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2nd June 2023
Ropinirole use in amyotrophic lateral sclerosis (ALS) significantly delays the time to the first disease progression, according to a recent, but small, randomised placebo-controlled trial with an open-label extension phase.
ALS is a rare neurological disease affecting motor neurons (MNs) in the brain and spinal cord that control voluntary muscle movement. ALS is also a progressive disease characterised by muscle atrophy and weakness caused by selective vulnerability of MNs. In Europe, only one drug, riluzole is licensed for the treatment of ALS. Ropinirole is a dopamine D2 receptor agonist that is approved for the use in the treatment of Parkinson’s disease. However, recently, drug-based screening studies have revealed how ropinirole may also be effective in ALS.
In the current study, published in the journal Cell Stem Cell, Japanese researchers conducted a phase 1/2a, randomised, double-blind, placebo-controlled trial, followed by an open-label extension, of ropinirole in patients with ALS. A total of 20 patients with sporadic ALS received either ropinirole or placebo (3:1) for 24 weeks in the double-blind phase of the study, in which safety, tolerability and the therapeutic efficacy were assessed. This was followed by a four- to 24-week open-label extension study in which patients originally assigned to placebo switched to ropinirole.
For the study, a number of parameters were assessed with the primary outcome based on adverse events. In total, there were 11 secondary outcomes including functional outcomes such as the revised ALS functional rating scale (ALSFRS-R) score, which assessed patient’s disability; survival; and time to the first disease progression event.
In the 24-week double-blind part of the trial, 13 patients received ropinirole and seven a placebo. There was no significant difference in the overall incidence of adverse events (92.3% vs 85.7%, ropinirole vs placebo). In addition, there was no significant effect of treatment on ALSFRS-R scores (mean between group difference, MBGF = 1.46, 95% CI -3.15 to 6.07).
However, beyond the initial 24-week period, there was a persistent increase in between-group differences in ALSFRS-R scores (MBGF = 9.86, 95% CI 4.07 – 15.66, p < 0.001). Differences in survival favouring ropinirole occurred but were only apparent during the open-extension phase. However, across the whole trial period, this difference was significant (median difference = 9.0, 95% CI 1 – 12).
One of the most impressive findings was how the ropinirole group had a longer period of time (27.9 weeks) before their first disease progression event (p = 0.008).
The authors estimated the effect size of ropinirole on the ALSFRS-R score over 48 weeks to be 1.46 to 9.86. This translated into a 21-60% slower rate of functional decline, which was considered to be clinically meaningful. Nevertheless, they recognised that the small sample size – of 18 completing the 24-week double-blind phase and only eight completing the extension phase – limited the generalisability of their findings.
28th September 2022
Use of tofersen in patients with amyotrophic lateral sclerosis (ALS) with mutations in the gene encoding for superoxide dimutase 1 (SOD1), reduced cerebrospinal fluid levels of the SOD1 protein and neurofilament light chain (a marker of axonal damage) but failed to improve clinical endpoints. This was the interim conclusion of an on-going study by researchers from the VALOR and OLE working groups.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord and has a prevalence of approximately 6 cases per 100 000. ALS is both relentless and incurable and begins with a progressive paralysis and usually leads to death within 3 to 5 years of diagnosis.
However, in the majority of cases, the intellect appears to remain intact while the motor system degenerates. While the cause remains uncertain, superoxide dismutase 1 (SOD1), which is an antioxidant enzyme that protects cells from reactive oxygen species toxicity, was the first gene in which mutations were found to be causative for ALS. Moreover, around 2.3% of ALS cases are due to SOD1 mutations.
Tofersen is an antisense oligonucleotide that bind to the SOD1 mRNA and in doing so, prevents it from being read, thereby stopping SOD1 protein production and potentially slowing disease progression. The present study is part of the VALOR trial which is divided into three parts, A, B and C.
The first two parts evaluated the safety, tolerability, and pharmacokinetics of ascending doses of tofersen in adults with ALS and a SOD1 mutation, whereas the primary objective of Part C was to evaluate the clinical efficacy of tofersen.
VALOR was a phase 3, double-blind, randomised trial that included 24 weeks of treatment and a follow-up period of 4 – 8 weeks and then an on-going open-label extension phase. Eligible patients were randomised 2:1 to intrathecal tofersen (100 mg) or placebo administered as three doses once every two weeks, then five doses once every 4 weeks for a total of 24 weeks.
Upon completion of VALOR, participants could opt to continue in the open-label phase, lasting up to 236 weeks. In the present analysis, researchers reported data at week 52. In their analysis, participants were classed as an ‘early-start’ cohort, i.e. where they had been randomised to tofersen from the start of the trial and ‘delayed-start’ where individuals randomised to placebo, switched to active treatment for the open-label phase.
In addition, the trial included a group of patients estimated to have either faster or slower disease progression. The primary efficacy endpoint in VALOR was a change from baseline to week 28 in the Amyotrophic lateral sclerosis Functional Rating scale-Revised (ALSFRS-R score) which is a measure of functional capacity (ranging from 0 to 48, with higher scores indicating better function).
Secondary outcomes included cerebrospinal fluid concentrations of SOD1 protein, plasma neurofilament light chains, the percent of the predicted slow vital capacity and the handheld dynamometry megascore, which provided a measure of strength and again, with higher scores meaning greater strength.
Tofersen and ALS outcomes
A total of 108 participants with 42 unique SOD1 mutations were enrolled, 72 given tofersen, of which 39, were deemed to be in the faster progression group. The mean ALSRFS-R score among the tofersen group was 36.9. In addition, 62% of those in the tofersen group were also prescribed riluzole and 8% edaravone.
For the primary outcome, the adjusted mean change in ALSFRS-R score was -8.14 in the placebo group and -6.98 in the tofersen group which was not significantly different (mean difference = -1.2, p = 0.97).
There were also no significant differences for the secondary outcomes although in the faster progressing group SOD1 proteins were reduced by 29% in those receiving tofersen compared to an increase of 16% in the placebo group. Similarly, there was a 60% reduction in neurofilament light chains in the tofersen-treated faster progression group compared to a 20% increase in the placebo group.
For the open-label extension group, at 52 weeks, the change in ALSFRS-R score from the VALOR baseline was -6.0 points for early-start participants compared to -9.5 points for the delayed-start group. In other words, patients who started tofersen earliest, irrespective of whether they were fast or slower progressing, had a small decline in ALSFRS-R score.
Other differences indicative of improvements between early and delayed starters compared to the VALOR baseline were also seen with predicted slow vital capacity (-9.4% vs -18.6%, early vs delayed) and for handheld dynamometry megascore (-0.17 vs -0.45, early vs delayed)
The authors concluded that while there was no significant difference in the decline in a composite measure of ALS progression for patients given tofersen compared to placebo, the potential effects of early vs later use of the drug is being further investigated in the open-label extension study.
Miller TM et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS New Eng J Med 2022