Prof. Katarzyna Kotulska-Jóźwiak: In SMA, we are no longer talking only about stopping the disease, but also about real improvement in functioning

Professor, what do we already know about the effects of antisense olinucleotides in SMA? How effective and safe is this treatment?

At the moment there is one antisense olinucleotide for spinal muscular atrophy - nusinersen - registered quite a long time ago, in 2016 in the United States, in 2017 in the European Union. This is a drug with a very rich history regarding both clinical trials and use in clinical practice. It is also the first not only registered, but also the first used drug in spinal muscular atrophy in Poland, available in the drug program from 2019, which is also a very long time.

We have evidence not only from these studies, which were conducted both in patients with symptoms of spinal muscular atrophy and, after some time, in patients in the pre-symptomatic phase of the disease, that is, to prevent the development of this neurodegenerative disease, which is very severe in its natural course. We already know that the drug is extremely effective and maintains its efficacy over the long term. In symptomatic patients, we not only have a stabilization of disease symptoms, as we would expect, looking at the natural history of the disease and what happens in its course, but there is also improvement in the vast majority of patients.

And what do the results of the DEVOTE study say about the patients' improved condition and reduced neurofilament levels?

Maybe I'll start by saying that nusinersen was registered at the very beginning at the maximum dose tested at the time, that is, it was found in a clinical trial, which, by the way, ended prematurely because its results were so good in the preliminary analysis, that this highest dose used in the trial is the best, because it is safe and effective. As a result, this particular dose, 12 mg, was registered. From preclinical studies, or animal studies, it was known that higher doses were doses that could also be tried, because they were doses that were completely safe and probably more effective. And the DEVOTE study, which was conducted over the last three years, tested the efficacy and safety of a higher dose of nusinersen: a significantly higher dose, because, as I said, the standard one is 12 mg, and the higher one is 50 mg - that's the initial dose, and then 28 booster doses, so it's a significantly higher dose of the substance. It turned out that this treatment is safe and met the expectation set in the clinical trial before the drug, that is, it effectively improves the condition of patients with spinal muscular atrophy.

Neurofilaments are such components of a nerve cell that have recently been used as a biomarker, that is, as something that we can in the blood or in the cerebrospinal fluid examine and that indicates to us that the nerve cell is damaged, because under normal conditions it is a substance that is inside the cell. So if it's found in the blood outside the cell, or in the cerebrospinal fluid, it indicates that something has happened to the cell and a component of it has leaked out. And indeed, we know from many studies that in many neurodegenerative diseases - including spinal muscular atrophy - neurofilaments appear in high amounts precisely in the blood and cerebrospinal fluid, and in the course of treatment their concentration decreases, which correlates with clinical improvement in patients.

You mentioned that we already have a 7-year experience in Poland with a 12 mg dose of nusinersen. What results have patients obtained in such actual clinical practice, and what can a higher-dose regimen do for them?

We have in the drug program, because we use nusinersen in the drug program, quite clearly described treatment efficacy criteria. They are based on the assumption that by stopping the process of neurodegeneration, we should cause stabilization of the symptoms of the disease. What we see in the drug program, in roughly 70-80% of patients, is a much better effect, because improvement. And it's an improvement that can be seen in the patient's daily functioning. For someone who has an incapacitated hand, the appearance of additional hand function - one that can be measured and seen - is something that is extremely important. Very often, patients with spinal muscular atrophy are active people, often professionally active, so for them, any of these activities that facilitate daily life, independence, is an extremely important thing. And depending on the patient group, from 70 some to 80% of patients we see improvement, not just stabilization.