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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 form of the disease.
The drug tofersen was developed to treat a rare genetic form of amyotrophic lateral sclerosis, or ALS. Three advisors voted in favor of effectiveness, five voted against it and one abstained.
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“The trial that was presented unfortunately did not meet the primary and secondary endpoint,” said Dr. Liana Apostolova, a professor of neurology at Indiana University School of Medicine who voted against tofersen’s effectiveness.
But the panel voted unanimously that the drug could have a clinical benefit in reducing a protein that is 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 the data isn’t fully conclusive but said “there are several aspects of the data that do suggest strong clinical evidence.”
“And again, my decision also weighed in the fact that there really is an unmet need,” she added.
Accelerated approval is an FDA designation that clears drugs faster if they fill an unmet medical need for serious conditions. Such an approval would require Biogen to study the drug further to verify its clinical benefits.
The FDA typically follows the advice of its advisory committees but is not required to do so. It will make a final decision on April 25.
ALS, most commonly known as Lou Gehrig’s disease, is a progressive and fatal neuromuscular disease that causes nerve cells in the brain and spinal cord to waste away over time, causing people to lose control of muscles needed to move, speak, breathe and eat. The disease eventually causes paralysis and even death, and generally affects people between 40 and 70 years old.
The drug targets a form of ALS in people with mutations in a specific gene passed down through generations within families. Those mutations can cause a protein called SOD1 to accumulate to toxic levels, which can ultimately 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 around 2% of the 168,000 people who have ALS globally, according to Biogen. That number is even smaller in the U.S., with roughly 330 people affected by the SOD1 mutation. The median survival time from diagnosis with 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 impacted by ALS hope the drug could pave the way for more research on how to target the cause of disease, potentially leading to new treatments for the estimated 5,000 new people in the U.S. who get diagnosed with ALS every year. Globally, researchers from the National Institutes of Health expect ALS cases to increase 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 extended its review of the application by three months.
The advisory panel drew on controversial data from a phase three clinical trial of tofersen. The drug failed to slow progression of ALS in that trial, but both Biogen and FDA staff pointed to the study’s potential limitations. The trial’s length was 28 weeks, which may not have been enough time to observe tofersen’s effect on disease progression.
The panel focused on evaluating tofersen’s effect on key proteins associated with the development of ALS. Patients in the trial who received tofersen saw their SOD1 protein levels decline between 26% and 38% compared with those given a placebo, according to an FDA review of the company’s data.
But the panel specifically zeroed in 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 the disease’s 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 by week 28 of the study, compared to an average 12% increase in people who were given 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 trial but switched to tofersen in 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 likely to predict the drug’s clinical benefit in people with SOD1-ALS.
“It appears that NFL is bad for neurons and is tied with neuronal death. So if it’s lower, then neuronal death should 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 lead to slower decline in patients.
The panel also considered tofersen’s safety data. In the phase three trial, the most common adverse events associated with the drug were pain in the joints and muscles as well as fatigue.
Roughly 18% of people who received tofersen experienced serious adverse events compared to 14% of those who were given the placebo, according to the FDA’s review. But FDA staff noted that many of the reported events were related to “underlying disease progression,” not the use of tofersen. None of the adverse 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 form of ALS in 2019. He participated in Biogen’s early clinical trial on tofersen and continued to use the drug even after the trial concluded, which Burell believes extended his life for six more 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 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 the most recent member to get diagnosed with the rare form of the disease, but taking tofersen extended her life for several months and “gave us that precious time together.”
“That is a miracle, the miracle of having 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.
“We all know that early intervention leads to better outcomes. Without tofersen, I have zero chance of survival and I have no hope,” Haddad said, adding: “Today you have the power to help me and my family’s legacy of death.”
More research on tofersen ahead
Biogen outlined its plans for verifying tofersen’s benefits if the drug wins accelerated approval from the FDA. The company will collect data from ATLAS, which is designed to investigate whether the drug can help delay the onset of ALS in patients with the SOD1 mutation.
The study launched in 2021 and includes 150 participants, which is almost 50% of the SOD1-ALS population to date, Biogen said. The company also plans to continue evaluating data from the ongoing extension of the phase three clinical trial, which it expects to conclude in 2024.
“Biogen is committed to confirming the clinical benefit of 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.