Tofersen Fails to Slow SOD1-ALS in VALOR Trial, But Hopeful Trends Seen
Tofersen, an experimental treatment for amyotrophic lateral sclerosis (ALS) patients with mutations in the SOD1 gene, failed to significantly slow the rate of disease progression relative to a placebo in a Phase 3 trial.
These top-line findings mean that the VALOR study (NCT02623699), which is testing tofersen in 108 adults with SOD1-ALS, did not meet its primary goal. Trends favoring tofersen were seen across other measures, however, including assessments of muscle strength, life quality, and lung function.
“The disappointment that will be felt amongst the [ALS] community  is tinged with some encouragement  that  the  trends in  the secondary  measures are consistently heading in the right direction,” Brian Dickie, PhD, director of research development at the MND Association, said in a press release.
Biogen, the company developing tofersen, is in communication with regulatory agencies and other stakeholders to determine likely next steps for tofersen’s development.
As previously announced, the company will now expand its ongoing early access program to include the broader SOD1-ALS population in countries where such programs are allowed and access to the medication can be ensured. To date, only patients with very rapidly progressing disease were able to acquire the medication through this compassionate use program.
“Following discussions with investigators, bioethicists, and having listened to the voice of patient advocacy groups, we will broaden early access to tofersen to all eligible SOD1-ALSÂ patients through our already established expanded access program,” Alfred Sandrock, Jr., MD, PhD, head of research and development at Biogen, said in a separate release.
Mutations in the SOD1 gene account for up to 20% of cases of familial ALS, and up to 2% of sporadic disease cases. Tofersen is an RNA-based medication designed to reduce production of the abnormal SOD1 protein originating from the mutated gene.
VALOR is an international, placebo-controlled, pivotal Phase 1/2/3 trial that tested tofersen in ALS patients with SOD1 mutations. In its Phase 1/2 portion, the therapy was found to be generally safe and significantly lowered SOD1 levels in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord.
The Phase 3 part enrolled 108 patients, who were randomly assigned to eight spinal canal injections of tofersen (100 mg) or a placebo, given over six months. Among participants, 60 had rapidly progressing disease, while the remaining 48 had slower-progressing disease.
Its main goal was to assess the effects of 28 weeks of treatment on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, a measure of disability, among people with rapidly progressing disease. Results showed no significant difference in these scores between those given tofersen or placebo.
But trends toward benefits with tofersen — while not statistically significant — were seen for some secondary measures, including slow vital capacity (a measure of lung function) and hand-held dynamometer (a measure of muscle strength). Similar trends were evident in patient-reported measures of disease severity, quality of life, and fatigue.
Notably, total levels of SOD1 protein in the CSF were markedly lower among treated patients than those on a placebo — by 38% and 26% in the faster- and slower-progressing groups, respectively. A similar difference was seen for levels of neurofilament light chain (NfL), a marker of damage to brain cells.
“The results from the VALOR study are encouraging as they show reduction of SOD1 protein, reduction of neurofilament, a potential biomarker for neurodegenerative disease, and positive signals across multiple key endpoints including measures of important aspects of the daily lives of SOD1-ALS patients,” said Timothy Miller, MD, PhD, principal investigator of VALOR and director of the ALS Center at Washington University School of Medicine in St. Louis.
Of the 108 patients enrolled in VALOR, 95 decided to move into its ongoing, open-label extension (NCT03070119),where all are receiving tofersen. This study is due to end in June 2024.
Analyses of data from VALOR and the extension study indicate that people who started on tofersen earlier in the disease course tended to have better long-term outcomes, according to Biogen.
“Data from the tofersen Phase 3 study and its open-label extension showed signs of slowing disease progression in people with SOD1-ALS,” Sandrock said.
“There  are questions that need to be addressed, on whether  the drug  needs  to be given  earlier  in the disease  and over a longer  time  period, as well as whether the  levels of  the toxic  SOD1  protein  are still too high and need to be knocked down  even more,” Dickie said.
The most common adverse events (side effects) reported in tofersen-treated patients were headache, pain in extremities, back pain, falls, and pain related to treatment administration.
Most adverse events were mild to moderate in severity; serious adverse events occurred in 18.1% of patients on tofersen and 13.9% of those on placebo. In the tofersen group, 5.6% of participants discontinued treatment due to an adverse event, while none in the placebo group did. One tofersen-treated patient died during the study, but the death was determined to be unrelated to treatment.
Biogen is currently running another study, called ATLAS (NCT04856982), testing tofersen in people with SOD1 mutations who have not yet developed ALS but show elevated NfL levels. This study is actively recruiting adults at sites in the U.S., Canada, Europe, Asia, Brazil, and Australia.
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