NEJM (IF=176) The latest advances in the treatment of frostbite! Phase 3 clinical results of antisense oligonucleotides in the treatment of frostbite suggest that its efficacy remains to be evaluated

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Amyotrophic lateral sclerosisALS is commonly known as frostbite
.
About 2% of ALS cases are associated
with mutations in the gene encoding superoxide dismutase 1 (SOD1).
More than 200 ALS-associated SOD1 mutations have been described and correlated
with variable rates of progress.
Neuronal degeneration in this disease is thought to be caused
by increased toxic function of the mutated SOD1 protein.
Tofersen is an antisense oligonucleotide administered intrathecessically designed to reduce the synthesis
of SOD1 proteins by inducing degradation of RNase H-mediated SOD1 messenger RNA 。 On September 22, 2022, the VALOR and OLE Working Group published a research paper entitled "Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS" online in The New England Journal of Medicine, which conducted a 28-week 3-phase randomized trial.
To study the efficacy and safety of Tofersen in adults with SOD1 ALS
.
Overall, in patients with amyotrophic lateral sclerosis of type SOD1, within 28 weeks, Tofersen reduced the concentration of SOD1 in the cerebrospinal fluid and the neurofilamentin light chains in plasma, but did not improve clinical endpoints and was associated
with adverse events.
During the extension phase, the potential impact of early onset compared to delayed start-up of Tofersen is being further evaluated
.
Amyotrophic lateral sclerosisALS is a neurological disorder
.
The neurons that innervate muscle movement slowly degenerate and die, and the muscles shrink a little, and the patient gradually appears and aggravates symptoms such as muscle weakness, muscle atrophy, dysphagia, drinking water and coughing, and unclear speech, and gradually loses the ability to exercise and take care of life until death
.
In the Phase III trial conducted in this study, there were 108 subjects with 42 SOD1 mutations
.
The researchers randomly assigned SOD1 amyotrophic lateral sclerosis subjects in a 2:1 ratio, and eventually 72 participants received Tofersen (39 were expected to progress faster) and 36 received a placebo (21 were expected to progress faster
).
Receive 8 doses of Tofersen (100 mg) or a placebo within 24 weeks
.
The researchers designed the primary endpoint as the ALS Functional Rating Scale–Revised, ALSFRS-R; Ranges from 0 to 48, with higher scores indicating better function), and the faster
disease progression is expected.
Secondary endpoints included changes in total SOD1 protein concentrations in cerebrospinal fluid (CSF), changes in neurofilament Light Chains (NfL) concentrations in plasma, changes in slow lung capacity, and changes in 16-muscle handheld dynamometers
.
The findings suggest that the Tofersen group had a greater
reduction in SOD1 concentrations in the cerebrospinal fluid and plasma light chain concentrations in plasma compared to the placebo group.
In the rapidly progressing subgroup (preliminary analysis), the change in ALSFRS-R score was −6.
98 in the Tofersen group and −8.
14 in the placebo group by week 28 (difference, 1.
2 points; 95% confidence interval [CI], −3.
2 to 5.
5; P = 0.
97)
。 There was no significant difference
in results for secondary clinical endpoints between the two groups.
A total of 95 participants (88%) entered the Open Label extension
.
Further through a 52-week open-label extended joint analysis, the results were compared at the start of the trial (participants who started using Tofersen in the early start cohort with participants who switched from placebo to the
drug at week 28 (delayed start cohort).
The study found that at 52 weeks, the ALSFRS-R score varied by −6.
0 in the early start cohort and −9.
5 in the delayed start cohort (a difference of 3.
5 points; 95% CI, 0.
4 ~ 6.
7)
。 Non-multiplicity adjustment differences
were seen at other endpoints in favor of early onset inference.
In addition, adverse events associated with lumbar punctures are common
.
Serious neurologic adverse events occurred in
7% of Tofersen subjects.
Overall, in patients with amyotrophic lateral sclerosis of type SOD1, within 28 weeks, Tofersen reduced the concentration of SOD1 in the cerebrospinal fluid and the neurofilamentin light chains in plasma, but did not improve clinical endpoints and was associated
with adverse events.
During the extension phase, the potential impact of early onset compared to delayed start-up of Tofersen is being further evaluated
.

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