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Wednesday, July 28, 2021

Alzheimer’s Drug Debuts to Controversy

Excitement over Biogen’s aducanumab to treat Alzheimer’s has been muted by scientists’ doubt about its effectiveness.

For the first time in 18 years, U.S. health regulators approved a new drug in June to treat Alzheimer’s — in spite of concerns over whether or not the therapy is effective. Biogen’s Aducanumab is the first drug approved to treat a cause of the disease. But many experts were skeptical that clinical trials demonstrated the drug could delay cognitive decline. 

Aducanumab reduces a buildup of protein in the brain called amyloid-β, which has a correlation to Alzheimer’s. Some scientists think that it causes the disease. However, the relationship is still being studied.  

The FDA approved the drug based on two phase III trials that were halted in March 2019 when they were still ongoing. At that time, researchers looked at the data and concluded it did not warrant continuation of the trials. 

In an unusual move, Biogen revived the drug application months later after taking a deep dive into the data and determining that in one of the trials, those patients who got the highest dose of the drug had a statistically significant reduction in cognitive decline. Aducanumab showed no benefit at lower doses in that trial, and no benefit at any dose in the other trial. The trials, with their associated data, remain unpublished and incomplete.

Huge Need

Worldwide, 35 million people have Alzheimer’s, an incurable, progressive neurodegenerative disease. That number is expected to rise as the population ages. Aducanumab has only been tested on people with the early stage of the disease.

The aducanumab antibody is the latest in a line of drugs aimed at amyloid plaques; every other contender has failed to demonstrate improved cognition. Many scientists are skeptical that these plaques are even the right place to look for a treatment, much less if researchers are targeting the correct patients at the correct doses.

“The problem with most of the amyloid trials is that they didn’t disprove anything,” says Bart De Strooper, director of the UK Dementia Research Institute in London. “They just proved that a drug, in the way it was applied, didn’t work.” After evaluating the data, an independent panel of experts argued that Biogen’s interpretation was incorrect. Scott Emerson, a biostatistician at the University of Washington in Seattle and panel member, said the drug company’s approach was like “firing a shotgun at a barn and then painting a target around the bullet holes.”

The director of the University of Southern California’s Alzheimer’s Therapeutic Research Institute in San Diego, Paul Aisen, also consults for Biogen. He says the drug is “an effective therapy.” But even Aisen admits that “this was a problematic data set. It was a very fraught situation.”

And then there are the side effects. In both trials, almost 40% of patients developed brain swelling. While most had no symptoms due to the swelling, it has the effect of necessitating regular brain scans in patients taking the drug, creating a load for patients, treating neurologists, and health-care systems.

FDA Grants Accelerated Approval

While 10 of 11 panelists at the meeting in Novermber concluded that the data did not demonstrate effectiveness of the drug (one panelist was uncertain), the FDA seemingly discarded that input when it approved the drug in June. Three panelists have since resigned their positions. In his resignation letter, Dr Aaron Kesselheim, a professor of medicine at Harvard Medical School, wrote that the FDA’s decision was “probably the worst drug approval decision in recent history.” He added, “This will undermine the care of these patients, public trust in the FDA, the pursuit of useful therapeutic innovation, and the affordability of the health care system.”

The FDA changed its review to the accelerated approval program, usually reserved for cancer treatments. This means that Biogen now has nine years to complete a “post-marketing” trial to confirm the drug’s usefulness. Scientist worry this sets a poor precedent. “This opens the door to drug companies seeking to use the accelerated approval program as a way of getting drugs on the market based on extremely low-quality evidence or boost-hoc data fishing,” says Kesselheim. 

However, the director of the FDA’s Center for Drug Evaluation and Research disagrees. “We decided that the accelerated approval pathway fits well here,” says Dr. Patrizia Cavazzoni. It “allows for there being some residual uncertainty on the drug’s clinical benefits while making the drug available to patients rather than having to wait.”

Researchers are also wary that the emphasis will now be on similar, anti-amyloid drugs at the expense of other targets, such as those seeking to clear another toxic protein called tau. “This is going to set the research community back 10-20 years, says George Perry, a neurobiologist at the University of Texas at San Antonio.

Banking On Biogen

Meanwhile, Biogen’s stock price leapt up to close 38.3% higher on the day of the announcement, its highest level in six years. The company said that it would sell the new drug, marketed as Aduhelm, for $56,000 a year. 

Medicare is expected to cover 85-90% of those eligible for treatment: people who are in early-stage Alzheimer’s and test positive for a component of amyloid brain plaques. Although the FDA approval doesn’t limit use to a specific group, it’s unlikely that either Medicare nor any payer would make it available for a broader population. 

With approximately 1.5 million Americans eligible for treatment, which is administered via a monthly infusion, Wall Street analysts are projecting peak annual sales in a range from $10 billion to $50 billion. 

Japanese drug company Eisai has been observing developments closely. It has rights to 55% of profits on aducanumab in the U.S. and 80% in Japan and most of Asia. Japan has a huge population of older adults, but Credit Suisse pharma analyst Fumiyoshi Sakai predicted its national health care system would limit annual sales there to about $914 million. Shares of Eisai were quickly bid up to their daily limit after the announcement. 

Approval of aducanumab sent shares of other companies developing Alzheimer’s treatments soaring. Maria Carrillo, chief science officer for the patient-advocacy group Alzheimer’s Association in Chicago, thinks such signs are hopeful. “History has shown us that approvals of the first drug in a new category invigorate the field, increase investments in new treatments and encourage greater innovation,” she says. 

Only time will tell who is right.