A pedestrian walks past Biogen Inc.’s headquarters in Cambridge, Massachusetts, on Monday, June 7, 2021.
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The Food and Drug Administration’s independent advisory panel voted against the effectiveness of on Wednesday biogenic ALS drug under investigation 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 for effectiveness, five against, and one abstained.
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“Unfortunately, the presented study did not meet the primary and secondary endpoints,” said Dr. Liana Apostolova, a professor of neurology at Indiana University School of Medicine, who voted against Tofersen’s effectiveness.
However, the panel unanimously agreed that the drug could have clinical benefit by reducing a protein linked to the severity of the disease.
Michelle Mielke, a professor of epidemiology at Wake Forest University School of Medicine who voted for the drug, acknowledged the data is not entirely conclusive, but said, “There are several aspects of the data that point to strong clinical evidence .”
“And again, my decision also took into account the fact that there really is an unmet need,” she added.
Expedited approval is an FDA designation that approves drugs faster when they meet an unmet medical need for a serious medical condition. Such approval would require Biogen to further study the drug to confirm its clinical utility.
The FDA generally follows the advice of its advisory committees, but is not required to do so. A final decision will be made on April 25th.
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 deteriorate over time, causing people to lose muscle control, they need to move, talk, breathe and eat. The disease eventually leads to 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 through generations 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 SOD1 mutation, or about 2% of the 168,000 people who have ALS worldwide. In the US, that number is even lower, with about 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 occurring within families.
Families affected by ALS are hoping the drug could pave the way for more research to tackle the disease’s cause, potentially leading to new treatments for the estimated 5,000 new people in the US diagnosed with ALS each year. Globally, researchers at the National Institutes of Health expect ALS cases to increase by almost 70% to approximately 376,000.
Review of mixed efficacy data
The FDA accepted Biogen’s application for full approval of Tofersen in July. In October, the agency extended the review of the application by three months.
The advisory panel relied on controversial data from a phase III clinical trial of Tofersen. The drug failed to slow the progression of ALS in this study, but both Biogen and FDA staff noted the potential limitations of the study. The duration of the study was 28 weeks, which may not have been enough time to observe the effect of Tofersen on disease progression.
The panel focused on evaluating Tofersen’s effect on key proteins associated with the development of ALS. According to an FDA review of the company’s data, the SOD1 protein levels of patients in the study who received Tofersen decreased by 26% to 38% compared to those who received placebo.
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 conditions, such as ALS, and are linked to disease severity and progression in patients, according to the FDA review.
Biogen’s phase 3 study found that people who received Tofersen experienced a 55 percent reduction in NfL levels by week 28 of the study, compared with an average increase of 12 percent for people who received placebo. An ongoing study of Tofersen had similar results: People who received the drug in the phase 3 study maintained their lowered NfL levels over time.
Those who received a placebo during the phase 3 study 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 said Tofersen’s reduction in NfL likely predicts the drug’s clinical utility in people with SOD1-ALS.
“It appears that NFL is bad for neurons and is associated 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 staffers, who presented their review of Biogen’s data ahead of the panel vote, also said these “convincing reductions” in NfL are expected to result in a slower decline in patients.
The panel also considered Tofersen’s safety data. In the phase 3 study, the most common adverse events associated with the drug were pain in the joints and muscles, and fatigue.
According to the FDA review, about 18% of people who received Tofersen experienced serious adverse events compared to 14% of people who received the placebo. However, FDA staff noted that many of the reported events are related to “underlying disease progression” and not to Tofersen use. None of the adverse events were fatal.
Public Requests for Consent
During public comments, Alison Burell said her family believes Tofersen significantly slowed the progression of the disease in her husband Cory, who died from the rare form of ALS in 2019. He participated in Biogen’s early clinical trial on Tofersen and continued taking the drug after the trial was completed, which Burell believes extended his life by another six months.
“Tofersen gave Cory time with his boys, made memories and showed them that they never give up,” Burrell said. “I ask that you commend your agreement to support Tofersen. Please give hope to others with SOD1.”
Cassandra Haddad also asked the panel to recommend approval, noting that her family has a SOD1-ALS “body count” of 33. She said her late mother was the youngest member to be diagnosed with the rare form of the disease, but took Tofersen to extend her life by several months and “gave us this precious time together.”
“It’s a miracle, the miracle of having access to a drug that specifically targets our genetic mutation and extends our lives,” Haddad said. She added that she herself participated in Biogen’s ongoing Tofersen study called ATLAS and is being monitored for ALS symptoms.
“We all know that early intervention leads to better outcomes. Without Tofersen, I have no chance of survival and no hope,” Haddad said, adding, “Today, you have the power to help me and the legacy of my family’s death.”
Further research on Tofersen ahead
Biogen outlined its plans to review Tofersen’s benefits if the drug receives accelerated FDA approval. The company will collect data from ATLAS, which aims to study whether the drug can help delay the onset of ALS in patients with the SOD1 mutation.
The study started 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 the ongoing extension of the Phase 3 clinical trial, which is expected to conclude in 2024.
“Biogen is committed to confirming the clinical utility of Tofersen in SOD1-ALS as soon as possible,” said Stephanie Fradette, Biogen’s director of clinical development and leader of the ALS portfolio.
Correction: FDA advisors voted against Tofersen’s effectiveness. A previous version of this story misrepresented the exact nature of this vote.
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