Background
Antisense oligonucleotides (ASO) are biological substances that can reduce the production of a specific gene/protein. Biogen and Ionis Pharmaceuticals partnered to advance ASOs therapies and chose as their first target superoxide dismutase 1 (SOD1); the first gene discovered to cause ALS/MND in 1993. A small change in the composition of the SOD1 gene leads to an abnormal SOD1 protein. Over the years, it was determined that this abnormal protein causes ALS/MND by becoming toxic to motor neurons (in jargon, toxic gain of function).
| Approved in: | Commercial Name: |
| Bahrain | Qalsody |
| Canada | Qalsody |
| Chile | Qalsody |
| China | Qalsody |
| European Union | Qalsody |
| Japan | Qalsody |
| Oman | Qalsody |
| Spain | Qalsody |
| Qatar | Qalsody |
| United Arab Emirates | Qalsody |
| United States | Qalsody |
Proposed Mechanism of Action
Tofersen’s (commercial name Qalsody) active ingredient is a small, lab-made piece of genetic material (ASO) designed to stick to a specific RNA molecule in a cell, causing, in this case, a lower expression of SOD1. This therapeutic strategy was thought as a logical treatment for SOD1 linked ALS/MND given SOD1 toxic gain of function mechanism.
Clinical Trials
A phase 1-2 clinical trial of tofersen (the SOD1 ASO) with 50 participants started in 2016 at 17 sites in the United States, Europe and Canada with the goal of assessing safety, tolerability and of its effect inside the human body. The study showed that the compound was safe and was effectively reducing the expression of SOD1. Furthermore, there was a trend towards slowing of disease progression in three different measures of ALS/MND progression. Results were published in the New England Journal of Medicine in July 2020.
Based on the promising phase 1-2 trial, in April 2021, Biogen announced the intent to offer a first stage of early access to a subset of individuals affected by SOD1-ALS beginning with individuals who have the most rapidly progressive disease. This program began in July 2021 and was called VALOR. The second stage, aimed at providing access to the broad SOD1-ALS population would be triggered by phase 3 study results that indicate safety and efficacy, yielding no need for additional studies.
On October 17, 2021, six months after the start of the VALOR trial, a presentation and press release described the results of the study indicating that tofersen did not demonstrate statistical significance in the primary measure of disease progression as measured by the ALSFRS-R. However, multiple secondary and exploratory measures of motor function, respiratory function, muscle strength and quality of life suggested the potential of a positive effect. Reduction in SOD1 levels resulting in a statistically significant reduction in CSF neurofilament light chain levels (NfL) was also observed, suggesting potential perseveration of neuronal health.
On June 3, 2022, additional 12-month open label extension (OLE) data was presented, demonstrating a more robust effect for all participants originally treated with tofersen in the first six months (termed “early-start”) as compared to those on placebo (termed “delayed-start”). Reduction of target SOD1 levels was sustained in months 6-12 of the OLE and plasma NfL levels in the delayed-start group were reduced to levels of the early start group. ALSFRS-R was significantly higher in the early-start group after twelve months of OLE, as is respiratory function, muscle strength and two quality of life questionnaires. The data also indicated a trend towards stabilized or improved functions during months 6-12 in the delayed-start group, as well as effect on survival in the early-start group. Results from the VALOR study were published in the New England Journal of Medicine on September 21 2022.
On July 26, 2022, the U.S. Food and Drug Administration (FDA) accepted Biogen’s New Drug Application for tofersen and granted it Priority Review. On April 25th, the FDA granted accelerated approval to Biogen’s tofersen, now named Qalsody, for the treatment of those cases of MND/ALS associated with mutations in the SOD1 gene. The conditional approval means that Biogen will be required to continue to collect data on the effects of the treatment and report to the FDA any concerns around ongoing effectiveness. On May 30th 2024, the European Medicine Agency (EMA) granted market approval for Qalsody under ‘exceptional circumstances’. Biogen will need to provide further data to the EMA on the long term effectiveness and safety of their compound.
Qualsody is the first approved disease modifying treatment that targets a genetic cause of ALS.
Early Access Program
Since 2021, Biogen has “expanded eligibility for its ongoing early access program to all people with SOD1-ALS, in countries where such programs are permitted by local regulations and future access may be secured.” Individuals with an ALS diagnosis associated with a mutation in the SOD1 gene are eligible to receive tofersen free-of-charge provided their clinician is able to prescribe and deliver the treatment. The EAP program has been discontinued in the US following FDA approval of Qalsody and it will be discontinued in those countries in the EU where tofersen is commercially available (source here).
Biogen has also initiated the ATLAS study in 2021 to determine if pre-symptomatic treatment of SOD1 mutation carriers may represent more optimal timing of intervention. Given that individuals with SOD1 mutations can be recognized as at-risk of developing ALS through genetic testing prior to onset of symptoms, tofersen represents a tremendous opportunity to determine if treatment in pre-symptomatic individuals could provide a more robust effect on disease progression. Please find more information regarding the ATLAS trial here.
Dose and Administration
Qalsody is delivered directly in the cerebrospinal fluid with a spinal injection (intrathecally). Because its delivery requires highly specialized personnel and close monitoring, it can only be delivered in a healthcare facility equipped for intrathecal administration. The recommended dose is 100 mg/15 mL per administration. The treated individual will receive a dose every two weeks for three times and then a maintenance dose once every four weeks.
Reported Side Effects
The most common side effects of Qalsody are: pain in the arm, back, legs, muscle or joints; increased level of proteins and/or blood cells in the cerebrospinal fluids and fever. More serious side effects include: Inflammation of the spinal cord (myelitis) and/or irritation of the nerve roots (radiculitis), swelling of the optic nerve (papilledema) and increased pressure inside the skull (elevated intracranial pressure), inflammation of the brain linings (aseptic meningitis.)
Real-world Evidence
Real-world evidence is the clinical evidence about the usage and potential benefits or risks of an approved medical treatment. This is usually obtained from data derived from electronic health records, medical claims, or registries during delivery of health care (outside of well-controlled clinical trial). Several studies across the world have been following people with ALS/MND carrying SOD1 mutations who have been treated with tofersen (Qalsody). A recent study from Smith et al., reported real world experiences of seven people diagnosed with SOD1-ALS who were treated with Qalsody at Washington University in Saint Louis from November 2021 to February 2024. During the treatment period, all participants experienced “robust and sustained declines” in blood levels of neurofilament light chain (NfL is a biomarker of damaged or degenerating neurons). Researchers estimated that the participants progressed at a rate 52% slower than expected following treatment with Qalsody. In addition, muscle strength improved for five of the study participants with “notable” (non-quantifiable concept) improvement in “functional independence.”
Disease stabilization and functional improvements have also been reported by clinicians conducting similar research in Europe. In Italy, out of 17 people with SOD1-ALS who were treated for at least four years, nine substantially stabilized or slightly improved, while four had such a slow progression that their disease trajectory did not allow the researchers to identify changes. Published data from Germany showed that five people who took part in a Qalsody early access program began to stabilize or improve after four to six weeks of treatment. One person improved by nine ALSFRS-R points, an outcome the researchers directly attributed to the treatment.
For decades, the general consensus among neurologists and neuroscientists has been that ALS/MND treatments would only be able to slow down or stop further progression of the disease. Function that had already been lost would probably not be recovered. Qalsody real world data are showing that functional improvement is possible and provide hope for all people living with ALS/MND.
Summary
Qalsody (tofersen) has been approved by the FDA and EMA for use in the US and EU for MND/ALS patients carrying SOD1 mutations. Based on the available evidence, it is the opinion of the SAC that tofersen is likely to have a significant benefit for people living with ALS/MND caused by a mutation in the SOD1 gene, particularly in those starting treatment earlier.
The pre-symptomatic ATLAS trial is an important next step in the evaluation of tofersen for SOD1-ALS, both as the confirmatory trial for the accelerated approval conditions and as a landmark for all future ALS trials.
Biogen should continue to explore options that could provide access to people living with SOD1-ALS who stand to benefit from tofersen as indicated by detailed analysis of the data presented to date. The SAC encourages any member organization to reach out to the company directly to enquire whether any plans exist for their country or region.
The SAC welcome a new addition to the treatment options for MND/ALS patients and hope that this treatment becomes available to as many patients as possible.
International Alliance of ALS/MND Associations
August 2024
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.