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Tofersen, an investigational antisense oligonucleotide developed to treat an inherited form of amyotrophic lateral sclerosis (ALS), changed biomarkers and curbed neurodegeneration but did not improve motor control and muscle strength at 6 months, the trial showed.

In a subgroup of patients with fast-progressing SOD1 ALS, the 28-week change in scores on the ALS Functional Rating Scale-Revised (ALSFRS-R) was -6.98 points with tofersen and -8.14 points with placebo (difference 1.2 points, 95% CI -3.2 to 5.5, P=0.97), reported Timothy Miller, MD, PhD, of Washington University in St. Louis, and colleagues.

The drug led to greater reductions in superoxide dismutase 1 (SOD1) protein in cerebrospinal fluid and plasma neurofilament light protein (NfL), a marker of neurodegeneration, the researchers wrote in the . Secondary clinical endpoints did not differ significantly between the two groups.

Data from the open-label extension, however, suggested that long-term use of tofersen may have clinical benefits.

Of 95 study participants who entered the -- some of whom were originally assigned to placebo (the delayed-start cohort) -- the change in the ALSFRS-R score at 52 weeks was -6.0 points for early starters and -9.5 points for delayed starters (difference 3.5 points, 95% CI 0.4-6.7). Differences favoring early-start tofersen also emerged for secondary endpoints.

"We see clear evidence that the drug slows down the initiating factor -- a SOD1 mutation -- as well as the neurodegenerative disease process," Miller said in a statement.

"We didn't see substantial clinical improvement at 6 months, but the stabilization in function and strength at longer time points suggests it may take time for people to heal from the damage that has already been caused," Miller observed.

Around 2% of ALS cases are caused by mutations in SOD1. Neuronal degeneration in SOD1 ALS is considered to be caused by of the mutant SOD1 protein.

Tofersen mediates the degradation of SOD1 messenger RNA to reduce SOD1 protein synthesis. It was previously studied in a of SOD1 ALS patients. In July, drug maker Biogen announced that the and granted priority review for tofersen in SOD1 ALS.

VALOR was conducted at 32 sites in 10 countries and included 108 SOD1 ALS patients. Participants had assessments at baseline and 28 weeks to measure function in the four ALSFRS-R subdomains: bulbar, fine motor, gross motor, and breathing. (Total scores on the ALSFRS-R range from 0 to 48, with higher scores indicating better function.)

The primary endpoint was the change from baseline to week 28 on the ALSFRS-R among a subgroup of participants predicted to have faster-progressing disease. Overall, 72 people (including 39 with fast-progressing disease) received eight doses of intrathecal tofersen over a 24-week period, and 36 people (including 21 with fast-progressing disease) received placebo.

Baseline clinical characteristics were similar in the two trial groups for use of riluzole (Rilutek), edaravone (Radicava), or both; time from onset of disease symptoms; baseline mean ALSFRS-R score (approximately 37 in each group); and percentage of predicted slow vital capacity.

Baseline concentrations of NfL were 15% to 25% higher in the tofersen group. The rate of decline in the ALSFRS-R score from screening to day 15 (approximately 42 days) was also greater in people who received tofersen.

Neurologic serious adverse events occurred in 7% of tofersen recipients and included myelitis, chemical or aseptic meningitis, lumbar radiculopathy, increased intracranial pressure, and papilledema.

In a prespecified combined analysis of VALOR and open-label extension participants at 52 weeks, people who started tofersen at the beginning of VALOR -- regardless of fast or slow progression -- had a smaller numeric decline in ALSFRS-R scores, the percentage of predicted slow vital capacity, and handheld dynamometry megascores compared with those who started tofersen in the open-label extension 28 weeks later.

"Limitations in interpreting the results of the combined analysis include the absence of adjustment of the widths of confidence intervals for multiple comparisons in the analysis of differences between the early-start and delayed-start cohorts, approximately 20% of missing endpoint data that required imputation, and the results of the VALOR component of the trial being known at the time of analysis," Miller and co-authors acknowledged.

"The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the ongoing extension phase," they wrote.

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