The Food and Drug Administration may have an easier time reviewing a closely watched medicine for ALS, after a group of agency advisers appeared to support a conditional approval during a meeting Wednesday.
The advisers voted 9-0 that the drug’s effect on an important protein linked to nerve damage was “reasonably likely” to predict a clinical benefit — a conclusion that aligns with the FDA's standards for granting a so-called accelerated approval.
Yet when asked whether the available data provide “convincing evidence” of the medicine’s effectiveness, the group, which mostly consists of experts in neurology and clinical science, disagreed in a 5-3 vote. The ninth member abstained.
“I think it meets the standards of accelerated approval, but not for traditional approval,” said Thomas Montine, the committee’s chair and a “no” in the second vote. “This was a difficult decision that weighed heavily on me.”
While the FDA isn’t required to follow the recommendations of its advisory committees, it typically does. The agency is expected to issue a verdict on the medicine, which is being developed by Biogen under the name tofersen, by April 25.
Scientists specifically designed tofersen to treat cases of ALS, or amyotrophic lateral sclerosis, caused by rare mutations in a gene called SOD1. Estimates hold that less than 500 of the roughly 30,000 ALS patients in the U.S. have this form of the neurodegenerative disease. As it’s hereditary, SOD1 ALS often passes from generation to generation, affecting many members of the same family.
Heading into the meeting, FDA staff signaled an openness to giving the drug a conditional approval. They acknowledged issues with Biogen’s application — namely that the key clinical trial meant to show tofersen’s benefits had limitations and failed to hit its main goal. Yet, agency staff also noted how regulatory flexibility can be offered to new therapies meant to treat diseases like ALS, which is often rapid, always fatal and has few treatment options.
"The purpose of noting these limitations in the study design is not to try to explain away a negative study or turn it into a positive study," said Teresa Buracchio, acting director of the FDA office that reviews drugs for the brain and nervous system, on Wednesday. "However, the agency considers that the data appear to suggest the treatment effect of toferson in SOD1 ALS."
Biogen’s trial enrolled 108 participants and ran for around six months. It found tofersen was not significantly better than a placebo at slowing the functional decline associated with ALS, as measured by a scoring system that evaluates the ability of patients to perform essential tasks like walking, talking, eating and breathing.
After learning of tofersen’s failure, Biogen officials met with FDA staff twice to discuss possible next steps for their drug. The agency told Biogen that securing a full approval based on the single, failed trial would be challenging.
Biogen ended up asking for accelerated approval, a type of clearance which relies on the FDA’s belief that a drug’s effect on a marker of disease is likely to provide some level of benefit to patients. Specifically, Biogen’s application focused on a protein called neurofilament light chain.
Research suggests that, when nerve cells are damaged, this protein is found at elevated levels in the blood and fluid around the brain and spine. Some studies have shown particularly large amounts of it in ALS patients. Over the course of Biogen’s trial, levels decreased 55% in tofersen-treated patients and increased 12% in placebo-treated patients.
Similar changes were seen in an “open-label” extension trial that allowed all patients in the main study to receive tofersen, Biogen said. The company believes tofersen effectively blocks the mutated SOD1 gene and thereby benefits nerve cells, as demonstrated by the lower levels of neurofilament light chain.
To date, the FDA has not approved an ALS drug based on “biomarkers” like neurofilament. The three therapies currently marketed in the U.S. — riluzole, Radicava and Relyvrio — were each cleared because of their effects on either function or survival, or both in Relyvrio’s case.
But interest in and understanding of this protein has grown over the past decade and especially in the last few years. Neurofilament is “increasingly becoming recognized as the leading biomarker to use” in ALS drug research, according to Cathy Lomen-Hoerth, director of the ALS Center at the University of California, San Francisco.
The approved medicines for ALS “represent an important advance … but none of them bends the curve enough for patients to feel the difference in terms of disease progression,” Timothy Miller, a neurology professor at Washington University in St. Louis, said as part of Biogen’s presentation.
“The published data and the anecdotal stories,” Miller added, “suggest that tofersen has a major impact on disease progression and is clearly a game changer."
However, scientists are still trying to discern exactly how neurofilament relates to function and survival in ALS patients. In the trial that supported Relyvrio’s approval, for example, the drug did not have a significant effect on neurofilament light chain, even though it appeared to help patients live a median of five months longer compared to a placebo.
Biogen is currently running another late-stage trial with presymptomatic ALS patients who are already showing elevated levels of neurofilament light chain. The trial has enrolled 84 of a target 150 participants, but isn’t expected to produce results until 2027. Given the rare nature of SOD1 ALS, both the FDA and its advisers questioned how Biogen will confirm tofersen has an effect on the disease course.
To all nine members of the FDA advisory committee, the data collected so far are supportive enough to warrant a conditional approval.
“My conclusion is that yes, we do have sufficient entirety of the data to conclude that there is a reasonable likelihood of [neurofilament light chain] predicting clinical benefit and supporting accelerated approval,” said Tanya Simuni, director of the Parkinson's Disease and Movement Disorders Center at Northwestern University’s Feinberg School of Medicine.
The experts did hold some concerns, though. Regarding safety, four patients in the main trial’s drug arm and 10 in the open-label study experienced serious neurological events like spinal cord inflammation or swelling of the eyes due to increased pressure around the brain.
The FDA’s own statistician also identified issues with how Biogen designed and analyzed that trial.
The agency and the company acknowledged, too, that participants across the trial declined much less than expected, adding uncertainty to the results.
Biogen believes the drug’s benefits are more pronounced when patients are given it for longer periods of time, and expects the open-label study will help alleviate some of the concerns surrounding it.
For the FDA, tofersen presents yet another test of its flexibility toward experimental treatments for neurodegenerative disorders. If approved, it could set a precedent for how experimental ALS therapies are studied and reviewed, much like how Biogen’s Aduhelm made waves when it received an accelerated approval in Alzheimer’s disease almost two years ago.
ALS patients, meanwhile, have found a rare source of hope in tofersen. Like many diseases of the brain and nervous system, ALS has proven complex and difficult to treat. Even with the approved therapies, most patients live just two to five years after first showing symptoms.
During a part of Wednesday’s meeting dedicated to public input, patients and healthcare providers spoke about the devastation caused by inherited ALS. Three members of one family described how 22 of their relatives lost their lives to SOD1 ALS. Another family had, across seven generations, lost 33 people to the disease.
Most of the public forum speakers were in favor of tofersen’s approval, hopeful that the drug, even if far from a cure, could keep them alive and functioning longer.
“My real-life functional experience and my data show that tofersen has contributed to the stabilization of my ALS,” Larry Falivena, who has SOD1 ALS and participated in Biogen’s trial, said at the meeting. “Tofersen is the opportunity to break the cycle of genetic ALS for families who've been devastated by this disease for generations.”