- The FDA’s independent panel of advisors voted against approving accelerated approval of Biogen’s ALS drug for a rare and aggressive form of the disease.
- The vote is not binding on the FDA, although the agency often follows the panel’s guidelines. It will make a final decision on April 25.
- The drug tofersen was developed to treat a rare genetic form of amyotrophic lateral sclerosis, or ALS.
A pedestrian walks past Biogen Inc. headquarters on Monday, June 7, 2021. in Cambridge, Massachusetts, USA.
Adam Glanzmann | Bloomberg | Getty Images
The Food and Drug Administration’s independent panel of advisors declined Wednesday to approve accelerated approval of Biogen’s 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 advisers voted in favor of the remedy, five voted against and one abstained.
“Unfortunately, the trial that was presented failed to meet its primary and secondary endpoint,” said Dr. Liana Apostolova, a professor of neurology at Indiana University School of Medicine, who voted against tofersen.
Michelle Mielke, a professor of epidemiology at Wake Forest University School of Medicine who voted in favor of the drug, acknowledged that the data isn’t completely conclusive, but said, “There are several aspects of the data that suggest strong clinical evidence.”
“And again, my decision also factored in the fact that there really is an unmet need,” she added.
Accelerated Approval is an FDA designation that releases drugs more quickly if they address an unmet medical need for serious conditions. Such approval would require Biogen to study the drug further to verify its clinical benefits.
The committee’s vote is a blow to Tofersen’s chances of approval. The FDA generally follows the advice of its advisory committees, but is not required to do so. It will make a final decision on April 25.
ALS, more commonly known as Lou Gehrig’s disease, is a progressive and deadly neuromuscular disease that causes nerve cells in the brain and spinal cord to waste away over time, causing people to lose control of the muscles needed to move, speak, breathe and eat. The disease eventually causes paralysis and even death, and generally affects people between the ages of 40 and 70.
The drug targets a form of ALS in people with mutations in a specific gene that is passed down from generation to generation within families. Those mutations can cause a protein called SOD1 to build up to toxic levels, which can eventually damage the nervous system and lead to the development of ALS.
Only a few thousand people worldwide have been diagnosed with that kind of SOD1 mutation, or about 2% of the 168,000 people worldwide who have ALS, according to Biogen. That number is even smaller in the US, 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 company.
The SOD1 mutation is associated with 20% of cases that occur within families.
Families affected by ALS hope the drug can pave the way for more research into tackling the root cause of the disease, potentially leading to new treatments for the estimated 5,000 new people in the U.S. who are diagnosed each year. get ALS. Worldwide, researchers at the National Institutes of Health expect the number of ALS cases to increase by nearly 70% to about 376,000.
The FDA accepted Biogen’s application for full approval of tofersen in July. In October, the agency extended the review of the application for three months.
The advisory panel drew on controversial data from a phase three clinical trial of tofersen. The drug failed to slow the progression of ALS in that study, but both Biogen and FDA staff pointed out the potential limitations of the study. The duration of the trial was 28 weeks, which may not have been enough time to observe the effect of tofersen on disease progression.
The panel focused on evaluating the effect of tophersen on key proteins associated with the development of ALS. Patients in the trial who received tofersen saw their SOD1 protein levels drop between 26% and 38% compared to those who received a placebo, according to an FDA review of the company’s data.
But the panel focused specifically on the drug’s effect on another important protein called neurofilament light, or NfL. High levels of the protein are found in a variety of neurological conditions such as ALS and are associated with disease severity and progression in patients, according to the FDA review.
Biogen’s phase three study found that people who received tofersen saw a 55% reduction in NfL levels at week 28 of the study, compared to an average 12% increase in people who received a placebo. An ongoing study of tofersen had 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 study but switched to tofersen in the extension study saw a 44% drop in NfL levels, the FDA added.
In a unanimous vote, the panel said that tofersen’s reduction in NfL likely predicts the drug’s clinical benefit in people with SOD1-ALS.
“It seems that NFL is bad for neurons and is related to neuronal death. So if it’s lower, neuronal death should be lower,” said Dr. David Weisman, director of the ANA Clinical Research Center.
The FDA staff, who presented their review of Biogen’s data before the panel voted, also said those “convincing reductions” in NfL are expected to lead to a slower decline in patient numbers.
The panel also considered the safety data of tofersen. In the phase three study, the most common side effects of the drug were pain in the joints and muscles, as well as fatigue.
About 18% of people who received tophersen experienced serious side effects, compared to 14% of those who received the placebo, according to the FDA’s assessment. But FDA staff noted that many of the reported events were related to “underlying disease progression,” not tophersen use. None of the side effects were fatal.
During public comments, Alison Burell said her family believes tofersen significantly slowed the progression of the disease in her husband Cory, who died in 2019 from the rare form of ALS. the trial was over, which Burell says extended his life for another six months.
“Tofersen gave Cory time with his guys, made memories and showed them never to give up,” said Burrell. “I ask that you please recommend your approval in support of tophersen. Please give hope to others with SOD1.”
Cassandra Haddad also urged the panel to recommend approval, noting that her family has an 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 she was taking tophersen. extended her life by several months and “gave us that precious time together.”
“That’s a miracle, the miracle that we have access to a drug that specifically targets our genetic mutation and extends our lives,” Hadad said. She added that she herself participated in Biogen’s ongoing study on tophersen called ATLAS and is being monitored for ALS symptoms.
“We all know that early intervention leads to better outcomes. Without tophersen, I have no chance of survival and no hope,” Haddad said, adding, “Today you have the power to protect me and the legacy of my family’s death. to help.”
Biogen outlined its plans to verify the benefits of tofersen if the drug receives accelerated FDA approval. The company will collect data from ATLAS, which is designed to study 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, which is nearly 50% of the SOD1-ALS population to date, Biogen said. The company also plans to continue evaluating data from its ongoing phase three clinical trial expansion, which is expected to be completed in 2024.
“Biogen is committed to confirming the clinical benefit of tofersen for SOD1-ALS as soon as possible,” said Stephanie Fradette, Biogen’s clinical development lead and ALS portfolio head.
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