Long-awaited ALS drug could pave the way for more brain treatments

The US Food and Drug Administration (FDA) will soon make a decision on the approval of new drugs for a rare form of amyotrophic lateral sclerosis (ALS). The long-awaited decision is expected to demonstrate the agency’s vision for nerve drugs and its willingness to be flexible in regulating these therapeutics.

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New treatments are desperately needed because people with this disease face a degenerative condition that causes neuronal cell death, usually leading to fatal respiratory failure within three years of symptom onset.¹Tofersen, developed by Biogen, a biotechnology company of Cambridge, Massachusetts, and Ionis Pharmaceuticals of Carlsbad, California, did not slow patient decline in a Phase III trial.²However, some say the exam is too short. Others point to beneficial signs, such as a reduction in a biomarker of neuronal damage and death called neurofilament light chain (NFL). For this reason, Biogen has asked the FDA to approve the drug on an “accelerated” basis to ensure that future trial data will determine its efficacy and get it to patients faster.

If approved, tofersen would be the latest example of the agency’s evolving approach to neurodrug development that could boost industry investment in brain diseases. A vote of confidence for this drug would also increase interest in using the NFL as a tool to measure brain health and test drugs in the future. hmm,” says Valentina Bonetto, a neuroscientist at the Mario Negri Institute of Pharmacology in Milan, Italy.

Nature We are looking at how this decision, which is due by April 25th, will change the nerve medicine landscape.

Will the FDA approve tofersen?

In March, FDA convened a panel Describe the tofersen dataset. Her nine independent advisers unanimously endorsed that the available evidence supports the “reasonably likely” possibility that Tofelsen would help her SOD1 ALS patient, and that the drug rallied in favor of early approval of This rare disease is caused by genetic mutations that affect the protein SOD1, which forms toxic masses in motor neurons in the brain, brainstem, and spinal cord. Government agencies typically follow advisory committee recommendations.

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The antisense drug tofelsen binds to SOD1 mRNA and slows the production of the protein. By reducing the accumulation of neurotoxins, Tofelsen aims to conserve motor neurons and help people live stronger and longer.

Biogen to Test Tofelsen in Phase 3 VALOR Trial²SOD1 108 ALS patients received tofelsen or placebo. At the end of the six-month trial, the drug was assessed using her ALSFRS-R, a questionnaire that tracks changes in physical function over time. Recipients of Tofelsen did less well than recipients of placebo, according to this study. However, the drug did reduce levels of both SOD1 and NFL. The results of an open-label extension of the trial indicated that 6 months may be too short to see efficacy.

FDA advisers cited this “line of evidence” as a reason in favor of expedited approval. However, they did not support full approval and voted against 5 to 3 (with 1 abstention). Some panelists believe this is important, as full approval requires little or no follow-up of the drug. “Does the data provided collectively … provide a convincing level of efficacy?” asked Tanya Simuni, a neurologist at Northwestern Medicine in Chicago, Illinois. “The short answer is no. …we need more data.”

What does this mean for future nerve medicines?

The FDA’s willingness to scrutinize and discuss the tofersen data highlights the agency’s new flexibility in neurological drug development. Robert Baloh, Global Head of Neuroscience, Novartis in Basel, Switzerland, said: “Companies look at this and think, ‘Oh, we should do business in that space because it increases our chances of success.'”

Tofersen’s deliberations also highlight the rise of the NFL as a drug development tool.

NFL is a rod-shaped protein that serves as an internal scaffold for neurons. When a neuron is damaged or dies, it drains her NFL debris into the cerebrospinal fluid and blood. Neuroscientists have long speculated that levels of NFL could be used to measure brain health. The use of this marker gained momentum in laboratories and clinical trials about a decade ago after researchers discovered how to accurately measure NFL levels in the blood.³.

Pharmaceutical companies have incorporated NFL tracking into nearly 100 clinical trials for a variety of diseases, including Alzheimer’s, Parkinson’s, and Huntington’s (see Biomarker Adoption). However, that measurement has not yet been used for regulatory approval. For Jens Kuhle, a neurologist at Basel University Hospital in Switzerland, Tofelsen’s endorsement would be “an important testament to NFL principles.”

Kuhle said the NFL could be used as a tool to figure out which multiple sclerosis drugs work best for which patients, paving the way for “personalized” neurological prescribing. He speculates that one day NFL measurements may be used more widely to identify and track brain damage as part of routine care. He said, “In the future, I’m sure people will measure NFL when they go to their GP, just like they measure cholesterol.”

Will tofersen defuse or reignite the debate over the FDA’s use of accelerated approval for nerve drugs?

In 2021, the FDA approved aducanumab, developed by Biogen, for the treatment of Alzheimer’s disease.its accelerated approval divided the neuroscience communityand later an inquiry by the U.S. Congress found that “Full of irregularities”Critics questioned not only the reliability of the data on aducanumab, but also Biogen’s choice of a budget-busting price tag for the drug.

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Tofersen’s approval application has important differences, such as the number of people affected. More than 6 million people in the United States have Alzheimer’s disease. Only 330 people have her SOD1 ALS.

Scott Ayton, a neuroscientist at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia, means that these neurodegenerative diseases are “different beasts” and require different regulatory calculations.Ayton Rare diseases need more flexible regulation, he said, because small patient numbers make it difficult to conduct and replicate trials.

But giving Tofelsen the go-ahead isn’t without risks for patients and the clinical trial ecosystem, he adds. “An unintended consequence of these rapid approvals are poorly designed and conducted clinical trials,” he says. In the case of Tofelsen, Biogen designed a Phase III trial that was too short to conclusively assess the drug’s efficacy. Regulators, physicians and patients today need to make the most of definitive data sets. “If the approval threshold is low, the industry wants a lower threshold,” he says Ayton.

When the advisory panel asked about flaws in the trial’s design, Biogen senior medical director Stephanie Fradit said, “We fell short of our target.” But SOD1 ALS is rare. Because of this, she said, there is a limited data set to guide trial design decisions. “Certainly, this is not meant to be an excuse, but an acknowledgment of why things were so different than we expected.”