A pedestrian walks past the headquarters of Biogen Inc. in Cambridge, Massachusetts, USA, Monday, June 7, 2021
Adam Glanzman | Bloomberg | Getty’s paintings
The Food and Drug Administration’s independent advisory panel voted against the effectiveness Wednesday Biogen’s experimental ALS drug for a rare and aggressive form of the disease.
Tofersen was developed to treat a rare genetic form of amyotrophic lateral sclerosis, or ALS. Three advisers voted for effectiveness, five were against, and one abstained.
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“The study that was presented unfortunately failed to fulfill its primary and secondary endpoints,” said Dr. Liana Apostolova, a professor of neurology at the Indiana University School of Medicine, who voted against tofersen’s effectiveness.
But the panel voted unanimously that the drug could have clinical advantages in reducing a protein that’s related to disease severity.
Michelle Mielke, a professor of epidemiology at Wake Forest University School of Medicine who voted for the drug, acknowledged that the data shouldn’t be entirely conclusive, but said “there are several features of the data that suggest strong clinical evidence.”
“And again, my decision was also weighed down by the incontrovertible fact that there really is an unmet need,” she added.
Accelerated approval is an FDA designation to remove drugs faster in the event that they meet an unmet medical need for serious conditions. Such approval would require Biogen to further study the drug to confirm its clinical profit.
The FDA often follows the advice of its advisory committees, but shouldn’t be obligated to accomplish that. The ultimate decision might be made on April 25.
ALS, commonly referred to as Lou Gehrig’s disease, is a progressive and fatal neuromuscular disease that over time causes nerve cells in the brain and spinal cord to die, causing people to lose control of the muscles needed to maneuver, speak, breathe and eat . The disease eventually causes paralysis and even death and customarily affects people between the ages of 40 and 70.
The drug targets a form of ALS in individuals with mutations in a selected gene that’s passed down from generation to generation in families. These mutations may cause a protein called SOD1 to build up to toxic levels, which might eventually damage the nervous system and result in the development of ALS.
Based on Biogen, only a number of thousand people worldwide have been diagnosed with this sort of SOD1 mutation, or about 2% of the 168,000 ALS victims worldwide. This number is even lower in the US, with about 330 people affected by the SOD1 mutation. Based on the company, the average survival time from diagnosis of a rare form of ALS to death is 2.7 years.
The SOD1 mutation is related to 20% of cases running in families.
Families affected by ALS hope the drug could pave the way for more research into how you can goal the cause of the disease, potentially resulting in latest treatments for the roughly 5,000 latest people in the US diagnosed with ALS annually. Worldwide, scientists at the National Institutes of Health expect the number of ALS cases to extend by almost 70% to around 376,000.
Mixed efficacy data review
FDA adopted Biogen’s application for full approval of tofersen in July. agency in October expanded consideration of the application for three months.
The advisory panel relied on controversial data from phase three clinical trial from the tofersen. The drug didn’t slow the progression of ALS on this trial, but each Biogen and FDA staff identified potential limitations to the study. The length of the study was 28 weeks, which can not have been enough to see the effect of tofersen on disease progression.
The panel focused on assessing the effects of tofersen on key proteins involved in the development of ALS. Patients in the study who received tofersen saw a 26% to 38% reduction in SOD1 protein levels in comparison with those that received a placebo. FDA review company data.
But the panel focused specifically on the drug’s effects on one other key protein called neurofilament lumen, or NfL. High protein levels are present in various neurological disorders, similar to ALS, and are related to the severity and progression of the disease in patients, based on an FDA review.
Biogen’s Phase 3 study found that those that received tofersen saw a 55% reduction in NfL levels by week 28 of the study, compared with a mean increase of 12% in those given a placebo. An ongoing study of tofersen produced similar results: those that received the drug in the Phase 3 trial maintained reduced NfL levels over time.
Individuals who received a placebo during the third phase of the study but switched to tofersen in the extension study saw a 44% decrease in NfL levels, the FDA review added.
In a unanimous vote, the panel concluded that the reduction of NfL by tofersen may predict the drug’s clinical profit in individuals with SOD1-ALS.
“Plainly NFL is damaging to neurons and is related to neuronal death. So if it’s lower, then neuronal death needs to be lower,” said Dr. David Weisman, director of the ANA’s Clinical Research Center.
FDA staff who provided a review of Biogen’s data ahead of the panel’s vote also said these “convincing reductions” in the NfL are expected to guide to a slower decline in patient numbers.
The panel also took under consideration Tofersen’s safety data. In the phase III study, the most typical drug-related adversarial events were arthralgia, myalgia, and fatigue.
Based on an FDA review, roughly 18% of those that received tofersen experienced serious unwanted side effects in comparison with 14% of those given a placebo. But FDA staff noted that many of the reported events were related to “progression of the underlying disease” and never to the use of tofersen. None of the adversarial events were fatal.
Public requests for consent
During public comments, Alison Burell said her family believed that tofersen significantly slowed the progression of the disease in her husband Cory, who died of a rare form of ALS in 2019. He participated in Biogen’s early clinical trials of tofersen and continued to make use of the drug even after the trial ended, which Burell said prolonged his life by one other six months.
“Tofersen gave Cory time along with his boys, creating memories and showing them that they never hand over,” said Burrell. “Please recommend support for tofersen. Please give hope to others at SOD1.”
Cassandra Haddad also urged the panel to recommend approval, noting that her family’s “body count” for SOD1-ALS is 33. She said her late mother was the last member to be diagnosed with the rare form of the disease, but taking tofersen prolonged her life by a number of months and “gave us this precious time together.”
“It is a miracle, a miracle of gaining access to a drug that targets our genetic mutation and prolongs our lives,” Haddad said. She added that she herself joined Biogen’s ongoing tofersen study called ATLAS and is being monitored for ALS symptoms.
“Everyone knows that early intervention leads to raised outcomes. Without tofersen, I don’t have any likelihood of survival and no hope,” Haddad said, adding: “Today you’ve gotten the power to assist me and my family’s legacy of death.”
More research on tofersen lies ahead
Biogen has outlined its plans to review the advantages of tofersen if the drug receives accelerated approval from the FDA. The corporate will collect data from ATLAS, which goals to research whether the drug might help delay the onset of ALS in patients with the SOD1 mutation.
The study began in 2021 and includes 150 participants, representing nearly 50% of the SOD1-ALS population to this point, Biogen said. The corporate also plans to proceed evaluating data from the ongoing Phase 3 clinical trial extension, which is anticipated to finish in 2024.
“Biogen is committed to confirming the clinical advantages of tofersen in the treatment of SOD1-ALS as soon as possible,” said Stephanie Fradette, Head of Marketing at Biogen.
Disclaimer: FDA advisors voted against the effectiveness of tofersen. The previous version of this story incorrectly stated the exact nature of this vote.