Why doctor: What are the current treatment options in France for people suffering from amyotrophic lateral sclerosis?
Professor Claude Desnuelle: Today, – apart from Tofersen which we will talk about next – we have only used Riluzol since the 90s because research has shown that it prolongs patient survival. I would still point out that there are many other drugs that have been shown to prolong survival… But it depends on how we did the studies. For example, for Relyvrio that we used a little last year, some studies showed that it prolonged survival phenomenally then others ultimately showed that it did not, so we stopped everything.
ALS: “I have seen therapeutic trials in all directions over the past 20 years”
What are the difficulties faced by researchers in finding a treatment for this neurodegenerative disease?
On the one hand, over the past 20 years I have seen therapeutic trials in all directions. Until recently, around 5 or 6 years ago, for a drug to be used in therapeutic trials in ALS, it was necessary to prove that it was effective in a mouse model with a particular mutation… But we finally realized that we cured and improved generations of mice without succeeding in treating a single human with this principle. So we must believe that this principle of the mouse model was bad.
Furthermore, we consider that there are two main causes to be treated in ALS, but without success:
-Inflammation present in the cells surrounding motor neurons and which largely contributes to the evolution of the disease and its rapid progression. The idea is therefore to obtain molecules which fight against this inflammation, but we have not found much in six years.
-Energy mechanisms: we consider that motor neurons lose their capacity to produce energy and then function less well, so we are looking for drugs that aim to boost this cellular energy system. Here again, experience shows that we have not gone very far, other than a few molecules.
Finding a cure therefore seems almost mission impossible…
Until now we had the impression of inevitability, a disease that we could do nothing about, while there is still hope, particularly for genetic forms. Today, they only represent 10% to 15% of SLAs, but we hope there are many more! 90% of these patients share four genes, and for the remaining 10%, these are extremely rare mutations.
Tofersen: “a gene therapy which is done by injection every month directly into the spinal cord”
Among these four known mutations, we now have a drug which we are practically sure is effective for one of them because it corrects the effects of the mutation in the gene: it is Tofersen, whose name commercial is Qalsody®. In principle, the EMA should grant authorization for use in the coming months. Currently, it is already accessible through special access in France for patients whose mutation we have detected. It can also be given in the family to people in whom we have found this mutation, even if ALS has not yet declared itself. We also realized that this treatment was capable of leading the patient to recovery, something considered, until recently, to be miraculous in ALS. It is a gene therapy which is done by injection every month directly into the spinal cord, via lumbar puncture.
And for the three other known genes, do we have any hope of treatment?
Currently, there are tons of trials for these other three genes. These tests will lead us to something in the months, even years, to come. The day we can treat 10% of SLAs will already be fantastic progress.
For these genetic forms, we will most likely find treatments.
Can we imagine that there are more genetic forms of the disease than those we currently know?
What we are doing more and more now in France is that in addition to the genetic test to find out if ALS is linked to a known genetic form, we systematically sequence the patient’s entire genome to study it. Thanks to this technique, we will undoubtedly find mutations unknown until now. Even though there will certainly not be 100% of forms that will be genetic, we can hope that this proportion of 15% will rise to 30-35%. And for these genetic forms, we will most likely find treatments.
Today we know that there is not one ALS but ALS. How could this change the situation for treating patients?
For more than 20 years we had been completely pedaling because we did not have this notion… We felt it, as doctors and researchers, but we had not demonstrated it. Now that we know that there are many different ALS, if we manage to distinguish them and carry out targeted therapeutic trials according to the marker present, I think we will have much more success from a therapeutic point of view. Indeed, it is obvious that if there are patients carrying different diseases and you give them the same treatment, statistically it will respond once and then another time, it will not respond. Unfortunately, for the moment, we do not have a marker to identify these patients.
