Aduhelm is the first new Alzheimer’s drug in nearly two decades. But some disease experts express doubts on whether it can actually slow down cognitive decline.

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The U.S. Food and Drug Administration just approved a controversial drug meant to treat Alzheimer’s disease. With the condition affecting nearly 6 million people in the country, and with these numbers being expected to triple over the next 40 years, millions of Americans have anticipated the historic decision. 

However, the regulating agency’s very own independent advisory committee and disease experts are casting doubts about the decision, saying more evidence is needed to show the drug’s effectiveness. 

But now that the FDA has green-lighted an allegedly unproven treatment that also carries a wide array of risks, do we expect a slew of Aduhelm lawsuits in the near future?

How Does Aduhelm Work?

If you look at the brain of an Alzheimer’s patient through imaging techniques, you’ll get to see clear and undeniable damage. And the majority of this damage is because of the accumulation of two specific proteins, beta-amyloid and tau. 

Some scientists believe in a theory called “the amyloid hypothesis,” which states that preventing the accumulation of beta-amyloid would slow down or prevent cognitive decline and memory problems linked to Alzheimer’s, which explains why much of the attention has been on this protein when it comes to treating the disease.

The drug, aducanumab, which will be sold under the brand name Aduhelm, is an anti-amyloid monoclonal antibody that is meant to be administered intravenously once a month. It is intended to slow the worsening of Alzheimer’s by targeting the brain-destroying toxic protein, beta-amyloid. 

It is said to be the first treatment to attack the root cause of the condition, unlike other drugs that address the very symptoms of Alzheimer’s. 

The FDA has granted approval to the drug through the accelerated approval pathway, which allows for earlier approval of drugs that treat a serious illness where there is an unmet medical need based on a surrogate endpoint. 

In clinical trials, a surrogate endpoint is a substitute indicator used in place of a stronger indicator to tell that a treatment works. In Aduhelm’s case, the surrogate endpoint is its ability to clear beta-amyloids. 

However, in past trials, a number of drugs have also worked on clearing beta-amyloids, for which they were successful, but demonstrated no clinical benefit in slowing down cognitive decline. 

The accelerated approval program is given by the agency on a conditional basis, which means that Biogen, the manufacturer of the new Alzheimer’s drug, will have to conduct a large, post-approval clinical trial to show that Aduhelm and its ability to remove the toxic proteins have clear benefits on cognition. 

If the company fails to do so, FDA has the authority to withdraw its approval of the treatment. 

Aduhelm Approval: A Timeline

It’s not everyday that you get to witness a company stop its trials on a supposedly promising drug that it is developing, and then months later, ask the U.S. Food and Drug Administration to reconsider its approval — but that’s exactly what happened with Aduhelm. 

Aducanumab or Aduhelm, developed by Biogen and its partner, Japanese pharma Eisai, has been a closely watched medicine for a long time. And in the field of Alzheimer’s where treatment after treatment failed to demonstrate a significant improvement in cognition, it’s no wonder Aduhelm had scientists and experts buzzing. 

At first, the drug seemed to be promising, but many casted their doubts on its effectiveness as time passed, with questions mainly looking for an important thing: a solid conclusion. 

How did the company go from stopping its trials to reversing its decision and asking the regulating agency once again to consider sales of the Alzheimer’s drug? 

To answer this question, it’s important to look at the timeline of events that brought the drug to where it is today:

March 2015 – Biogen (then Biogen Idec) presented data from the analysis of PRIME, the Phase 1b study of aducanumab, at the 12th International Conference on Alzheimer’s and Parkinson’s Disease in Nice, France.

In the data presented, aducanumab showed acceptable positive results on clinical and radiologic measurements in patients with mild Alzheimer’s Disease. The presentation of the data quickly took the conference by storm, with mixed positive and cautiously positive reactions from experts. In the end, the announcement alone was enough to shoot up Biogen’s shares by 10 percent.

August 2016 – A Phase lb study was published, based on one year of monthly intravenous infusions of aducanumab in patients with mild AD, accompanied with brain scans to measure beta-amyloid plaques. 

The results were said to be convincing enough to justify further development of the drug for the treatment of AD. As such, Biogen announced that it would not conduct a Phase 2 trial for aducanumab, as FDA did not require the company to do so. This decision received criticism from a number of experts. 

This is because Phase 2 is a crucial stage in drug development. According to an article written by Dr. Jason Karlawish, an Alzheimer’s disease specialist at the University of Pennsylvania, “Phase 2 results are an opportunity to learn how to dose a drug to achieve the right balance of safety and benefit, a fact of great importance for aducanumab.”  

September 2016 – Biogen launched two global Phase 3 clinical trials of aducanumab called ENGAGE and EMERGE. However, as Dr. Karlawish noted in the article, skipping phase 2 trials meant that the two phase 3 clinical trials did not have enough information on effective doses of the drug. 

In fact, as the company was enrolling participants for the trials, they were also learning about dosing and had to make changes on the instructions on the dosage given to people who are APOE4 carriers. APOE4 is a gene linked to late-onset Alzheimer’s. 

March 2019 – Biogen and Eisai announced that they are cancelling the clinical trials after an independent committee’s analysis showed they were unlikely to hit their primary endpoint. 

October 2019 – Biogen announced that it would restart pursuing regulatory approval for the drug. It turns out that a larger dataset showed that the Phase 3 EMERGE trial indicated that higher doses reduced the rate of clinical decline by 23% versus placebo.

However, the identical ENGAGE trial failed to demonstrate the same results, with only 2% reduction in clinical decline versus placebo. 

December 2019 – Biogen presented the findings in the final analysis at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) Conference. Many experts were skeptical about the full data, but the company thought it was enough to file for a BLA, or a Biologics License Application, which is an application for the approval of marketing of any licensed product. 

August 2020 – Submission of the BLA by Biogen was completed. The company also requested Priority Review. 

November 2020 – The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted against the approval of the drug. The agency, however, decided to continue with the review process for aducanumab, and said it was pushing its decision on whether to approve the company’s application for BLA from March to June 7.

June 7, 2021 – FDA grants accelerated approval for aducanumab

The Scientific Community Reacts

The FDA decision quickly became controversial not only among doctors, but also among the agency’s own advisers.  

In a JAMA article, FDA advisers Caleb Alexander, M.D., Scott Emerson, M.D., Ph.D., and Aaron Kesselheim, M.D., the same advisers who reviewed Biogen’s clinical data on aducanumab and strongly objected to its approval during an FDA advisory committee meeting in November 2020, restated in the article why they were not convinced of the drug’s effectiveness.

According to the three experts, the analysis reported by Biogen failed to explain why the two Phase 3 clinical trials involving aducanumab generated dissimilar results. They added that the long history of failures in clinical trials that focus on destroying amyloids means that the difference between the results of the company’s two trials are indicative of a false positive finding.    

The experts also threw shade on how the regulating agency and Biogen had combined efforts in determining whether the available data is enough to file for approval. “This undertaking reflected an unusual degree of collaboration between the FDA and the manufacturer of aducanumab, and the arrangement has been criticized as having potentially compromised the FDA’s objectivity,” the experts wrote. 

Dr. Patricia Cavazzoni, director of the FDA Center for Drug Evaluation and Research, said that despite data on Aduhelm being complicated because of uncertainties in its clinical benefits, the agency approved the drug because the need for treatments is urgent and because the ability of the drug to reduce beta-amyloid plaques is likely to have benefits in AD patients. 

To many AD patients, the approval granted to Aduhelm means looking forward to a better life, and that’s also what supporters of the drug choose to emphasize. 

“Accelerated approval based on a biomarker and requiring a confirmatory trial is a common FDA strategy for cancer drugs and was a good approach for aducanumab,” Jeffrey Cummings, MD, ScD, of the University of Nevada in Las Vegas, told MedPage Today. “Patients get the drug without waiting 5 more years, and additional data will help us understand the efficacy and safety of the treatment.”

However, some Alzheimer’s doctors who believe that the approval granted lacked enough evidence see this as a new challenge and a huge responsibility. Now that the drug is approved, doctors will feel obliged to prescribe it, since they know that many patients would willingly try the drug and ignore existing problems because it is FDA approved.

Some experts also fear that the approval is based on weak scientific evidence, and that allowing unproven treatments may affect FDA’s standards for other serious illnesses that also lack treatments. 

Aduhelm Risks and Side Effects

Old man and woman

A known risk of Aduhelm include amyloid-related imaging abnormalities or ARIA, which is characterized by an inflammation of the brain accompanied with bleeding, which can be mild or fatal if not properly monitored.

In fact, in the clinical trials, 41% of Aduhelm-treated participants experienced this side effect, which was detected by MRIs. The most common symptom from the side effects was headache, which was experienced by 24% of those who suffered from brain swelling and bleeding. Others also had nausea and dizziness. These side effects prompted 6% of participants to withdraw from the trial. 

The FDA’s advice is to monitor patients regularly for any side effects using MRIs. However, doctors see this as another problem because this kind of monitoring is more difficult when done outside of a clinical trial. 

The same side effects were seen in past trials of anti-amyloid drugs. However, many experts still believe that it does not have enough evidence to convince them to push for its approval. 

A Potential Blockbuster Drug for Biogen

Although deemed a failure just two years ago, Aduhelm is now projected to be a blockbuster drug for its manufacturer. And that’s despite the fact that the approval from FDA didn’t specify which patients are eligible to receive the IV drug, as only patients with early-stage Alzheimer’s with amyloid deposits in their brains were studied in the clinical trials. 

Even so, demand for the drug is expected to be sky high, as around 6 million Americans are affected by Alzheimer’s and these staggering numbers of patients are likely to be eligible to receive the drug. 

But another problem with taking Aduhelm is that patients have to undergo expensive brain scans first to determine if they are eligible to receive the drug, and then it must be administered once a month via intravenous infusion at a medical facility. 

Biogen said it would charge around $56,000 a year for each patient. However, billions of dollars in additional costs are expected with the screening and monitoring stages per patient, and these figures are likely to be covered by Medicare, which, according to its spokesman, is still reviewing the agency’s decision. 

There is much confusion, however, if other insurers are going to cover it, as they would have to decide whether a 22% reduction in cognitive decline in patients receiving the highest dose of the drug is remarkable enough to be grounds for reimbursement. 

But even with all these problems, Brian Skorney, an analyst at Robert W. Baird & Company, told The New York Times that the drug will most likely generate $7.5 billion in revenue in 2025. “This changes it from a declining revenue company to a growth company,” he added.

What’s the Future Like for Aduhelm?

The approval of Aduhelm or aducanumab has quickly divided the scientific community, with some being enthusiastic about the FDA decision, and some who are unpersuaded by it. 

However, this is not the first time that an approval granted by the FDA has been controversial in the past years. For instance, the hernia mesh medical device, which was approved through a fast-track program that rushes products onto the market, quickly led to complications in patients and ultimately resulted in thousands of lawsuits.

Several hernia mesh lawsuits filed by plaintiffs involved defective hernia mesh products which made them suffer from a plethora of side effects and permanent complications.

And now, with all these looming concerns from experts about the Food and Drug Administration approving an Alzheimer’s drug that has not been proven to work better than a placebo, carries some risks including brain swelling and bleeding, and puts patients on a lifetime procedure of pricey MRIs and doctor visits, it is likely that Aduhelm lawsuits are also to be expected in the future.

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