Early Tofersen Treatment May Help to Slow SOD1-ALS Progression

Tofersen reduced toxic SOD1 protein and NfL marker of nerve cell damage

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Early treatment with Biogen’s experimental therapy tofersen slows disease progression in people with amyotrophic lateral sclerosis (ALS) associated with SOD1 gene mutations, compared with patients who started treatment after a six-month delay, according to findings from a Phase 3 trial and its open-label extension study.

These benefits were accompanied by sustained reductions in levels of SOD1 and neurofilament light chain (NfL), a marker of nerve cell damage.

The updated findings from the VALOR Phase 3 trial (NCT02623699) and its open-label extension study (NCT03070119), were recently published in The New England Journal of Medicine (NEJM). The study, “Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS,” was funded by Biogen.

“The ALS community has been actively pursuing new medicines for decades,” Merit Cudkowicz, MD, co-principal investigator of VALOR and professor at Harvard Medical School, said in a Biogen press release. “To have data like these published in NEJM gives us energy and hope. We are now seeing in the data what we suspected about tofersen for a long time — that it has the potential to make a clinical difference for people living with SOD1-ALS.”

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What is tofersen designed to do?

Mutations in the SOD1 gene are found in as many as 20% of people with familial ALS, and up to 2% of sporadic ALS patients. Tofersen is an RNA-based therapy designed to reduce levels of toxic SOD1 protein made by the mutated gene.

Biogen’s application for tofersen is currently under the U.S. Food and Drug Administration’s accelerated approval pathway, which may grant conditional approval based on early clinical data. A decision is expected in early 2023.

The company’s application was supported in part by data from the Phase 1/2/3 VALOR trial and its open-label extension. In the Phase 1/2 portion of VALOR, scientists showed that single- and multiple-ascending doses of tofersen were generally well-tolerated and reduced toxic SOD1 levels in people with ALS.

The Phase 3 part then enrolled 108 adults with SOD1-ALS — including 60 patients who were predicted to have fast-progressing disease — at 32 centers across 10 countries.

After a four-week screening period, participants were randomly assigned to receive 100 mg of tofersen or a placebo, for 24 weeks (about six months). Treatment was administered by injection into the spine every two weeks for the first three doses, and every four weeks for the next five doses.

A total of 95 participants who completed the placebo-controlled portion chose to enroll in the trial’s open-label extension, where all receive tofersen for up to seven years.

The main goal of the Phase 3 trial was to determine if tofersen could slow functional decline, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R), in the 60 fast-progressing patients after 28 weeks.

Although ALSFRS-R scores declined slightly less in the tofersen group than among those given a placebo (a mean of 6.98 vs. 8.14 points), the difference was not statistically significant. Other secondary measures of disease progression, such as lung function, muscle strength, and time to death or permanent ventilation, also were not different between the two groups.

What were the significant findings of the VALOR Phase 3 trial?

However, the treatment reduced the amount of SOD1 protein in the fluid around the brain and spinal cord by 29% in fast progressors, compared with a 16% increase for the placebo group. NfL blood levels also decreased by 60% in these tofersen-treated patients, but increased by 20% in those on placebo.

“The lowering of neurofilament, a marker of [nerve fiber] injury and neurodegeneration along with the clinical data, highlights the potential of tofersen,” Cudkowicz said.

In January 2022 (the time of data cutoff), 67 patients were still receiving tofersen in the open-label extension. Of them, 49 had been assigned to the medication in the original VALOR trial — the early-start group — while the remaining 18 had first been on the placebo and switched to tofersen upon entering the extension study — referred to as the late-start group.

After one year, patients who started treatment earlier experienced an average six-point decline in their ALSFRS-R scores, as compared with 9.5 points in those who started tofersen six months later — a significant difference.

The decline in lung function also was significantly lower in the early-start group compared with the late-start group (9.4% vs. 18.6%). Muscle strength measures also showed a significant difference favoring the early-start group (a decline of 0.17 vs. 0.45 points).

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Median survival times could not be estimated because most patients were alive at the time of the analyses, but available data indicated that the time to death, and time to death or permanent ventilation were significantly reduced by more than 60% in those who started treatment earlier.

“I see three key take home points from these data,” said Timothy Miller, MD, PhD, principal investigator of VALOR from Washington University School of Medicine. “First, tofersen clearly leads to lowering of SOD1 protein, as would be expected. Second there is substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process. And third, there is a meaningful clinical benefit when looking at the later time points in the open label extension.”

The fact that significant effects were seen in data from the extension study after one year, but not the primary analysis at 28 weeks, “suggests that a trial duration of more than 28 weeks may be required to determine the effect of tofersen in patients,” the researchers noted.

Among tofersen-treated patients, 7% experienced serious neurological side effects such as myelitis (spinal cord inflammation). The most common side effects related to treatment included headache, procedural pain, and pain in the limbs and back.