FDA advisers reject Biogen’s ALS drug for a rare and aggressive form of the disease.

A pedestrian walks past the headquarters of Biogen Inc. on Monday, June 7, 2021, in Cambridge, Massachusetts, U.S.

Adam Glanzman | Bloomberg | Getty Images

An independent panel of advisers to the Food and Drug Administration declined to endorse its accelerated approval on Wednesday. of Biogen An investigational ALS drug for a rare and aggressive form of the disease.

Tofersen was developed to treat a rare genetic form of amyotrophic lateral sclerosis, or ALS. Three advisers voted in favor of the drug, five voted against it and one abstained.

“Unfortunately the trial presented did not meet the primary and secondary endpoints,” said Dr. Liana Apostolova, a professor of neurology at the Indiana University School of Medicine, who voted against Tofferson.

Michelle Melke, a professor of epidemiology at Wake Forest University School of Medicine who voted in favor of the drug, acknowledged that the data are not entirely conclusive but said “there are several aspects of the data that provide strong clinical evidence.” do.”

“And again, the weight of my decision was also the fact that there really is an unmet need,” he added.

Accelerated approval is an FDA designation that clears drugs quickly if they meet an unmet medical need for serious conditions. Such approval would require Biogen to conduct further studies of the drug to confirm its clinical benefits.

The committee’s vote is a blow to Tofferson’s approval chances. The FDA generally follows the advice of its advisory committees but is not required to do so. The final decision will be made on April 25.

ALS, commonly known as Lou Gehrig’s disease, is a progressive and fatal neurological disease that causes the loss of nerve cells in the brain and spinal cord over time, causing people to lose movement, speech, and function. , lose control of the muscles needed for breathing and eating. The disease eventually causes paralysis and 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 through the generations in families. These mutations can cause a protein called SOD1 to accumulate to toxic levels, which can eventually 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 who have ALS. This number is even lower in the United States. About 330 people Affected by SOD1 mutation. According to the company, the average survival time from diagnosis to death in the rare form of ALS is 2.7 years.

SOD1 mutations are associated with 20% of cases that run in 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 helping the 5,000 new people diagnosed with ALS in the U.S. each year. Therefore, the way for new treatment will be paved. Globally, researchers at the National Institutes of Health expect ALS cases to rise nearly 70 percent to 376,000.

Examining mixed efficacy data

FDA Accepted Biogen’s application for full approval of Tofferson in July. In October, the agency Extension Will review the application for three months.

The advisory panel drew on controversial data. Phase III clinical trial of tofersen. The drug failed to slow the progression of ALS in that trial, but Biogen and FDA staff pointed to potential limitations of the study. The length of the trial was 28 weeks, which was not long enough to see an effect of tofersen 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 tofersin had between 26 percent and 38 percent lower levels of SOD1 protein compared with placebo, according to one. FDA review of company data.

But the panel specifically zeroed in on the drug’s effect on another important protein called neurofilament light, or NfL. According to an FDA review, high levels of the protein are found in a variety of neurological disorders such as ALS and are associated with disease severity and progression in patients.

Biogen’s Phase 3 trial found that those who received toferson experienced a 55% reduction in NfL levels by the 28th week of the study, compared with an average increase of 12% in those who were given a placebo. was An ongoing study by Tofferson had similar results: People who received the drug in a phase three trial maintained their reduced NfL levels over time.

The FDA review added that NfL levels dropped by 44 percent in people who received placebo during the phase three trial but were switched to toferson in the extension study.

In a unanimous vote, the panel said that tophersen deficiency 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 associated with neuronal death. So if it’s low, then neuronal death should be low,” said Dr. David Weisman, director of the ANA Clinical Research Center. .

FDA staff, which presented its review of Biogen’s data before the panel voted, also said a “convincing reduction” in NfL expected a slower decline in patients.

The panel also considered Tofferson’s safety data. In the phase three trial, the most common drug-related adverse events were joint and muscle pain, as well as fatigue.

According to the FDA’s review, about 18 percent of people who received topherson experienced serious adverse events, compared with 14 percent of those who did not. But FDA staff noted that many of the reported events were related to “exacerbation of the underlying disease,” not toferson use. None of the adverse events were fatal.

Public applications for approval.

During public comments, Alison Burrell said her family believes Tofferson significantly slowed the progression of the disease in her husband, Corey, who died in 2019 from a rare form of ALS. He participated in Biogen’s initial clinical trial on tofersen and continued to use the drug thereafter. The trial resulted in what Borrell believes extended his life by another six months.

“Tofferson gave Corey time with his boys, making memories and showing them to never give up,” Brill said. “I ask you to please recommend your approval in support of Topherson. 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 a rare form of the disease, but she was taking Topherson. extended his life by several months and “gave us that precious time together.”

“It’s a miracle, a miracle to have access to a drug that specifically targets our genetic variation and extends our lives,” Haddad said. She added that she herself is enrolled in an ongoing trial called ATLAS on Biogen’s topherson and is being monitored for ALS symptoms.

“We all know that early intervention leads to better outcomes. Without Tofferson, I have no chance of survival and I have no hope,” Haddad said, adding: “Today you have me and my family. has the power to help the legacy of death.”

More research on Tofferson ahead

Biogen outlined its plans to validate Toferson’s benefits if the drug wins fast-track 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 SOD1 mutations.

Biogen said the study was launched in 2021 and included 150 participants, which is about 50% of the SOD1-ALS population to date. The company also plans to continue to evaluate data from the ongoing expansion of the Phase III clinical trial, which is expected to conclude in 2024.

“Biogen is committed to confirming the clinical benefit of toferson for SOD1-ALS as soon as possible,” said Stephanie Fredette, Biogen’s clinical development lead and head of the ALS portfolio.

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