The VALOR study was a 3-part trial to examine the efficacy, safety, tolerability, PK (pharmacokinetics) and PD (pharmacodynamics) of BIIB067 (tofersen). Part A was the single ascending dose (SAD) component of the study, Part B was the multiple ascending dose (MAD) component of the study and Part C was the fixed dose component of the study. Hence, the overall phase of development of the study was 1/2/3. In total, the study enrolled an estimated 183 participants, with 99 in Part C.
Approximately 10 percent of all ALS cases are genetic and about a fifth of those are caused by SOD1 gene mutations, which is the second most common cause of genetic ALS. Tofersen is an antisense oligonucleotide, that works by targeting and reducing protein created by mutated SOD1. The mutated protein is toxic and leads to ALS by damaging the nerve cells that control movement. Tofersen aims to decrease the production of the mutant protein.
Parts A and B were completed in Jan 2019. Analysis of this data showed promising results which were announced in May 2019.
This component of the study involved 50 people with ALS who had an SOD1 genetic mutation. Participants received five doses of either 20, 40, 60 or 100 milligrams (mg) of the experimental drug or a placebo, through a lumbar puncture, or spinal tap, over approximately 3 months. Researchers examined the safety, dosage and exploratory efficacy of the experimental drug.
Researchers found that the 10 people who were given 100 mg of the experimental drug had a 37 percent reduction of the SOD1 protein in spinal fluid when compared to 12 people who received the placebo.
Consequently, Biogen initiated Part C which was a phase 3 clinical trial. The trial enrolled 108 people with SOD1 ALS. The trial lasted 32 weeks and participants received 8 doses of the drug or a placebo. There was a 1-in-3 chance of being assigned to the placebo group.
On 17 October 17 2021, Biogen announced the results of the phase 3 VALOR study, indicating that while tofersen did not demonstrate statistical significance in the primary measure of disease progression, as measured by the ALSFRS-R, 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 correlating with a statistically significant reduction in CSF neurofilament light chain levels (NfL) also suggest potential perseveration of neuronal health. Further analysis of the trial data by the scientific and medical community will be necessary to better understand these complex results and how they correlate to a potential for a clinically meaningful effect in people living with ALS caused by mutations in the SOD1 gene.
Biogen also announced their intent to continue with “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.” Biogen stated that they may revise or discontinue this program if no clear path forward is established for tofersen, or if another trial is required.
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.
Although the primary endpoint was not reached, the promising secondary endpoint data support the potential for tofersen to provide some benefit to patients. It may well be that the drug needs to be administered earlier in disease or may require a longer timeframe to show true disease modification.
The expanded access program will enable longer term data on effectiveness to be gathered. The ATLAS study will show us if the drug is effective when administered early in disease. For now, the data requires further analysis.
People with symptomatic SOD1-ALS are eligible for consideration in the Biogen Tofersen Expanded Access Program. Applications for access to the program must be made through your neurologist. MND patients cannot apply directly themselves.
We expect recruitment for the ATLAS study in Australia for pre-symptomatic treatment of SOD1 mutation carriers to begin shortly. Further information on the ATLAS trial is available here.