A pedestrian walks past Biogen Inc. headquarters in Cambridge, Massachusetts, U.S., on Monday, June 7, 2021.
Adam Glanzman | Bloomberg | Getty Images
The Food and Drug Administration’s independent panel of advisors on Wednesday voted against the effectiveness of Biogen’s investigational ALS drug for a rare and aggressive type of the disease.
The drug tofersen was developed to treat a rare genetic type of amyotrophic lateral sclerosis, or ALS. Three advisors voted in favor of effectiveness, five voted against it and one abstained.
“The trial that was presented unfortunately didn’t meet the first and secondary endpoint,” said Dr. Liana Apostolova, a professor of neurology at Indiana University School of Medicine who voted against tofersen’s effectiveness.
However the panel voted unanimously that the drug could have a clinical profit 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 in favor of the drug, acknowledged the information is not fully conclusive but said “there are several facets of the information that do suggest strong clinical evidence.”
“And again, my decision also weighed within the incontrovertible fact that there really is an unmet need,” she added.
Accelerated approval is an FDA designation that clears drugs faster in the event that they fill an unmet medical need for serious conditions. Such an approval would require Biogen to review the drug further to confirm its clinical advantages.
The FDA typically follows the recommendation of its advisory committees but just isn’t required to achieve this. It can make a final decision on April 25.
ALS, mostly often called Lou Gehrig’s disease, is a progressive and fatal neuromuscular disease that causes nerve cells within the brain and spinal cord to waste away over time, causing people to lose control of muscles needed to maneuver, speak, breathe and eat. The disease eventually causes paralysis and even death, and customarily affects people between 40 and 70 years old.
The drug targets a type of ALS in individuals with mutations in a particular gene passed down through generations inside families. Those mutations may cause a protein called SOD1 to build up to toxic levels, which might ultimately damage the nervous system and result in the event of ALS.
Only a couple of thousand people worldwide have been diagnosed with that sort of SOD1 mutation, or around 2% of the 168,000 individuals who have ALS globally, in accordance with Biogen. That number is even smaller within the U.S., with roughly 330 people affected by the SOD1 mutation. The median survival time from diagnosis with the rare type of ALS to death is 2.7 years, in accordance with the corporate.
The SOD1 mutation is related to 20% of cases that occur inside families.
Families impacted by ALS hope the drug could pave the best way for more research on the best way to goal the reason behind disease, potentially resulting in latest treatments for the estimated 5,000 latest people within the U.S. who get diagnosed with ALS every yr. Globally, researchers from the National Institutes of Health expect ALS cases to extend by nearly 70% to around 376,000.
Reviewing mixed efficacy data
The FDA accepted Biogen’s application for full approval of tofersen in July. In October, the agency prolonged its review of the appliance by three months.
The advisory panel drew on controversial data from a phase three clinical trial of tofersen. The drug did not slow progression of ALS in that trial, but each Biogen and FDA staff pointed to the study’s potential limitations. The trial’s length was 28 weeks, which can not have been enough time to watch tofersen’s effect on disease progression.
The panel focused on evaluating tofersen’s effect on key proteins related to the event of ALS. Patients within the trial who received tofersen saw their SOD1 protein levels decline between 26% and 38% compared with those given a placebo, in accordance with an FDA review of the corporate’s data.
However the panel specifically zeroed in on the drug’s effect on one other key protein called neurofilament light or NfL. High levels of the protein are present in a wide range of neurological disorders like ALS and are related to the disease’s severity and progression in patients, in accordance with the FDA review.
Biogen’s phase three trial found that individuals who received tofersen saw a 55% reduction in NfL levels by week 28 of the study, in comparison with a median 12% increase in individuals who got a placebo. An ongoing study of tofersen had similar results: Individuals who received the drug within the phase three trial maintained their lowered NfL levels over time.
Those that received a placebo in the course of the phase three trial but switched to tofersen within the extension study saw a 44% decline in NfL levels, the FDA’s review added.
In a unanimous vote, the panel said tofersen’s reduction in NfL is more likely to predict the drug’s clinical profit in individuals with SOD1-ALS.
“It seems that NFL is bad for neurons and is tied with neuronal death. So if it’s lower, then neuronal death ought to be lower,” said Dr. David Weisman, director of the ANA Clinical Research Center.
The FDA staff, which presented its review of Biogen’s data before the panel voted, also said those “convincing reductions” in NfL are expected to guide to slower decline in patients.
The panel also considered tofersen’s safety data. Within the phase three trial, probably the most common opposed events related to the drug were pain within the joints and muscles in addition to fatigue.
Roughly 18% of people that received tofersen experienced serious opposed events in comparison with 14% of those that got the placebo, in accordance with the FDA’s review. But FDA staff noted that lots of the reported events were related to “underlying disease progression,” not using tofersen. Not one of the opposed events were fatal.
Public pleas for approval
During public comments, Alison Burell said her family believes tofersen substantially slowed the disease’s progression in her husband Cory, who passed away from the rare type of ALS in 2019. He participated in Biogen’s early clinical trial on tofersen and continued to make use of the drug even after the trial concluded, which Burell believes prolonged his life for six more months.
“Tofersen gave Cory time together with his boys, making memories and showing them to never surrender,” Burrell said. “I ask you to please recommend your approval in support of tofersen. Please give hope to others with SOD1.”
Cassandra Haddad also urged the panel to recommend approval, noting that her family has a SOD1-ALS “body count” of 33. She said her late mother was probably the most recent member to get diagnosed with the rare type of the disease, but taking tofersen prolonged her life for several months and “gave us that precious time together.”
“That could be a miracle, the miracle of gaining access to a drug that specifically targets our genetic mutation and extends our life,” Haddad said. She added that she herself has joined Biogen’s ongoing trial on tofersen called ATLAS and is being monitored for ALS symptoms.
“Everyone knows that early intervention leads to raised outcomes. Without tofersen, I actually have zero likelihood of survival and I haven’t any hope,” Haddad said, adding: “Today you might have the facility to assist me and my family’s legacy of death.”
More research on tofersen ahead
Biogen outlined its plans for verifying tofersen’s advantages if the drug wins accelerated approval from the FDA. The corporate will collect data from ATLAS, which is designed to research whether the drug may help delay the onset of ALS in patients with the SOD1 mutation.
The study launched in 2021 and includes 150 participants, which is nearly 50% of the SOD1-ALS population up to now, Biogen said. The corporate also plans to proceed evaluating data from the continuing extension of the phase three clinical trial, which it expects to conclude in 2024.
“Biogen is committed to confirming the clinical good thing about tofersen for SOD1-ALS as quickly as possible,” said Stephanie Fradette, Biogen’s clinical development lead and ALS portfolio head.
Correction: The FDA advisors voted against the effectiveness of tofersen. A previous version of this story misstated the precise nature of that vote.