Late last year, Biogen disclosed results from a closely watched study evaluating an experimental drug for Lou Gehrig’s disease, also known as ALS or amyotrophic lateral sclerosis. They showed the drug, called tofersen, wasn’t better than a placebo at slowing progression of the fatal nerve disorder, dealing yet another blow to patients and caregivers, who currently have very limited treatment options.
Despite those results, Biogen recently submitted an approval application to the Food and Drug Administration and on Tuesday, the company announced the agency has agreed to review it on an expedited basis. Biogen had not previously disclosed its submission.
A verdict on approval is expected by Jan. 25, the company said.
The FDA’s decision to review comes a little more than a year after it granted approval to another Biogen drug with a mixed track record in clinical testing. Last June, the drug, which is now sold as Aduhelm, became the first in the U.S. cleared to treat Alzheimer’s disease itself rather than its associated symptoms. While historic, the approval was also exceedingly controversial, and Biogen has since all but scrapped Aduhelm as a product because of challenges getting doctors to prescribe it and insurers to pay for it.
With an application under review, tofersen could present another test of the FDA’s flexibility on drugs that have failed to generate the evidence typically needed for approval — and, especially, those targeting brain and nervous system disorders with few treatment options.
Biogen is asking for what’s known as an accelerated approval, which is based on a drug’s impact on a biomarker that’s “reasonably likely to predict clinical benefit.” In tofersen’s case, approval hinges on the apparent effect it has on a protein that’s of increasing interest in ALS research.
When levels of this “neurofilament light chain” protein are elevated in the blood or the fluid around the brain and spine, it’s a likely indicator of neurological damage. “In ALS in particular, the levels are quite high,” Toby Ferguson, head of the neuromuscular development unit at Biogen, said in an interview.
According to the company, the data gathered so far show that patients treated with tofersen experienced substantial reductions in the amount of neurofilament light chain in their blood plasma. Specifically, that failed study, named VALOR, as well as a so-called “extension” study found 40% to 50% declines in this protein.
“That’s been a very consistent observation,” Ferguson said.
However, changes in neurofilament light chain have not previously been used by the FDA to approve a drug, adding to the uncertainty surrounding Biogen’s case for tofersen’s approval.
While the drug failed to meet its goal in Phase 3 testing, Biogen is including in its application additional analyses it claims are supportive. According to the company, patients who’ve been taking tofersen for longer report feeling better and functioning better on measures like breathing and muscle strength. Researchers have also observed a trend that suggests earlier treatment decreased the risk of death, added Ferguson.
“In a disease in which the primary feature is loss of strength, we are potentially observing their strength stabilizing,” he said. “Likewise, for measures of breathing and function, we see something similar. So we're affecting core features of the disease, and particularly in patients who were treated earlier.”
But whether such observations end up supporting an approval in the absence of conclusive evidence of benefit isn’t clear.
Ferguson said Biogen had been working with the FDA to find a path forward for tofersen, sharing data from VALOR and the extension study — which allowed patients in the drug arm to continue receiving it and patients in the placebo arm to switch onto treatment. In a statement, Biogen said that before the FDA decides on approval, it first plans to convene an advisory group of neuroscience experts to go over the tofersen application at a yet-to-be determined date.
It’s not unprecedented for the FDA to clear a drug for having an effect on a disease-related protein. With Aduhelm, for example, the agency concluded that its ability to break up patches of amyloid beta — a brain protein linked to Alzheimer’s — met its standard for accelerated approval.
Yet, tofersen isn’t an exact parallel to Aduhelm, which was specifically designed to target amyloid. Tofersen wasn’t designed to target neurofilament light chain, but rather a different protein that research suggests in rare instances can cause ALS when mutated.
Biogen’s drug has shown it can reduce this “SOD1” protein, too. According to Ferguson, results from VALOR and the extension study found treatment with tofersen leads to lower SOD1 levels after about eight weeks, lower neurofilament light chain levels after about 12 weeks and then suggestions of clinical change after about six months.
The changes in SOD1 indicate tofersen is working as intended, but they’re “not a predictor of clinical efficacy,” Ferguson said. “That's distinct from neurofilament, where we do think it has a relationship with clinical efficacy.”
Part of the reason for that is researchers currently don't have measurement tools that can differentiate between the normal SOD1 protein and the toxic, mutated form that kills motor neurons, Ferguson said. By contrast, neurofilament light chain is much more easily measured, with proven research-grade assays, and is more closely tied to neurological damage. Medical device developers like Quanterix and LabCorp have also been working on commercial-grade tests for neurofilament light chain, with the latter company launching one earlier this month.
Biogen estimates about 330 people have SOD1 ALS in the U.S., meaning an approval, should the FDA grant one, would be for only a sliver of the approximately 17,000 to 31,000 people with ALS in the country.
In addition to tofersen, the FDA is currently evaluating another experimental treatment for ALS. Developed by Amylyx Pharmaceuticals, the drug was found in clinical testing to have both functional and survival benefits that doctors have characterized as “incremental” but also “important.”
The FDA expects to convene — for an unusual second time — its panel of neuroscience advisors on Sept. 7 to weigh in on Amylyx’s application. An approval verdict should come by Sept. 29.
If approved, Amylyx’s drug would be the first new ALS treatment in more than five years to become available in the U.S. Currently, most people with the disease live two to five years after diagnosis.