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expert reaction to results of a phase 3 clinical trial of tofersen for motor neurone disease

Results of a phase 3 clinical trial looking at the use of tofersen for motor neurone disease (MND) has been published in New England Journal of Medicine (NEJM).

This Roundup accompanied an SMC Briefing.


Dr Paul Wright, Principal Scientist, LifeArc, said:

“This is promising and potentially exciting news for people with MND whose condition is caused by a faulty SOD1 protein. Although faulty SOD1 causes a small proportion of MND, it’s the first evidence that reducing SOD1 protein production could work and will provide further insight into how SOD1 causes MND. The SOD1 protein is known to aggregate – or clump – and it would be interesting to see if this approach could offer hope to other neurodegenerative diseases where protein aggregation is also seen.

“Because the paper shows the benefits are seen after a longer period of time, it also highlights the need to have better tests to spot the disease earlier, to identify the exact type of disease a person has, and to monitor how it progresses. It’s likely the disease is easier to treat and people will respond better if personalised treatments are given before more nerve damage occurs.”  


Dr Brian Dickie, Director of Research Development, Motor Neurone Disease Association, said:

“I share the positive view of neurologists that this treatment has the potential to deliver a significant benefit in modifying the disease course. It is, of course, limited to a small, relatively rare subset of people with ALS, but given that treatments to date have been modest in slowing the disease, a genuinely positive impact will deliver new insight that should hopefully help open the door to novel treatments for other forms of the disease.

“The other encouraging point is the biomarker-based evidence, which provided investigators with early encouraging data that the drug was both hitting its intended target and also reducing nerve cell damage, in advance of notable clinical changes in motor function.

“These latest trial results raise the important issue of whether earlier treatment in the disease course may be even more effective or, indeed, whether this strategy can delay or even prevent the onset of disease in asymptomatic mutant SOD1 gene carriers – a question that is being currently being addressed by Biogen through their ATLAS study ( )“


Prof Michael Swash, Emeritus Professor of Neurology and Hon Consultant Neurologist, Barts Health NHS Trust, 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. So there’s a cost-benefit analysis for NICE to consider. Immense pressure will develop for licensing but the benefit appears to be much less than, for example, therapy for spinal muscular atrophy. 

“More work needs to be done, but a well-conducted trial heading, at last, in the right direction.”


Dr Adolfo López de Munain, Clinical Chief at the University Hospital of Donostia and scientific director of CIBERNED, said:

“The article reflects a well-planned and executed work, which justifies its interest for NEJM. It is a phase 3 trial in a very specific subgroup of amyotrophic lateral sclerosis (ALS) patients, carriers of a mutation in a gene (SOD1). This limits the external validity of its conclusions but homogenizes the sample. ALS is a multifactorial disease and this makes it difficult – in my opinion, it is the cause of so much therapeutic failure – for a pathway focused on a specific therapeutic target to be successful. It should be noted that, if we look at the different genes involved in familial forms of ALS, virtually all cellular/metabolic functions may be involved. Therefore, the trial has limited external validity but high internal validity.  

“108 patients have been enrolled with 72 patients in the active arm (those who received treatment and not placebo), and these have been distributed between slowly (33) and rapidly (39) progressing patients, which is well done but somewhat small numbers for a 28-week progression. They were mostly taking Riluzole and a few were taking Edaravone (other ALS treatments) simultaneously.  

“There is a significant difference in the time of illness from onset (8.3 months for those with rapid progression and 39.6 for those with slow progression). This difference is normal, and the time for the fast ones is short, which is fine because I am persuaded that any therapy will work better or only work in early stages (unfortunately, by the time symptoms debut the disease has been evolving for some time). In other words, the design seems correct and feasible to replicate with more cases.

“As for the results, there are significant differences in some biomarkers of neuronal damage (neurofilaments), but at week 28 the [functional] difference of those treated is not statistically significant in the group of those who progress rapidly. Many patients (95) are still in the 236-week open-label extension (the study continued without a placebo group) and it seems that putting the treatment early generates a smaller drop in the functional assessment scale. It also allows us to venture that perhaps in a cut-off at 52 weeks the differences could be increased by introducing mortality as a secondary variable of analysis, but, a priori, the trial fails in the essential aspect, which is to avoid disease progression.  

“Another issue to highlight is that in this disease, as in other neurodegenerative diseases, it is one thing to improve biomarkers and another to recover or halt the progression of the disease. By analogy, annulling the causes of the fire is not the same as putting it out, and this in turn is different from recovering the burnt forest.  

“The age of the patients is approximately 50 +/- 12 years. The ideal would be to do a trial in presymptomatic patients. For example, you could do a trial in presymptomatic carriers with the mutation and measure conversion rate to clinical as well as biomarkers.  

“Finally, and this is positive, the rate of side effects of intrathecal administration [in the space where the cerebrospinal fluid is located] with 15 ml injections (8 doses in total) during 24 weeks is reasonable (4 related events in the treated group, which is 7%, although there are 7 cases with pleocytosis [increased cells in the cerebrospinal fluid] and 6 with increased proteins, which could suggest a myelitic process). This would make it necessary in successive studies to include an MRI to monitor it.  

“Company press releases are rarely not optimistic. I believe that the outcome of the trial today is negative. Overall it is an interesting study, but it needs follow-up and possibly a design in presymptomatic patients if some doubts about these myelitis are clarified.”  



Phase 3 Trial of Antisense Oligonucleotide Tofersen for SOD1-ALS by Miller et al. was published in New England Journal of Medicine at 22:00 UK time on Wednesday 21st September.



Declared interests

Dr Adolfo López de Munain: “No declaration of conflict of interest”

For all other experts, no reply to our request for DOIs was received.


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