By Roz Plater on April 26, 2023 — Fact checked by Michael Crescione

The Food and Drug Administration (FDA) has approved the drug toferson as a treatment for people with a rare genetic form of amyotrophic lateral sclerosis (ALS).

The regulators are requiring the drug’s manufacturer, Biogen, to continue testing toferson on people who have a gene mutation that causes this type of ALS but haven’t developed symptoms yet of the disease.

ALS, also known as Lou Gehrig’s disease, is a fatal neurological disease that targets nerve cells in the spinal cord and brain. As the disease progresses, people with ALS lose control of the muscles they need to move, speak, eat, and breathe.

About 2% of people living with ALS globally have a mutation in a gene called superoxide dismutase 1 (SOD1)

In the United States, it’s estimated this form of ALS affects about 330 people.

What to know about the new drug tofersen

The drug tofersen targets the genetic mutation by stopping toxic SOD1 proteins from being made.

Tofersen was tested in a phase three clinical trial called VALOR. The trial spanned 28 weeks with 108 participants from 10 countries. The drug is injected via lumbar puncture into the spinal canal.

Researchers concluded that tofersen reduced concentrations of SOD1 and reduced another protein called neurofilament light (NFL) over the 28 weeks.

However, they said it “did not improve clinical end points and was associated with adverse events.”

Dr. Timothy Miller is a professor of neurology and the director of the Miller Lab and the ALS Center at the Washington University School of Medicine in St. Louis, Missouri.

He is also the principal investigator in the Tofersen trial. He has been involved in the research of the drug for more than two decades. The trial was sponsored by Biogen, but Miller is an independent researcher.

“It (tofersen) did not achieve statistical significance on the difference between placebo and drug at 28 weeks. There is a hundred percent agreement on that,” Miller told Healthline.

“But if you look at it at 52 weeks… now you see statistically significant differences that are much more clear and stabilization of function,” he added.

Miller says researchers discovered that the testing period didn’t include healing time.

“I think we didn’t know that at the time that we started. You can think of it as putting the fire out… stopping the neurogen disease process. But then it takes time for the neurons to heal to be able to renovate the muscles to show that effect on quality of life, to show the effect on strength,” Miller explained.

Still, he believes the drug is effective.

“I’m clearly convinced by the clinical effects and the data,” he said. “I witnessed the changes we’ve seen and people living with ALS.”

“Improvement is extremely rare in ALS… It’s a relentlessly progressive downhill course” he added. “I’m very much hoping that this will be available for people with SOD1 mutations.”

How FDA approval works

In March, the FDA panel of outside advisers made a two-part recommendation.

The group voted unanimously that tofersen had a clinical benefit in reducing the so-called NFL protein associated with severity of the disease.

However, in a 5-to-3 vote with one abstention, the panel voted against the effectiveness of the drug to treat the SOD1 version of ALS.

The FDA wasn’t bound by the recommendation from its board of advisors. The agency had three options.

It could have either given the drug full approval, it could not approve it, or it could give it an accelerated approval.

That last option was the route the FDA took, meaning Biogen will have to conduct those further studies to verify the clinical benefits for the drug to stay on the market.

Dr. Santosh Kesari is a neurologist at Providence Saint John’s Health Center in Santa Monica, California, and the regional medical director for the Research Clinical Institute of Providence Southern California.

“We don’t have enough testing time or testing data,” he told Healthline. “I think if the study was designed to some preset goals… and they’re not met… then it’s hard for the FDA to approve it.”

“I think the most intriguing part was the NFL… the neurofilament light where they saw that patients who got the drug, their NFL levels went down compared to the placebo group where it actually went up,” Kesari explained. “The NFL is thought to be a good marker of brain damage or neuronal damage as a surrogate for impacting neurodegenerative diseases in general.”

Expanding access to ALS drug

Some people are getting treated with tofersen through an “expanded access.”

That allows people to get the drug outside of a clinical trial.

Dr. Neil Shneider is the director of the Eleanor and Lou Gehrig ALS Center and Director of the ALSA/ALS Clinic at Columbia University in New York.

Shneider has had about a half-dozen patients receiving tofersen under the expanded access program and says he has seen the benefits.

“People I have treated have done much better than their family members with the same mutation. In my opinion and limited experience with the drug, it slows progression, it slows the rate at which function is lost,” he told Healthline.

“It extends people’s mobility and function. And that of course translates into an improved quality of life. People live more independently, they live better longer on the drug, in my opinion,” Shneider added

“Not everybody is going to have the same outcome… People will respond differently to this drug depending on the specific mutation and nature of their disease,” he added.

Looking to the future for ALS treatment

Shneider says he suspects that further tests may prove the drug to be effective.

“I think that a trial that was properly designed, based on the knowledge now that we have about tofersen and about the timing of its effects… I think would demonstrate its efficacy. I’m confident in that,” Shneider said.

“But I think we need to get this drug to ALS patients and families and continue to work to provide whatever additional evidence is needed to effect full approval,” he added.

He also says families who have someone with the SOD1 version of ALS should take note.

“If they’ve lost family members with this, I would encourage them to get predictive testing and genetic counseling to be prepared” he explained. “Ultimately I believe these approaches are not just for people who already have the disease, symptomatic individuals… but for pre-symptomatic individuals at risk.”

Biogen is currently conducting an ATLAS study. The goal is to determine if tofersen might delay the onset of symptoms or the decline in function with people who carry the SOD1 gene mutation.

Original Article