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The New Alzheimer’s Drug Aducanumab (Aduhelm®):  Noteworthy on Many Levels

The latest buzz in medicine came this week when the Food and Drug Administration (FDA) approved a new medication for the treatment of Alzheimer’s Disease. The monoclonal antibody generically known as aducanumab has the brand name of Aduhelm®.  Its approval is noteworthy for several reasons: 

  • It is the first drug approved for treating Alzheimer’s since 2003;
  • It works in a totally different manner than the existing 2 classes of dementia drugs; and
  • Its approval is highly controversial for reasons I will highlight below.

Alzheimer’s Disease impacts over 6 million patients and millions of unpaid family caregivers. It is a progressive disease that causes irreversible decline in cognitive and day-to-day physical functioning. It is understandable to be excited about the potential surrounding this new drug therapy. But this drug has a unique situation. Here are the main issues that will help you get a better sense of the value and controversy behind the drug Aduhelm.  

Alzheimer’s Disease is characterized by clumps of amyloid, a type of protein, that accumulates in the brain. Aduhelm is a monoclonal antibody that specifically targets amyloid and has been shown in clinical trials to reduce these deposits. However, this effect occurred only with the highest dose tested. Aduhelm is the first drug to successfully reduce amyloid plaques. This is noteworthy because amyloid plaques are believed to be one of the causes of Alzheimer’s Disease, and the drug therefore has the potential to alter the course of disease progression. We believe but currently do not know for sure if reducing the amyloid deposits actually will translate to improvement in the signs and symptoms of Alzheimer’s Disease.

So, what is the controversy? The controversy surrounding FDA approval of Aduhelm stems from the questionable effectiveness of the drug in clinical trials along with safety concerns. Two effectiveness studies were started in 2018 with a goal of enrolling over 3000 patients. They were halted in March 2019 after enrolling only a fraction of the targeted number of patients because a planned interim data evaluation determined that the studies’ clinical endpoints could not be reached. Rather than give up on the study drug altogether, researchers subsequently looked back at the data collected from the partially completed studies. They identified that in one of these two halted studies, data from a subset of patients receiving the higher dose of the medication did achieve the primary endpoints of the study. Long story short, the manufacturer subsequently brought these positive findings to the FDA. Unfortunately, this kind of unplanned evaluation of data, and especially from a study that was halted early, justifiably raised many scientific eyebrows.

In November 2020, the FDA Advisory Committee reviewed the data on aducanumab. All 10 committee members voted to not recommend aducanumab based on lack of effectiveness and safety concerns. The Advisory Committee’s vote is merely a recommendation to the FDA and is not binding.

Fast forward to the June 2021 decision, the FDA approved aducanumab on the condition that additional, post-marketing studies (referred to as Phase 4 trials) will be conducted to verify its clinical benefit. In other words, studies to prove that the drug is effective in achieving its ultimate clinical outcomes of improved cognitive and physical functioning are being conducted after the drug is already approved. This is highly atypical of the usual US drug approval process but is consistent with the FDA’s Accelerated Approval Program. Another clinical consideration when using Aduhelm is that the drug was studied only in patients in the early stage of the disease. The ability to reduce amyloid deposits might be different in more advanced stages of the disease. Yet, the FDA granted approval for treating Alzheimer’s Disease (in general), without specifying mild, moderate or severe stage.

The widely anticipated announcement of the FDA’s decision regarding Aduhelm was immediately followed by a deluge of conversation in the press and on social media. In response to the extensive “attention surrounding this approval,” by mid-afternoon of that same day, the FDA released a follow-up statement reaffirming its procedure to approve the medication: “At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward.”

Given the current questions about clinical benefit of Aduhelm, and until we have more information, it is important to consider other burdens of using this drug:  

  • It requires a one-hour intravenous infusion every four weeks.
  • It takes seven months of treatment before the full, effective dose is reached; Aduhelm must be started at low (subtherapeutic) doses that are increased every two months.
  • Brain MRIs are required before therapy is started, at seven months (when full dose is reached), and again six months later to monitor for a possible side effect in the brain. This side effect was seen in about 40% of patients in the clinical trials.
  • Finally, the manufacturer priced the drug at $56,000 per year, far higher than what experts estimated and deemed reasonable based on cost-effectiveness analyses.

In summary, the approval of Aduhelm is noteworthy on many levels. Alzheimer’s Disease is a devastating condition that affects millions across America. Any therapeutic option that offers hope is worth considering, which is where the FDA landed this time. However, whether the benefits exceed the risks associated with this drug are foggy at best right now. Our existing drug therapy options for Alzheimer’s are no panacea and are associated with important side effects. Unfortunately, we may be at the same point with the new drug Aduhelm, but we need to await results of the Phase 4 studies.

Written by Hedva Barenholtz Levy, PharmD, BCPS, BCGP

6-8-21

This material is intended to encourage discussion with your health care provider.  It is informational only and does not replace the guidance of your health care team.