FDA Finally Approved an Alzheimer’s Drug–But Everything Surrounding It Is Controversial

Analysis

Aduhelm, the name used to market the Alzheimer’s medication Aducanumab. Biogen, a U.S. firm developed the drug. It is intended to be given intra-venous every four weeks.

The Food and Drug Administration (FDA) approved Aducanumab in June 2021, making it the first Alzheimer’s disease medication approved by the FDA since 2003. This is the first approved Alzheimer’s medication to target amyloid beta, a protein type that can cause brain plaques.

However, nearly everything is controversial about the drug, including the theories behind its development, the data from clinical trials, and the FDA approval. The purpose of this article is to simplify the complex information into a handful of points that might assist patients in making more informed decisions.

Key Dates Surrounding the FDA Approval of Aducanumab

July 2020: Biogen completes submission of aducanumab data (from previously discontinued clinical trials) to FDA.

November 2020: FDA external advisory committee rejects aducanumab because the data failed to prove the drug’s efficacy in reducing cognitive decline in Alzheimer’s patients.

June 2021: FDA grants accelerated approval for aducanumab for patients of all stages of Alzheimer’s disease, on the condition that Biogen conducts post-approval trials (phase 4 trials) to verify the efficacy of the drug.

Biogen’s Troubled Clinical Trials

Biogen started two practically identical phase 3 clinical trials in August 2015 to evaluate the safety and efficacy of different aducanumab doses in patients with early stage Alzheimer’s disease.

But in March 2019, Biogen terminated the trials after an interim futility analysis, run by an independent data-monitoring committee, predicted that the trials were unlikely to meet their primary outcomes.

Only seven months later, in a surprise press release, Biogen revoked its earlier decision citing that a new analysis with another three months of data produced positive results. The company stated, “The positive results of this new analysis were driven primarily by greater exposure to high dose aducanumab in the larger dataset as compared to data available at the time of the futility analysis.” In the same press release, Biogen announced its plan to apply for FDA approval, “based on discussions with the FDA, the Company plans to submit a Biologics License Application in early 2020.”

FDA Granted Approval Despite Experts’ Disapproval

It is a routine procedure for FDA to invite experts from “outside of the government with minimal conflict of interest,” to establish advisory committees outside the government and make non-binding suggestions for FDA consideration. In November 2020, the Peripheral and Central Nervous System Drugs Advisory Committee voted almost unanimously against the approval of Aducanumab. Out of the 11 members in the committee, 10 voted against the approval and one was uncertain.

Seven months later in June 2021, FDA granted accelerated approval to aducanumab as a treatment for patients of all stages of Alzheimer’s disease. FDA stated that accelerated approval allows drugs to treat serious medical conditions, such as Alzheimer’s disease. The FDA granted 2020 accelerated approval to aducanumab for patients with all stages of the disease.

Dr. Patrizia Cavazzoni, Director of FDA Center for Drug Evaluation and Research, wrote in a post-approval statement that the clinical trials data show a reduction in the amyloid-beta plaques, which “is expected to lead to a reduction in the clinical decline of this devastating form of dementia.” Cavazzoni also acknowledged that “the data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit.”

According to Biogen, although its clinical trials did not prove that the drug could slow down the progression of cognitive decline, they showed a reduction in amyloid beta plaque. FDA approved the drug quickly based upon the expectation that reducing amyloid-beta deposits would lead to a slower rate of cognitive decline among Alzheimer’s patients.

Along with the approval, FDA gave Biogen another opportunity to prove the assumption is true via post-approval trials (phase 4 trials), which is due by February 2030. Aduhelm must have been available for at least nine years to prove its effectiveness. FDA may remove the drug from market if the manufacturer fails to prove the benefit clinically nine years following the accelerated approval.

Another detail regarding the FDA approval of the drug is that it was originally approved for patients suffering from all stages Alzheimer’s disease. The FDA restricted the FDA’s treatment of patients suffering from early-stage Alzheimer’s disease one month after approval.

FDA Advisory Committee members Resign

Three members of the Peripheral and Central Nervous System Drugs Advisory Committee resigned within the first week after FDA approval. These were Joel Perlmutter from Washington University and St. Paul, Joel Perlmutter at Washington University in St. Louis, David Knopman (Mayo Clinic) neurologists, Dr. Aaron Kesselheim of Harvard Medical School. Louis.

In his resignation letter, Kesselheim called the FDA move “probably the worst drug approval decision in recent U.S. history.” Kesselheim also wrote on Tweeter, “Accelerated Approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval.”

Accelerated Approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval.

— Aaron Kesselheim (@akesselheim) June 7, 2021

Knopman and Perlmutter published a comment in Neurology in July 2021. They wrote, “the clinical benefit amounted to about 3 months’ worth of delay in decline over a year,” referring to the “positive results” in Biogen’s press release in October 2019. The authors stated that “Combining results from both trials showed no statistically significant clinical advantage for high-dose aducanumab .”

Side Effects & Safety Questions

Brain bleeding and swelling are possible side effects for Aduhelm. Before the FDA approval, Biogen did two phase-3 studies. The phase 3 studies started in August 2015, but Biogen pulled the plug on both studies three and a half years later, in March 2019. A futility analysis by an independent data monitoring panel found that the trials would not meet their primary goal. The trials did not prove that the drug could slow down cognitive decline in Alzheimer patients.

The safety data from the terminated phase 3 trials were published in JAMA Neurology in November 2021. Study was focused on Amyloid-related Imaging Abnormalities (ARIA), which may cause confusion, headaches, nausea and brain bleeding.

The data showed that 425 out of 1,029 patients, or 41 percent, who received the high dose of the drug–the dose that the FDA later approved–experienced either brain swelling or bleeding. Furthermore, 64 patients had to stop participating in the trials because of brain swelling or bleeding.

In September 2021, months after approval, a 75-year-old woman, a clinical trial patient who lived in Canada, experienced brain swelling after receiving infusions of the drug and died a few days later.

The Amyloid-beta Hypothesis

The theory behind Aduhelm, and other experiments in Alzheimer’s treatment is that excessive amyloid beta plaques within the brain can cause cognitive decline and disrupt normal brain communication.

In fact, the name of the disease comes from Alois Alois, a German pathologist who found amyloid beta plaques in the brains of patients.

But this hypothesis is not supported and it remains controversial.

Three-Quarters of FDA Funding Is From Drug Makers

The Project on Government Oversight is an independent, non-partisan watchdog. It investigates, exposes, and punishes corruption and abuses of power.

A two-part investigative report by POGO details the fact that the FDA is in the pocket of the industry it regulates. According to the report, almost three quarters of funding for FDA’s work is provided by drug manufacturers .

Part II of the report exposes the “voice” of the patients at FDA meetings is often funded by drug companies as well.

Japanese and European Agencies Disapprove of Aduhelm

In October 2020, Biogen applied for market permit in Europe. In December 2021, six months after FDA’s accelerated approval of Aduhelm, the European Medicines Agency rejected Biogen’s application to market Aduhelm in Europe.

The EMA thought that “the risks and benefits of Aduhelm were not outweighed by the potential for harm.”

In the same month Japan’s Committee on New Drugs rejected Biogen’s application and asked for more information to support the drug’s effectiveness.

Other Decisions from US Insurance and Hospitals

In an unusual move right after European and Japanese agencies rejected the drug, Biogen cut the price of Aduhelm in half from $65,000 to $28,200 per patient per year in the United States. Others believe it was in anticipation of the Center for Medicare and Medicaid Services covering the costs for American patients.

In April 2022, CMS announced that Medicare will cover the cost of Aduhelm only for Alzheimer’s disease patients enrolled in qualifying clinical trials. This coverage decision was met with “strong disagreement” from Biogen, whose CEO stated that the decision will “deny nearly all Medicare beneficiaries the right to access Aduhelm.”

Major hospital systems Cleveland Clinic and Mount Sinai decided not to prescribe Aduhelm due to concerns over its efficacy and safety, in July 2021.

US House Committee Investigates

The House Committee on Oversight and Reform announced an investigation stating “serious concerns about the steep price of Biogen’s new Alzheimer’s drug Aduhelm and the process that led to its approval despite questions about the drug’s clinical benefit” in June 2021.

In the months that followed, the House Committee asked both Biogen (and FDA) to produce records. The FDA was contacted by lawmakers who expressed concern at apparent flaws in the FDA’s review of Aduhelm and the lack of coordination between Biogen and the FDA.

The investigation’s results are not yet available.