– I see this as a breakthrough for the research we have conducted for over 30 years at Umeå University and Norrland University Hospital. We have never before seen such good results with any treatment, says Peter Andersen, senior physician in neurology and professor at the Department of Clinical Science at Umeå University.
– An important discovery is that it is now possible to greatly reduce the content of the disease-causing SOD1 protein and at the same time measure a clear braking effect against further disease development. When we diagnosed the patient at the neurologist in the spring and winter of 2020, the prognosis was at best 1.5–2 years. The patient has fared much, much better than expected.
The patient comes from a family in southern Sweden with a particularly aggressive type of ALS disease caused by a SOD1 gene mutation. When a relative became ill with ALS, the patient had submitted a research sample to the ALS research at Umeå University but chose not to take part in the results. However, the patient was a carrier of the disease and after experiencing muscle weakness four years ago, the patient understood that he too had been affected. The patient was immediately referred to the medical team at Norrland University Hospital, NUS, and was diagnosed with early ALS disease.
Since the summer of 2020, the patient has been part of the pharmaceutical company Biogen’s phase 3 study of a new gene therapy drug that is aimed specifically at patients with SOD1 mutations that cause misfolding and clumping of SOD1 protein in motor nerve cells. Every four weeks, the patient received the experimental treatment at a university hospital in Copenhagen.
Damage marker reduced by almost 90 percent
At the time of diagnosis in 2020, the patient’s measured value of the substance neurofilament L – a biomarker that shows the breakdown of nerve cells – was very high. Now four years later, it has been reduced by almost 90 percent.
– When the patient was diagnosed at NUS in April 2020, we measured a neurofilament L value of a whopping 11,000 nanograms per liter, which is very, very high even for an ALS patient. On the last measurements, after 50 injections of the new drug, it is down to 1,200-1,290, there is a sharp decrease in the damage marker, the normal level in a person of this age is below 560. In the blood, the level of neurofilaments has normalized and was at last hospital visit at 12, the normal value is less than 13, explains Peter Andersen.
The patient’s functional level, measured according to the ALSFRSR scale, is reduced compared to a healthy person (48 points) but has remained at almost the same level, around 35-37 points, for the past 18 months – this means that the patient’s functional level is reduced by approximately 26 percent compared to a healthy person.
A person with this aggressive type of predisposition to ALS that the patient has, without treatment, would have lost at least 1-1.5 points a month. This means that if the patient had not received the drug, the estimated course of the disease would have gone very quickly and led to a significant disability within 6–12 months and likely the patient’s death in 2021.
Inspiring results
– That this patient can still walk more or less unhindered up a flight of stairs still four years after the onset of the disease, it is actually a bit of a miracle to see, says Karin Forsberg, neurologist and researcher at the Department of Clinical Science, who works together with Peter Andersen and has been researching SOD1 and ALS for over two decades.
– To have succeeded with a drug in this way is a great success and an inspiration. But that in no way means that the job is done, but this is just the beginning. It is also important to remember that the drug in question is not a curative treatment, but it seems to be able to slow down the course of the disease. This gives us great hope for further developing drugs for ALS patients.
There are many types of ALS disease, and only 2-6 percent have ALS disease caused by a mutation in the SOD1 gene. Many of them have a familial occurrence of the disease, but mutations in SOD1 are also found in so-called sporadic ALS.
– Whether this drug has a similar effect on other types of ALS disease, we do not know today. Much more research is needed on this, says Peter Andersen.
The patient can basically do almost everything he could when the study began in the summer of 2020 – he speaks freely and is able to do everything himself, cut the grass, go shopping and take care of the children. Mentally, the patient also feels much better, above all thanks to the fact that he now feels hope.
“This is only the beginning”
The study in which the patient is participating ends this summer. The medicine is not yet available in Sweden, but it is approved by the American Medicines Agency FDA and on February 23, the European Medicines Agency, EMA, came up with a recommendation that the medicine should be used in patients with SOD1 gene mutations within the EU.
However, the regions’ joint council for new therapies (NT Council) has urged healthcare to wait to prescribe the drug pending a health economic assessment by the TLV Council.
– Our next step is to study the results from the patients who receive the drug. It has worked for some, but not everyone has had the same positive effect. It could possibly be a matter of dosage or a question of when during the course of the disease the treatment has been initiated. Is it perhaps the case that you need additional drugs to completely slow down the process? These are questions we must now move forward with. This is just the beginning, says Karin Forsberg.
She foresees that treatment in the future will take place based on which variant of ALS the person has and will likely consist of combinations of drugs. She emphasizes that a lot of research is being done both in Sweden and internationally to find new points of attack so that corresponding drugs can be developed for other patient groups, and she is hopeful that it will become a reality.
– We can measure on samples from the patient that the disease process is ongoing, but the patient’s body seems to be able to compensate even now four years after the patient started testing this new gene therapy drug. The Swedish ethics review authority approved participation in these studies and now several years later, both we and ALS doctors in other participating countries see a clear clinical braking effect on the majority of treated patients, says Peter Andersen.
– The next step will be to submit a new application to the Ethics Review Authority to be allowed to study the compensatory mechanisms that treatment with the drug seems to have activated. Here is perhaps a window to gain insight into how previously completely unknown parts of the nervous system function and the development of even better new drugs.
Film with ALS patient and Peter Andersen
Peter Andersen, professor, senior physician at the Department of Clinical Science talks about the study and the patient performs tests at Umeå University Hospital.
Longer filmed interview and more about the study
Get more information and watch a longer filmed interview with Peter Andersen and Karin Forsberg on the website for ALS research Umeå.
The patient has given written consent to participate in the publication. There is a strong desire from the family that their privacy be respected. Other people in this family have had ALS disease and passed away (none participated in the studies with the drug in question). Other patients have participated in previous tofersen studies with a lower dose or placebo and have passed out. The initiative for this publication takes place completely independently of the pharmaceutical company Biogen.
Background on the medicine and the measured values:
There are many types of ALS disease, some of which are hereditary, but the cause of the majority is still unknown.
About 2–6 percent of all ALS patients have a hereditary change (mutation) in the gene SOD1, which codes for the protein of the same name. The SOD1 protein is found in all cells in the body and has the normal function of neutralizing free radicals, a so-called antioxidant.
The drug in the phase 3 study called VALOR is tofersen, or Qalsody (Biogen). It is a so-called antisense oligonucleotide (ASO) that causes the mRNA that is formed when the gene that codes for the enzyme SOD1 is read to be broken down. The effect is that the new synthesis of the SOD1 protein decreases. This means that the drug blocks SOD1 formation itself.
Tofersen has only been tested in patients with SOD1 gene mutation and not in patients with other types of ALS disease.
During the first six months of VALOR, participating patients received either tofersen or placebo. The patients were then allowed to continue in the open treatment part (Open Label Extension, OLE) where everyone receives the active drug, i.e. torfersen. The OLE part of VALOR is now being completed. In an earlier phase-2 study – also with Swedish participation – tofersen was tested in different strengths (20, 40, 60 and 100 milligrams) and it was concluded that the highest dose was the optimal one.
The drug is given by injection into the spinal fluid and requires a lumbar puncture, which has caused minor headaches and backaches associated with the treatment. Otherwise, the patient feels that the side effects have been few and that the condition of the disease is more stable since the treatment began.
The same drug study has been carried out in several different countries and similar promising results as for the Swedish patient have been reported from researchers in, for example, Germany, Belgium, the USA and Canada. Those assessments have been made independently of the pharmaceutical company that developed the medicine.
The promising results in patients with SOD1-ALS disease have led to the ATLAS study, which evaluates whether early treatment with tofersen can prevent or delay disease development in healthy people who are carriers of the SOD1 disease predisposition. The ATLAS study has been ongoing since 2021.
For questions: Send e-mail to: [email protected] or read more on ALS research Umeå’s website.
Potential freezing conditions:
Karin Forsberg is a specialist in neurology at the neurological clinic, Norrland University Hospital and lecturer at the Department of Clinical Science, Neurosciences, Faculty of Medicine, Umeå University. She is principal and co-investigator in drug trials sponsored by Amylyx, Biogen, Ionis Pharmaceuticals, PTC-Pharmaceuticals, Sanofi and ITB-Med.
Peter Andersen is a Wallenberg Clinical Scholar, senior physician in neurology at the neurological clinic, Norrland University Hospital and professor at the Department of Clinical Science, Neurosciences, Faculty of Medicine, Umeå University. He is principal investigator for the VALOR and ATLAS drug trials sponsored by Biogen, and since 2014 has received fees from participation in advisory committees. The fees have gone to his employer Umeå University or to him as a private individual. He is also the principal investigator for several other ALS drug trials sponsored by competitors to Biogen. He is also a paid advisor for the European Medicines Agency EMA.
