In an open-label extension of a Phase III clinical trial sponsored by the pharmaceutical company Biogen, investigators have shown that the use of the drug tofersen for one year may help stabilize muscle strength and motor control in patients with an inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. At only six months, however, tofersen did not improve clinical symptoms, even though molecular signs of the disease were improved.

“[T]he 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,” explained Timothy Miller, MD, PhD, professor of neurology and codirector of the ALS Center at the Washington University School of Medicine in St. Louis. Miller led an international team of researchers on the study, which they published in The New England Journal of Medicine in the article “Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.”

Tofersen is an antisense oligonucleotide that is designed to block production of the SOD1 protein. In about two percent of ALS patients, the SOD1 gene is mutated, creating a misfolded version of the SOD1 protein that, in turn, leads to ALS.

The Phase III clinical trial included 108 ALS patients, all with mutations in the SOD1 gene. Two-thirds (72) of the participants were randomly assigned to receive eight doses of tofersen over a 24-week period, administered directly into the fluid surrounding their spinal cords. The remaining 36 participants received eight doses of a placebo. All participants underwent assessments at enrollment and at 28 weeks to measure motor function. They also gave samples of cerebrospinal fluid (CSF) and plasma so the researchers could measure levels of SOD1 and neurofilament light protein, a molecular marker of neurological damage.

“Tofersen led to greater reductions in the total SOD1 protein concentration in CSF and in the concentration of neurofilament light chains in plasma than placebo,” the investigators wrote in their article, but “clinical end points did not differ significantly between the tofersen group and the placebo group.”

When the trial ended, 95 of the participants continued into the open-label extension that will last up to four and a half years. All participants in the extension receive tofersen.

An analysis six months into the extension revealed a significant difference in motor function between those who had been on tofersen from the beginning, and those who had received a placebo for six months before starting tofersen. After a year on the drug, participants showed a stabilization of muscle strength and control—a remarkable finding, according to researchers.

“Most of the ongoing participants at our site have regained and/or maintained a number of their activities of daily living,” said Robert Bucelli, MD, PhD, who cared for 10 participants as Washington University’s site leader for the clinical trial. “[O]ur exams and strength measurements corroborate their history of improvement, stabilization, or both.”

“The vast majority of people living with ALS experience a relentlessly progressive downhill course, so the stabilization of function during the open-label extension is truly remarkable,” Miller added. “We see clear evidence that [tofersen] slows down the initiating factor—a SOD1 mutation—as well as the neurodegenerative disease process.”

Although the results of this trial only apply to people with ALS caused by mutations in SOD1, they could inform research that may benefit people with other forms of the disease. “I think this is hopeful news for people with any form of ALS,” Miller said. “It tells me that if we find the right therapy, we can change the course of the disease. We just need to find the right therapy.”

The open-label extension is ongoing, and researchers continue to monitor the participants’ motor function. In July, the Food and Drug Administration accepted Biogen’s new drug application for tofersen as a treatment for ALS linked to SOD1 mutations.

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