When is 'water inverse' going on? Biogen's ALS drug approval delayed to next April

Controversial reimbursement limits for the Alzheimer's drug Adderall, layoffs, organizational restructuring and allegations of business bribery... Many "domestic troubles and foreign aggression" have made Bojian tired to deal with, but the negative is not over.

On Oct. 17, Biogen revealed that its amyotrophic lateral sclerosis (ALS) drug Tofersen (BIIB067), originally scheduled for review by Jan. 25 next year, had been delayed by another three months by the FDA for approval, with the latest PDUFA date of April 25, 2023. In July, the FDA accepted Tofersen's new drug application and granted it priority review status.

Tofersen is an antisense oligonucleotide drug developed by Biogen in collaboration with Ionis Pharmaceuticals for the treatment of superoxide dismutase 1 (SOD1) -ALS. Tofersen binds to the mRNA encoding SOD1, allowing it to be degraded by ribonuclease, thereby reducing SOD1 protein production.

ALS is a progressive neurodegenerative disease with progressive skeletal muscle atrophy, weakness and fasciculation as the main clinical manifestations, and is also known as "ALS" in China. The age of onset is generally middle-aged and older, and survival is typically 3 - 5 years. The most common cause of death was respiratory failure. SOD1-ALS is a rare inherited form of ALS that accounts for only 2 percent of the approximately 168,000 ALS cases worldwide. Currently, there is no targeted treatment for SOD1-ALS.

While many genes are known to cause ALS, SOD1 is the most common. Because SOD1 is associated with a patient's family history, the cases it causes are also known as familial ALS. The researchers believe that the remaining 90 percent of ALS cases are called "sporadic ALS." Biogen is working to get Tofersen approved to treat patients with mutations in the SOD1 gene.

Last year, results from Tofersen's six-month VALOR trial showed that the study did not meet its primary endpoint. At the time, though, both Biogen and Ionis noted that many secondary and exploratory endpoint analyses showed a slowdown in disease progression. Later, 12-month consolidation data also showed that early use of Tofersen helped to consistently reduce neurofilament counts (an ALS biomarker) and slow the decline in many efficacy endpoints.

As an unproven alternative biomarker, some researchers have suggested that nutrients may measure neuronal cell death. Biogen is trying to win accelerated approval based on the drug's effect on reducing neurofilaments.

In patients with neurodegenerative diseases, levels of neurofilaments in the blood and cerebrospinal fluid may be elevated..Biogen said that in clinical trials, data showed that Tofersen caused a reduction in the volume of nonviolent activity, so the drug was effective..It should be noted, however, that there is still no broad consensus on the relationship between nutrients and ALS, and the FDA has never approved a drug based on the effect of reducing neurofilaments.

In a news release, Biogen said the FDA had asked for more information, but the company was unclear on what they were asking for. A Biogen spokesman said it "cannot provide additional details on regulatory interactions, but requests for information are standard procedure in the FDA review process."

So far, only three drugs have been approved by the FDA to treat ALS, except for Relyvrio (from Amylyx), which was just approved on September 29th. The others, riluzole, introduced in 1995, and edaravone, introduced in 2017, are less effective.

And the odds seem less clear for Biogen's Tofersen, compared with Relyvrio: Tofersen failed in a Phase III trial, but had an effect on nerve fibers;;Relyvrio, on the other hand, showed statistical significance in a Phase II trial, but no correlation with neural fiber levels, and a Phase III trial is ongoing.

Biogen may be able to speed approval because of the drug's effect on neurofilaments, but Tofersen's path to approval remains unclear given the FDA's cautious approach to ALS drugs.