-label extension of the VALOR trial suggest that treatment with the intrathecally administered antisense oligonucleotide tofersen may modify the disease course of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations and lead to improvements in function.
The phase 3 trial did not meet its primary endpoint of functional improvement at 28 weeks with tofersen versus placebo, but continued treatment appeared to be associated with clinical benefit at week 52, report Timothy Miller (Washington University School of Medicine, St Louis, Missouri, USA) and co-researchers in The New England Journal of Medicine.
They also highlight that at 28 weeks “tofersen was associated with reductions in the total concentration of SOD1 protein in CSF [cerebrospinal fluid], an indirect marker of target engagement, and the concentration of neurofilament light chains in plasma, a marker of axonal injury and neurodegeneration.”
VALOR – which is the final part of a three-part trial – enrolled 108 individuals with SOD1 ALS, of whom 60 met the trial-defined prognostic criteria for faster-progressing disease, which was “based on SOD1 mutation type and the estimated slope of the score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R)”, explain the study authors.
Participants were randomly assigned to receive eight doses over 24 weeks of tofersen 100 mg or placebo via an intrathecal bolus injection through lumbar puncture, followed by an open-label extension phase of up to 236 weeks in which tofersen-treated patients continued to receive the oligonucleotide (early-start cohort) and placebo-treated patients initiated tofersen (delayed-start cohort).
At baseline, the average age of patients in the tofersen group was 48 years, while it was 51 years in the placebo group. A comparable 62% and 61% were taking riluzole and an identical 8% of patients in each group were receiving edaravone.
The primary endpoint of the trial was the change at week 28 from baseline in the ALSFRS-R total score in the faster-progression subgroup, and this did not differ significantly among patients given tofersen and those given placebo, at adjusted mean reductions of 6.98 and 8.14 points, respectively.
In light of this negative result, the protocol did not allow for formal statistical testing of secondary endpoints, but in the faster-progression subgroup, individuals who received tofersen had a 29% reduction in the total levels of SOD1 in CSF compared with an increase of 16% among those given placebo.
The researchers also observed a 60% decrease in the mean concentration of neurofilament light chains in plasma among tofersen-treated patients in this subgroup versus an increase of 20% among placebo-treated patients.
In the open-label extension phase, which included 63 patients who had originally been assigned to receive tofersen and 32 to placebo, the reductions in total levels of SOD1 in CSF and neurofilament light chains in plasma were maintained up to the 52-week timepoint among the early-start subgroup, while the delayed-start subgroup experienced similar reductions after switching from placebo.
The early-start patients had a smaller numerical decline in the ALSFRS-R total score at 52 weeks than delayed-start patients, at adjusted mean reductions of 6.0 versus 9.5 points. This was also the case for change from baseline in the percentage of predicted slow vital capacity (−9.4 vs −18.6%) and in handheld dynamometry megascore (−0.17 vs −0.45).
This “possible signal of differences in clinical end points between the early-start and delayed-start cohorts […] suggests that a trial duration of more than 28 weeks may be required to determine the effect of tofersen in patients with this disorder”, say Miller and colleagues.
“Earlier or presymptomatic intervention is being investigated in the ongoing ATLAS trial”, they add.
The team also reported on the safety profile of tofersen, noting that “[m]ost adverse events across VALOR and the open-label extension were mild to moderate in severity and did not cause withdrawal or discontinuation of the trial agent.”
However, neurological serious adverse events, such as myelitis, chemical or aseptic meningitis and lumbar radiculopathy, occurred in 7% of participants receiving tofersen over the course of the study.
In an independent statement to the press, commentator Michael Swash (Barts Health NHS Trust, London, UK) said: “A big step forward, but it leaves open the question as to when to treat (early as possible?), for how long and, importantly, whether there is likely to be any sustainable benefit with continued therapy or after treatment cessation, especially evidence of acceptable improvement rather than slowed decline.”
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This independent news story was supported by an educational grant from L’Institut Servier, Suresnes, France.