An antisense oligonucleotide (ASO) that blocks production of the superoxide dismutase 1 (SOD1) protein is not statistically superior to placebo in slowing functional decline at 6 months in patients with amyotrophic lateral sclerosis (ALS) and a SOD1 mutation, new top-line results from a phase 3 study show.
However, although the study of tofersen (Biogen) did not meet its primary endpoint, results of several secondary endpoints signal a positive impact on the rate of neurodegeneration and other outcomes.
“The effects became more apparent with longer term follow-up in the extension study,” said study investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University School of Medicine, St Louis, Missouri.
“In general, you see that both being treated earlier and being treated longer have a greater effect on clinical function.”
The findings were presented here at the virtual ANA 2021: 146th Annual Meeting of the American Neurological Association.
Phase 3 Trial
About 5000 new cases of ALS are diagnosed every year in the US and this is expected to increase.
SOD1 gene mutations were the first genetic causes of ALS to be identified. Dominantly inherited SOD1 mutations are implicated in about 2% of all ALS cases.
These mutations create a defective SOD1 protein that fails to help clear toxins from the brain. The SOD1 protein clumps together, damaging the nervous system and leading to ALS symptoms.
The exact mechanism by which gene mutations cause degeneration of motor neurons is not completely understood, but tofersen is designed to block production of the SOD1 protein.
An earlier phase 1/2 clinical trial showed the treatment was safe and lowered SOD1 levels in the cerebral spinal fluid (CSF) in 50 ALS patients, and suggested it may slow ALS progression.
This new phase 3 study (VALOR) included 108 adult patients with muscle weakness attributable to ALS and a documented SOD1 mutation.
Participants were randomly assigned to receive tofersen 100 mg or placebo for 28 weeks. Both the drug and placebo were administered intrathecally. In an open-label extension (OLE) study, all patients received tofersen 100 mg.
The study looked at both “faster progressing” and “slower progressing” participants.
The primary endpoint was change in total score on the ALS Functional Rating Scale–Revised scale. This 48-point scale has four subdomains: fine motor, gross motor, bulbar function, and breathing.
Secondary endpoints included breathing and strength. Researchers also examined fluid biomarkers including total cerebrospinal fluid SOD1 and plasma neurofilament light (NfL).
A key exploratory endpoint was patient reported quality of life on the five-item ALS Assessment Questionnaire.
Both the faster and slower patients declined in function in the two study groups. The change among fast progressors in the placebo group was –8.14 vs –6.98 in the treatment group, for a difference of 1.2 (P = .97).
“There was relatively little difference and no statistical difference between the groups treated with tofersen versus treated with placebo,” said Miller.
However, he noted that in time, earlier initiation of tofersen “led to a slowing of decline in faster progressing participants and an apparent stabilization of clinical function in slower progressing participants.”
Levels of SOD1 in the CSF were significantly reduced in treated subjects vs placebo in fast progressors (P < .0001), suggesting target engagement. “It’s clear SOD1 is lowered by tofersen,” said Miller.
Noteworthy Drop in Disease Biomarker
Plasma NfL levels fell both in the rapid (by about 60%) and slowly progressing groups. Miller called this a “really impressive effect” on this marker of neuronal degeneration.
Once the placebo group received treatment, their NfL levels dropped, “but perhaps not to the same extent as those who were treated initially with tofersen,” noted Miller.
As for respiratory function, there was a trend in the rapidly progressing group toward stabilization of slow vital capacity (SVC), “and there may be some stabilization of the breathing in the open-label extension,” said Miller.
For patient-reported outcome, again, there may be some stabilization, said Miller.
There was very little difference between the treatment and placebo groups in terms of muscle strength.
He noted the “greater separation of tofersen and placebo as you look out at the longer timeframe” in the extension study, reflecting “effects on multiple different secondary endpoints.”
Almost all study subjects had at least one treatment emergent adverse event (AE), mostly mild to moderate in severity. Many events, such as falls, were consistent with ALS progression, or were related to the lumbar puncture procedure, such as headache or pain.
Some subjects treated with tofersen had a serious neurological AE, including two cases of myelitis; there were no similar events in the placebo group.
Many in the tofersen group had treatment-emergent CSF abnormalities. Changes included “a shift to high leukocytes and shift to high protein,” said Miller. “These are events we will continue to monitor closely.”
During a question-and-answer session, Miller said he doesn’t think a stronger level of SOD1 “knockdown” is needed. He pointed to the “substantial” reduction in the study, which indicates the drug is affecting the disease process. As well, there should be “much more substantial” lowering of levels in the spinal cord and brain stem, he said.
Miller noted the reduction in NfL levels was noteworthy. Typically levels of this biomarker go up and stay elevated in ALS. “I’m not aware of other studies that showed a major change in NfL in ALS,” he said.
Early Treatment Better?
Session moderator Bryan Traynor, MD, PhD, Laboratory of Neurogenetics, National Institute on Aging, asked if the lesser treatment effect in those initially receiving placebo hinted at the need for early treatment.
“This therapy is not going to bring back motor neurons; the idea is it would stabilize” disease progression, said Miller. “So wherever you are when you start it, you’re not going to get back the motor neurons, so earlier is always going to be better.”
Asked about gender differences in outcomes, Miller said he and his colleagues are now “digging into” responder analyses.
Queried about next steps, and possible filing with the FDA, Miller said that at this time he was “not able to comment on regulatory or those next steps.”
The study was funded by Biogen. Miller disclosed advisory board and clinical research support for Biogen; licensing agreement with, consultant for, and reagent for Ionis Pharmaceuticals Inc; consultant for Cytokinetics; consultant for UCB Pharma; and consultant for Disarm Therapeutics. Traynor disclosed no relevant financial relationships.
ANA 2021: 146th Annual Meeting of the American Neurological Association. Presented October 17, 2021.