Alzheimer’s Disease, Aduhelm, and The Fear of False Hope

As many have probably heard, the U.S. Food and Drug Administration (FDA) has approved Aduhelm (aducanumab) for the treatment of Alzheimer’s disease. We have not had a drug approved for Alzheimer’s disease in nearly two decades. This is a substantial decision. A good chunk of my vacation has unfortunately involved thinking about this decision. I may even change my mind as I start to discuss this further with patients and families over the next few weeks to months. This Ron Burgandy .gif best summarizes my current state of mind:

I will try to explain the complicated reasoning for this .gif in the following paragraphs.

A New Day

“Alzheimer’s disease is a devastating illness that can have a profound impact on the lives of people diagnosed with the disease as well as their loved ones,” said the director of the FDA’s Center for Drug Evaluation and Research, Patrizia Cavazzoni, M.D.

On this, we both agree. I have dedicated my life to teaching, studying, and caring for those with this complex and devastating brain disease. She goes on to say, “Currently available therapies only treat symptoms of the disease; this treatment option is the first therapy to target and affect the underlying disease process of Alzheimer’s. As we have learned from the fight against cancer, the accelerated approval pathway can bring therapies to patients faster while spurring more research and innovation.”

Harry Johns, CEO of the Alzheimer’s Association, has pushed a similar message, “It is a new day. This approval allows people living with Alzheimer’s more time to live better. For families, it means being able to hold on to their loved ones longer. It is about reinvigorating scientists and companies in the fight against this scourge of a disease. It is about hope.”

A False Hope?

This is where I and many in my field diverge from Dr. Cavazzoni and Mr. Johns. We are concerned this announcement is about false hope. There is a real possibility that this decision slows down research efforts against Alzheimer’s disease. Participants will back out of current trials or decline new trials to try this new drug.

As a disclaimer, I am a contributing member to the Alzheimer’s Association’s ISTAART (International Society to Advance Alzheimer’s Research). I have attended the last 5 Alzheimer’s Association International Conference meetings (they have been fantastic meetings). They have done important work for our patients, caregivers, researchers, and clinicians fighting this disease.

However, the Alzheimer’s Association has curiously lobbied for aducanumab over the past year, despite any new evidence to warrant this support. They have allegedly retaliated against my colleagues for an article raising doubts over the clinical benefits of aducanumab. Was this in the name of scientific integrity, or perhaps something less desirable? The Alzheimer’s Association claims that the $800,000 of support from Biogen has nothing to do with its punishment of my colleagues. They also contend there was no retaliation behind their decision.

Regardless, as evidenced by Biogen’s surging stock price gains on Monday, big dollars were made based on this decision.

The Amyloid Hypothesis

By way of background, the “Amyloid Hypothesis” has been around for 3 decades, and I discussed it in more detail in a previous Ordinary Times article (which ironically has an Alzheimer’s Association banner as the featured image). To summarize, there are biological reasons to support the idea that pathogenic versions of amyloid play a central role in this disease. However, halting production or clearing said amyloid, has not resulted in any clinical benefit for research participants to date. As other colleagues have astutely pointed out, there have been 41 previous trials targeting amyloid production or clearance in Alzheimer’s disease. Amyloid was lowered in 75% of those trials. Yet, despite target engagement, clinical worsening in the drug group over the placebo group was present in 40%. No change or benefit was realized in the remaining trials.

Despite those facts, many have suggested those studies were flawed for a variety of reasonable reasons (wrong patient selection, wrong dose, wrong version of amyloid targeted, etc.). An expansion of Alzheimer’s disease biomarkers has improved enrollment criteria for clinical trials. Aducanumab, jointly developed by Biogen and Eisai, was designed to selectively bind to neurotoxic insoluble fibrillar and soluble oligomeric aggregates of amyloid. The activated immune system then removes the toxic amyloid products. Initial reports out of phase I and II clinical trials showed dose-dependent clearance of amyloid plaques from the brain. More importantly, there was clinical improvement in the small subset of participants receiving the highest doses of the drug. Despite our previous failures, the field was hopeful with these preliminary results.

A New Contender Emerges

This hope spurred the launch of two parallel Phase III trials (EMERGE and ENGAGE). They were designed to evaluate the efficacy and safety of aducanumab in patients with mild cognitive impairment due to Alzheimer’s disease and mild dementia due to Alzheimer’s disease (confirmed with biomarkers of amyloid positivity). These studies recruited 3,482 participants encompassing 20 countries across 348 research sites. For the past 4 years, I have been seeing research participants testing this drug’s efficacy– both at Mayo Clinic and now at the University of Kansas Medical Center. In March of 2019, Biogen surprisingly halted these studies. The primary endpoints would not be met according to a futility analysis.

Primary Endpoints Defined

Given the previous failures, Biogen rightly designed these trials with prespecified primary endpoints for cognitive and functional outcomes – not whether amyloid was lowered. Additionally, both trials needed to meet these outcomes to be considered a success. The initial futility analysis suggested that one study was trending positive while the other study was clearly negative. Biogen’s team of statisticians performed post hoc analyses to determine why the studies had different results. Complicated studies targeting heterogeneous diseases force protocol deviations and amendments along the way.

For example, participants with an APOE4 genotype were initially given lower doses. A known side effect of the drug in APOE4 positive individuals (brain inflammation and bleeding) was the reason given. During the trial, researchers found that after pausing the drug and waiting for inflammation to resolve (evidenced by repeated brain MRI scans), they could push some with the APOE4 genotype to the higher doses without harm. Protocols changed to allow higher doses in more participants.

Moving Goalposts

At this point, it is important to note that the dropout rates were abnormally high for both studies. Fewer than 60% of patients completed the required dose regimen after 78 weeks. After this post hoc analysis, Biogen concluded that in the failed study (ENGAGE), there was a subset of participants who received the highest doses for a longer duration that resembled the clinical improvement of the positive study (EMERGE). This was potentially good news, and the trials planned to re-engage treatment and study visits to better test this hypothesis.

During the FDA expert review, Biogen suggested an imbalance of more rapid progressors (think more aggressive versions of Alzheimer’s) in the treatment arm drove the negative results for the ENGAGE study. A reasonable alternative interpretation is that an imbalance of slower progressors drove the positive results for the EMERGE study. In looking at the data closer, the placebo groups progressed at different rates between the two studies as well. The placebo group in the positive EMERGE study had faster progressors compared to the ENGAGE study. Perhaps this faster progression of the placebo group in the EMERGE study explains the significant difference between the placebo group and the treatment group more than any actual drug effect. Anyone who regularly diagnoses and treats patients with early stages of Alzheimer’s disease knows there is significant heterogeneity in disease progression and is not surprised by this result.

Who Needs Experts Anyways?

In November of 2020, an expert panel gathered to review the above information, including the updated post hoc analyses presented by Biogen. The expert panel overwhelmingly recommended against approval. Out of the 11 expert reviewers, none recommended approval of the drug. The FDA does not have to follow the advisory committee’s recommendations. In fact, in one study, the agency goes against final recommendations nearly 1 in 5 times. Those scenarios were a result of much closer panel decisions.

During the media briefing on Monday, Dr. Cavazzoni tried to address the controversy. She did not quote the published peer-reviewed literature behind these studies, because those do not exist yet. Aduhelm was instead approved via an “accelerated approval” pathway. This pathway is designated for serious and life-threatening illnesses. A drug only needs to meet a surrogate endpoint (reducing amyloid plaques was used in this case) that is “reasonably likely to predict clinical benefit.” Curiously, the other 75% of studies showing amyloid reduction without proven clinical benefit were not mentioned in the media briefing. Two members of that FDA expert panel have since resigned and I expect more to follow.

An Impossible Quagmire

Due to the lack of clinical evidence for the drug, the FDA is requiring Biogen to conduct a new randomized controlled clinical trial to verify the drug’s clinical benefit. This is exactly what many of us in the field think should happen; we just hoped it would be before actual drug approval. It’s unclear where that required trial will take place. I don’t see how it is possible to take place in the United States after this decision. According to the FDA, if that subsequent trial fails to verify clinical benefit, the FDA could withdraw approval of the drug. Let us talk about the ramifications of this decision.

The news coverage of complicated scientific problems has a bad track record, and I have little faith that they will be able to convey the complexities to our patients. We understand that patients, caregivers, and the field of Alzheimer’s research are desperate for better treatments. Desperation is not an indication for fast-track approval. This decision has thrown us into an impossible quagmire that threatens to pit researchers and clinicians against patients and patient advocacy groups. Alzheimer’s research centers and clinics will be overwhelmed with phone calls from patients and caregivers asking if this drug is right for them or their loved ones. And understandably so, given the lack of guidance by the FDA.

The FDA is essentially asking us to run a clinical trial for them and Biogen, not with research dollars, but with substantial healthcare dollars. This is a medication that will cost $56,000 per year, require multiple brain imaging scans, and close follow-up for potentially serious side effects. Even if patients avoid physical harm by Aduhelm, they run the risk of financial harm. Additionally, the FDA is also asking us to expand the demographic population since 80% of the study was Caucasian with Asians making up another 9%.

Approval without Guidance

Even more troubling than the FDA’s decision to approve, is their complete lack of guidance for indications and monitoring. The studies were done in mild cognitive impairment and mild dementia, but they have not outlined which disease stages are appropriate for the administration of Aduhelm. Biomarkers are not needed for the administration of Aduhelm. Despite the fact that trial participants required biomarker positivity for inclusion and the presented evidence that the drug works relies on the modification of said biomarkers. Extensive MRI monitoring with clear indications of when to stop the drug was present in the trial studies. Guidance on MRI monitoring and contraindications to drug administration is lacking in the approval decision.

The FDA will not even require a Risk Evaluation and Mitigation Strategy for Aduhelm. With a positive spin, all these signs point towards removing barriers for patients getting the medication. If we had good evidence that the drug worked and did not harm patients, I would be at the front of the parade. A less favorable interpretation of this barrier removal involves monetary gain. Biogen and its shareholders stand to make more money by treating more patients before another efficacy trial can be completed and the drug potentially removed from the market (if clinical benefits are not realized).

Insurance Companies to the Rescue?

In a twist of irony, it may be insurance companies, that provide us with the needed guidance that the FDA failed to provide. The Centers for Medicare and Medicaid Services (CMS) will likely launch a Medicare National Coverage Determination with an independent review for indications that they will approve coverage of the medication. If we go by the study trial design, one would posit that a patient would need the following:

1. Biomarker proven Alzheimer’s disease;
   • Insurance companies need to regularly cover these tests now
2. A disease severity (stage) of mild cognitive impairment or mild dementia;
3. Guidelines for MRI intervals and when to pause or stop the medication.

Will You Prescribe This Medication to Your Patients?

As one of my colleagues succinctly put it, “Physicians routinely apply a benefit-to-risk analysis when deciding whether to prescribe a drug. In this case, the ability to apply a benefit-to-risk analysis is compromised because we do not know what the clinical benefit is.” Practicing medicine these days involves shared decision-making with patients and families. Everyone has unique circumstances that factor into those decisions. I will not strongly recommend this medication to my patients or try to convince them they need to take it. My patients will be appropriately counseled about the known risks, some of which are serious. I will be clear that Aduhelm is not a cure for Alzheimer’s disease. At best, this may slow cognitive decline for some patients. If the patient and family want to pursue treatment after our discussion, and they meet the inclusion criteria the drug was tested in, I will not stand in the way of prescribing this medication.

Where is the Hope, Doc?

The number of studies targeting other pathways of this disease, not just amyloid, brings me significant optimism. Even if we look at Aduhelm, there is a silver lining here if we look hard enough. Our ability to pursue more accurate diagnoses of Alzheimer’s disease has been limited. We regularly diagnose patients far too late in their disease course because this is when symptoms are more obvious. Despite FDA approval for Amyloid and Tau PET scans, I have yet to clinically order one. They reportedly cost over $10,000 and insurance companies will not pay for them. Why? “Because we do not have any medications that modify Alzheimer’s pathophysiology, so why test for it?” Now with Aduhelm, we can at least say that we do.

I anticipate ordering more insurance-covered tests to get more accurate diagnoses for my patients, and we will be able to advance our knowledge and treatment of patients with a better understanding of their biological disease. I truly hope Aduhlem represents the initial crack in the dam to propel research forward that the Alzheimer’s Association and Biogen suggest it could be.