A pedestrian walks past the Biogen Inc. headquarters in Cambridge, Massachusetts, U.S., Monday, June 7, 2021.
Adam Glanzman | Bloomberg | Getty Images
On Wednesday, the Food and Drug Administration’s panel of independent advisors voted against the effectiveness of biogenic experimental ALS drug for a rare and aggressive form of the disease.
The drug tofersen was developed to treat a rare genetic form of amyotrophic lateral sclerosis, or ALS. Three councilors voted in favor of efficiency, five voted against and one abstained.
“The trial that was presented unfortunately did not meet the primary and secondary endpoints,” said Dr. Liana Apostolova, professor of neurology at Indiana University School of Medicine, who voted against the effectiveness. tofersen.
But the panel voted unanimously that the drug may have clinical benefit by reducing a protein associated with disease severity.
Michelle Mielke, a professor of epidemiology at Wake Forest University School of Medicine who voted in favor of the drug, acknowledged that the data is not entirely conclusive, but said “there are several aspects of the data that suggest strong clinical evidence. “.
“And again, my decision also weighed in that there really is an unmet need,” she added.
Accelerated approval is an FDA designation that clears drugs faster if they meet an unmet medical need for serious conditions. Such approval would require Biogen to study the drug further to verify its clinical benefits.
The FDA generally follows the advice of its advisory committees, but is not required to do so. He will make his final decision on April 25.
ALS, more commonly known as Lou Gehrig’s disease, is a progressive and fatal neuromuscular disease that causes the loss of nerve cells in the brain and spinal cord over time, causing loss of control of necessary muscles to move, talk, breathe and eat. The disease eventually leads to paralysis and even death, and usually affects people between the ages of 40 and 70.
The drug targets a form of ALS in people with mutations in a specific gene passed down from generation to generation within families. These mutations can cause a protein called SOD1 to build up to toxic levels, which can ultimately damage the nervous system and lead to the development of ALS.
According to Biogen, only a few thousand people worldwide have been diagnosed with this type of SOD1 mutation, or about 2% of the 168,000 people with ALS worldwide. This number is even smaller in the United States, with about 330 people affected by the SOD1 mutation. The median survival time from diagnosis of the rare form of ALS to death is 2.7 years, according to the society.
The SOD1 mutation is associated with 20% of cases that occur within families.
Families affected by ALS hope the drug could pave the way for more research into how to target the cause of the disease, potentially leading to new treatments for the nearly 5,000 new people in the United States who are being diagnosed. of ALS each year. Globally, National Institutes of Health researchers expect ALS cases to rise nearly 70% to around 376,000.
Review of mixed efficacy data
The FDA accepted Biogen application for full approval of tofersen in July. In October, the agency extended its three-month review of the application.
The advisory group relied on controversial data from a phase three clinical trial by tofersen. The drug failed to slow the progression of ALS in this trial, but Biogen and FDA staff pointed out the study’s potential limitations. The duration of the trial was 28 weeks, which may not have been long enough to observe the effect of tofersen on disease progression.
The panel focused on evaluating the effect of tofersen on key proteins associated with the development of ALS. According to a FDA Review company data.
But the panel specifically focused on the drug’s effect on another key protein called neurofilament light, or NfL. High levels of the protein are found in a variety of neurological disorders like ALS and are associated with disease severity and progression in patients, according to the FDA review.
Biogen’s phase three trial found that people who received tofersen saw a 55% reduction in NfL levels at week 28 of the study, compared to an average increase of 12% in people who received received a placebo. An ongoing study of tofersen has shown similar results: People who received the drug in the phase three trial maintained their lowered NfL levels over time.
Those who received a placebo during the phase three trial but switched to tofersen in the extension study saw a 44% drop in NfL levels, the FDA review added.
In a unanimous vote, the panel declared that the reduction in NfL by Tofersen is likely to predict the clinical benefit of the drug in people with SOD1-ALS.
“It appears that NFL is bad for neurons and is linked to neuronal death. So if it’s lower, neuronal death should be lower,” said Dr. David Weisman, director of the clinical research center at the ANA.
FDA staff, who presented their review of Biogen’s data ahead of the panel’s vote, also said these “compelling reductions” in NfL should lead to a slower decline in patient numbers.
The group also reviewed tofersen’s safety data. In the phase three trial, the most common side effects associated with the drug were joint and muscle pain and fatigue.
According to the FDA review, about 18% of people given tofersen experienced serious adverse effects, compared to 14% of those given the placebo. But FDA staff noted that many of the reported events were related to “underlying disease progression,” not tofersen use. None of the adverse events were fatal.
Public calls for approval
In public comments, Alison Burell said her family believed tofersen significantly slowed the progression of the disease in her husband Cory, who died of the rare form of ALS in 2019. He participated in Biogen’s first clinical trial on tofersen and continued to use the drug even after the trial ended, which Burell said extended his life by another six months.
“Tofersen gave Cory time with his boys, making memories and showing them to never give up,” Burrell said. “I ask you to please recommend your endorsement 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 the most recent member to be diagnosed with the rare form of the disease, but taking tofersen extended his life by several months and “gave us that precious time together”.
“It’s a miracle, the miracle of having access to a drug that specifically targets our genetic mutation and prolongs our lives,” Haddad said. She added that she herself has joined Biogen’s ongoing tofersen trial called ATLAS and is being monitored for symptoms of ALS.
“We all know that early intervention works best. Without tofersen, I have no chance of survival and I have no hope,” Haddad said, adding, “Today you have the power to help me and the legacy of my family’s death.”
More research on tofersen to come
Biogen outlined its plans to verify the benefits of tofersen if the drug gains fast-track FDA approval. The company will collect data from ATLAS, which is designed to determine whether the drug can help delay the onset of ALS in patients with the SOD1 mutation.
The study was launched in 2021 and includes 150 participants, or nearly 50% of the SOD1-ALS population to date, Biogen said. The company also plans to continue evaluating data from the ongoing phase three clinical trial extension, which it expects to conclude in 2024.
“Biogen is committed to confirming the clinical benefit of tofersen for SOD1-ALS as soon as possible,” said Stephanie Fradette, Biogen’s Chief Clinical Development Officer and ALS Portfolio Manager.
Correction: FDA advisors voted against the efficacy of tofersen. An earlier version of this story misrepresented the precise nature of this vote.