A protein that’s become increasingly important to ALS drugmakers is likely to get even more attention after a recent regulatory meeting signaled it could be used to support the approval of some experimental treatments.
The Food and Drug Administration convened last week a group of agency advisers to gather input on tofersen, a medicine developed by Biogen for patients with an inherited form of ALS, or amyotrophic lateral sclerosis.
The main clinical trial meant to show tofersen’s merits found it no better than a placebo at slowing the functional decline associated with ALS. However, Biogen said there were positive results, including that its medicine caused substantial reductions of a “biomarker” called neurofilament light chain, which is seen at elevated levels in certain body fluids when nerve cells are damaged.
At the meeting, the panel of nine advisers voted unanimously that tofersen’s effect on this protein was “reasonably likely” to predict a clinical benefit — a core requirement for what’s known as an accelerated approval. Wall Street analysts now expect the FDA, which is currently reviewing tofersen, to grant such an approval by late April.
The meeting’s outcome doesn’t just impact tofersen. If the FDA were to grant the drug a conditional approval, it would set a precedent for other experimental ALS therapies and likely shape how their developers design key studies and engage with regulators.
“I think it would be fantastic and really a very positive development if we can use a biomarker like neurofilament to approve an ALS therapy,” said Kasper Roet, CEO of QurAlis, a Cambridge, Massachusetts-based biotechnology company focused on ALS and other neurodegenerative disorders.
In an interview ahead of last week’s meeting, Roet said he expected the advisory committee’s discussions to be “very meaningful” for his company. That’s been true before, like last year, when the FDA asked outside experts on two separate occasions to weigh the pros and cons of an ALS drug from Amylyx Pharmaceuticals.
That drug, which has since received FDA approval and come to market under the brand name Relyvrio, showed positive effects on patient function and survival in a clinical trial of about 140 participants. Yet Relyvrio is far from a cure. Patients who took it still declined, and the drug wasn’t significantly better than a placebo on other health measures, such as reducing neurofilament light chain levels.
“Their neurofilament data wasn't actually that strong, but it was brought forward as something that is important to the FDA,” Roet said.
“Outside of what we take from that for our company, it is important that we get a biomarker that we can use as a surrogate endpoint for disease,” he added. “In the past that has really shown to be a catalyst of bringing meaningful therapies forward. It worked in [multiple sclerosis]. It looks like we might have that now in Alzheimer's disease. And we think neurofilament can be that for ALS.”
Rob Etherington, CEO of Clene Nanomedicine, said he’s also been keeping a close eye on tofersen, Relyvrio and how those drugs advanced through development.
Last fall, Clene announced its drug failed to hit the main goal in the Healey platform trial — a first-of-its-kind ALS study meant to hasten development timelines by simultaneously testing multiple therapies. An initial crop included five experimental medicines.
Clene hasn’t given up on its drug, though. The company said earlier this month that exploratory analyses from that trial yielded some positive findings. An open-label extension of the Healey study is also ongoing, with data anticipated late this year.
“If we've got biomarker data … and if our survival data checks out with the strength similar to or better than what Amylyx was using, then I think it becomes a conversation that we should have” with the FDA, Etherington said.
While interest in and understanding of neurofilament has grown considerably over the past several years, the exact role it plays in neurodegenerative diseases like ALS isn’t fully understood.
Stephen Scelsa, director of the ALS center at Mount Sinai Health System in New York, calls this protein an “important biomarker,” but notes that “changes do not always correlate with clinical outcomes.”
This was the case with Relyvrio, which showed significant impact on function and survival but not on neurofilament, as well as with tofersen, which had the opposite outcome. Biogen claims tofersen’s effects become more pronounced with longer exposure, so the main trial’s treatment period of 28 weeks likely wasn’t able to capture the drug’s full benefits.
Scientists specifically designed tofersen to combat mutations in SOD1, a gene that has been tied to ALS for decades. These mutations are exceedingly rare, with some estimates holding that less than 500 of the roughly 30,000 ALS patients in the U.S. have this form of the disease.
Editor’s note: This story has been updated to clarify the description of the active trial of Clene’s experimental drug.