F.D.A. Approves New Alzheimer’s Drug, Despite Controversy Over Its Effectiveness

The Food and Drug Administration (F.D.A.) approved the first medication designed to attack the Alzheimer’s process, rather than just disease symptoms, in early June of 2021. Aducanumab, which will be sold under the brand name Aduhelm, is a monthly intravenous infusion, and the first new medication for Alzheimer’s approved by the F.D.A. in over 18 years.

Currently Available Alzheimer’s Treatments

Excluding Aduhelm, there are currently only five prescription medications approved by the F.D.A to treat Alzheimer’s symptoms. Three of these medications are cholinesterase inhibitors, the fourth regulates glutamate activity, and the fifth combines the efforts of both. The approved cholinesterase inhibitors, Aricept (donepezil), Razadyne (galantamine), and Exelon (rivastigmine), work to fight the damage Alzheimer’s causes to acetylcholine levels.

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Namenda (memantine) is approved to treat moderate-to-severe AD and works by regulating glutamate activity to help with memory, attention, reasoning, language, and the ability to perform simple tasks. Namzaric combines donepezil and memantine to help treat moderate-to-severe AD. The combined efforts of these medications may improve cognition and overall mental abilities, as well as potentially and temporarily slow any worsening AD symptoms.

F.D.A.’s Approval Process

The F.D.A.’s Center for Drug Evaluation and Research (CDER) oversees the drug approval process before any drug may enter the market. In a drug’s early stages of discovery, known as preclinical research, it is screened for toxicity in animals. Then, after years of laboratory testing and with approval from the F.D.A., the manufacturers may transition to clinical trials testing on humans. Only 1 in every 1,000 compounds that enter laboratory testing make it to human testing.

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Once the F.D.A. approves human testing, the drug must go through three phases of clinical trials. Phase 1 takes about a year to complete, and generally involves 20 to 80 healthy volunteers to test the drugs overall safety. Then, in Phase 2, between 100 and 300 patient volunteers are utilized in a two-year trial involving a placebo medication. At this point, safety and side effects are reviewed before continuing with the trial. Phase 3, the longest phase running an average of three years, typically involves thousands of patients that are monitored in clinics and hospitals, where effectiveness and further side effects are monitored. This phase prioritizes including a wide range of patients in regards to age, race, gender, and severity of illness.

Once Phase 3 is complete, the findings of the clinical trials are presented to the F.D.A. for final approval. At this stage, the F.D.A. can deny approval of the new medication, approve it for market release, or request further information.

Post-Approval Trial

The F.D.A. has recognized that Aduhelm’s clinical trials provided insufficient evidence to demonstrate effectiveness, and therefore granted approval on the condition that Biogen conduct a new trial. While the drug is in the infrequently-visited Phase 4 trial, a several-year post-market study, it will still be available to patients. However, if Phase 4 fails to prove the effectiveness of the drug to the F.D.A’s standards, the organization could rescind its approval.

Director of the Center for Drug Evaluation and Research, Dr. Patrizia Cavazzoni, emphasized that the drug was approved through the accelerated approval program, designed “to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit.”

Although the F.D.A.’s approval is conditional, Aduhelm’s availability on the market places Alzheimer’s doctors, who are skeptical of the drug’s effectiveness, in a difficult position. Many have already expressed an ethical pull to make the drug available to their patients, despite the problematic evidence surrounding the drug.

How Does Aducanumab Work?

Aducanumab is a monoclonal antibody. It targets the protein known as amyloid, which clumps into plaques in the brains of Alzheimer’s patients and is considered to be the biomarker of the disease. There is substantial evidence that the drug is successful in reducing amyloid levels, which the F.D.A. said qualified it for accelerated approval. However, reducing amyloids does not necessarily equate to decreasing or even slowing symptoms of dementia. Through over two decades of clinical trials, it has been proven that amyloid-reducing drugs fail to address Alzheimer’s symptoms. Although Biogen officials claim that decreasing amyloid levels early on will help diminish symptoms long-term, this has not been officially tested or proven in any way.

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The controversy surrounding the approval of Aduhelm primarily involves two of the Phase 3 trials conducted by Biogen. One study suggested that the drug resulted in a slight slow of cognitive decline, while the other resulted in no benefits. Both trials were stopped early by the data monitoring committee who found that aducanumab did not show any benefits. This resulted in over a third of the 3,285 participants being unable to complete their treatments. “There’s so little evidence for effectiveness,” said Director of the California Alzheimer’s Disease Center at the University of Southern California, Dr. Lon Schneider, who also served as one of many site investigators helping to conduct the aducanumab trials. “I don’t know what caught the F.D.A.’s fancy here.”

The F.D.A.’s advisory committee met in November of 2020 to discuss Aduhelm’s approval and even faced division within itself. While an F.D.A. clinical analyst supported approval of the drug, an F.D.A. statistician wrote that another trial was needed as “there is no compelling, substantial evidence of treatment effect or disease slowing.” Ultimately, the committee rejected approval of Aduhelm, resulting in the F.D.A. extending its deadline by three months while requiring additional information from Biogen. Although Biogen has yet to release the submitted additional information to the public, it was apparently sufficient enough for the F.D.A.’s accelerated approval.

What Are The Side Effects?

As with many prescription medications, there are risks to consider. Brain swelling or bleeding was experienced by about 40 percent of Phase 3 participants. While no Phase 3 participants died from the trial or the effects of the drug, one safety trial participant did. However, similar side effects occur with other amyloid-reducing medications, and some doctors consider these effects to be manageable with consistent evaluations and regular brain scans.

What Is The Cost?

Biogen is expected to gain billions of dollars due to the drug’s new availability. Quickly after the F.D.A.’s approval, the company announced the list price of Aduhelm would come out to $56,000 a year. Further, insurer Cigna has projected that diagnostic and safety monitoring expenses will total to around $30,000 per patient during the first year of treatment, followed by half of that each subsequent year that treatment is given. Since Alzheimer’s primarily impacts our older population, most costs are expected to fall to Medicare’s Part B program. However, neither Medicare nor Cigna have announced how they intend to cover the new drug or its associated costs.

Ultimately, each patient living with Alzheimer’s differs from another, and it is imperative to discuss any new medication with your doctor before making any changes. To ensure further clinical trials and new medications are being tested to help end Alzheimer’s, consider signing this petition to demand an increase in funding for Alzheimer’s research.

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