September/October 2021

Aducanumab’s Approval Sparks an Uproar
By Jennifer Lutz
Today’s Geriatric Medicine
Vol. 14 No. 5 P. 14

The controversial decision to send the Alzheimer’s drug through the FDA’s accelerated approval pathway puts its use in question.

On June 7, 2021, the FDA approved aducanumab, the first ever disease-modifying drug for Alzheimer’s disease. Aducanumab was developed by Biogen and will be marketed under the brand name Aduhelm.1 The therapy is also the first new Alzheimer’s drug to be approved since 2003 and has stirred more than a little controversy—with the FDA already narrowing recommendations for use and Acting Commissioner Janet Woodcock, MD, calling for an independent investigation into the regulatory process behind the drug’s approval. Aducanumab works by decreasing levels of amyloid buildup in the brain, a key indicating factor in the development and progression of Alzheimer’s.

So why the controversy, and what exactly does the approval of this drug mean for providers, patients, and caregivers?

Aducanumab: A Human Monoclonal Antibody
The accumulation of amyloid-beta plaque is a defining feature of Alzheimer’s, and Biogen is betting that decreasing amyloid-beta levels will have a clinical effect by decreasing the progression of Alzheimer’s. The drug is administered via monthly IV infusions into the arm and acts as an amyloid-beta–directed antibody, decreasing buildup of the protein in the brain.2

“The FDA evaluated aducanumab as a drug designed to get rid of amyloid, and it does a fabulous job of that. The question is, will this have an impact on all the other symptoms of Alzheimer’s?” says Douglas Scharre, MD, director of the Division of Cognitive Neurology of the Center for Cognitive and Memory Disorders at Ohio State University’s Wexner Medical Center.

Ultimately, aducanumab was approved on the basis of this plaque clearance, using the accelerated approval pathway with beta-amyloid classified as a surrogate endpoint.

The Amyloid Hypothesis
In Alzheimer’s, brain cells responsible for storing, processing, and retrieving information degenerate and die. Scientists still don’t know what causes this, although genetics can predispose people to the disease. One prevailing idea is the amyloid hypothesis. Beta-amyloid, a small piece of the larger amyloid precursor protein, is stickier than other proteins and clusters in stages. The first stage is the formation of small clusters (oligomers). The oligomers form chains, called fibrils, which then form “mats” of fibrils called beta-sheets. Finally, these beta-sheets (along with other substances) form plaques.3 This plaque buildup is a cellular hallmark of Alzheimer’s (the other being a protein called tau). “Beta-amyloid is a normal constituent in the brain, but in people with Alzheimer’s, they have either decreased metabolism of amyloid or increased production, so it can build up abnormally compared to other people,” Scharre says.

The amyloid hypothesis argues that this plaque buildup is the first step in a cascade of processes, disrupting cell-to-cell communication and activating an immune response that leads to inflammation, further cell death, and other disease hallmarks such as tau-tangle formation.3 The hypothesis gained support when researchers discovered that in dominantly inherited mutations related to familial Alzheimer’s, beta-amyloid is produced in longer variants that clump together more readily.4 The hope is that clearing the plaque will slow disease progression.

Despite this, the hypothesis has come under scrutiny during 20 years of drug trials that failed to produce clinically significant results. In the early 2000s, drugs aimed at inhibiting the enzymes needed to produce beta-amyloid. Not only did these drugs fail but they also had significant side effects, and in some cases, worsened disease symptoms.4

The first study of an immunotherapy meant to elicit an active immune response used a synthetic molecule of beta-amyloid and was halted when 6% of participants experienced inflammation of the brain and meninges. In some cases, it was thought that these drugs were simply flawed, and in others, trial design was blamed. One theory was that the drugs were given to participants too late in disease progression to show significant clinical efficacy.4 As doubts grew regarding the beta-amyloid hypothesis, researchers turned hopeful eyes to aducanumab.

Unlike previous amyloid-targeted drugs, aducanumab focused on clearing plaque—a novel approach that seemed promising in 2016, when two initial trials suggested that it could significantly slow cognitive decline in people in the early stages of Alzheimer’s.4

Two Discontinued Trials, One FDA Approval
Hope for aducanumab seemed to crash in March 2019 when Biogen announced it was discontinuing development after the drug failed futility analyses in two nearly identically designed phase III clinical trials, ENGAGE and EMERGE. Unlike earlier failed drugs, the trials were not stopped for safety concerns but because it was projected that they wouldn’t meet their endpoints.5

Fast-forward to October 2019, when Biogen announced plans for regulatory filing for aducanumab. The explanation? New analysis of a larger dataset from phase III studies. The company indicates that the change can be explained via the timeline of the two clinical trials.6

The ENGAGE trial first enrolled patients on August 31, 2015. The EMERGE trial first enrolled patients on September 30, 2015. Participants in both trials were prescribed either a placebo, a low dose of aducanumab (3 mg/kg if an apolipoprotein E [APOE] carrier or 6 mg/kg if not), or a high dose (6 mg/kg if an APOE carrier or 10 mg/kg if not) to be given intravenously every four weeks for 78 weeks. Approximately 1.5 years after beginning the ENGAGE trial, the APOE carriers in the high-dose group were bumped up to 10 mg/kg. In brief, a greater number of study participants in the EMERGE study received the higher dose of aducanumab for a longer period.6

The planned futility analysis included 945 participants from ENGAGE and 803 participants from EMERGE who had completed the trial as of December 26, 2018. Between December 26, 2018, and March 21, 2019 (when trials were stopped), 139 additional participants completed the ENGAGE trial and 179 additional participants completed the EMERGE trial. In October 2019, at an investor’s conference, Biogen, using the larger dataset, cited this new analysis. The claim: The EMERGE trial met its endpoint with statistically significant results.

“In the clinical trials, it appeared that a small group of people who had very early symptoms showed significant changes over placebos; there was a slowing down of their decline,” Scharre says. “It was not a cure, a reversal, or an improvement; it was a slowing of the decline, and this seemed to be in individuals that were in the very earlier stages and took higher doses of the drug.”

Relying on this new data, Biogen applied for FDA approval, which was ultimately granted, giving it the green light to market its $56,000-per-year drug to the more than 6 million patients with Alzheimer’s—at all states of disease progression—in the United States.7

The failure of the FDA to specify whom this drug might benefit was a point of contention. Of the more than 6 million patients with Alzheimer’s, the majority are in the later stages of disease progression—a group that showed no benefit from aducanumab. The generalized approval raised concerns among the scientific community and garnered a response. The FDA, on July 8, 2021, narrowed its recommendations for the drug. The drug’s label was updated with indications and usage specific to “patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.”8 However, the FDA approval of the drug has in no way changed; aducanumab can be prescribed to patients at any state of disease progression.

Controversy and Confusion
The independent scientific advisory board voted against the approval of aducanumab, and three members have resigned following the drug’s approval.9 Most recently, several of those members (and one recused member) published a perspective in the New England Journal of Medicine questioning the use of beta-amyloid as a surrogate endpoint.10 Biotech has emphasized that aducanumab is the first drug to modify the progression of Alzheimer’s and that the FDA seems to agree.

“The studies were nearly identical in their design; one study failed, and one study was moderately successful in that it showed a modest but statistically significant effect in individuals receiving the high-dose treatment,” says G. Caleb Alexander, MD, a professor at the Johns Hopkins Bloomberg School of Public Health and codirector of the Johns Hopkins Center for Drug Safety and Effectiveness. Alexander is one of the 10 scientific advisory board members who voted against approving aducanumab.

Statistical significance is judged in relation to placebo. In this case, the EMERGE trial showed a 23% statistically significant improvement compared with placebo; the ENGAGE trial showed a 6% worsening. When a randomized analysis of all patients was performed (some had not completed the trial length), there was a 23% improvement and a 2% worsening, respectively. In essence, the drug was moderately effective when a subgroup (those with early signs of cognitive decline) received the higher dose for a longer duration.6

Alexander doesn’t believe the rewards outweigh the risks. “There are nontrivial rates of adverse events, most notably brain swelling and hemorrhage. Fortunately, in most cases it is asymptomatic, but in a subset of cases, it’s not. To make matters worse, many symptoms of brain swelling or brain hemorrhage are similar to those of progressive Alzheimer’s—things such as memory impairment, language impairment, falls, confusion, headaches, and fatigue. In clinical practice, it’s not going to be easy to discern who’s having an adverse response to the drug vs whose Alzheimer’s is clinically progressing,” Alexander says.

According to the drug’s label, brain swelling was reported in 41% of patients taking 10 mg/kg of aducanumab (compared with 10% in the placebo group). The majority of cases occurred within the first eight months (although they could occur at any time) and occurred more frequently in APOE carrier patients. Resolution of the swelling occurred for 68% of patients within 12 weeks, 91% in 20 weeks, and 98% overall after detection.2

The controversy is as easily linked to the regulatory process as to the drug itself. Regarding the potential for the drug to show real-world results, Alexander says, “that would be a surprising and welcome outcome, but it would hardly justify the regulatory actions that have been taken thus far.” The current investigation into that regulatory process is set to examine a supposedly close working relationship between Biogen and the FDA. In written correspondence with the FDA, a spokesperson says the administration “often works closely with industry to help foster drug development, understand emerging data, and advise on best approaches to development plans, especially in areas where there is a significant need for treatments for devastating diseases.”

The FDA has published guidelines pertaining to sponsorship of investigational new drugs (INDs). The FDA’s “Best Practices for Communication Between IND Sponsors and FDA during Drug Development” indicates that “ideally, sponsors and FDA work collaboratively during the drug development process, having a shared public health goal of early availability of safe, effective, and high-quality drugs to the American public.”

Much of the controversy can also be attributed to the FDA’s use of the Accelerated Approval Program, a pathway predominantly used for cancer drugs. The current approval marks the first time that the Accelerated Approval Program has been used for an Alzheimer’s drug and, like many cancer drugs passed under the same pathway, the approval doesn’t guarantee success. “The accelerated approval pathway allows the FDA to provide earlier access to patients, recognizing that there remains some uncertainty about whether the surrogate endpoint will accurately predict clinical benefit,” says an FDA spokesperson. The US health care system would be facing a growing cost without a clear return on its investment, leaving little reservoir for the 61.2 million people enrolled in Medicare.

While Imran Ali, MD, MS, MPH, physician fellow in palliative care/geriatric supportive oncology at Mount Sinai, cites a definitive need for improved Alzheimer’s treatments, he counts himself among many providers who disagree with Aduhelm’s approval. At the same time, when asked about the subsequent controversy, Ali says, “I think if it were a cancer drug, the approval would be received differently.”

With So Much Dissent, Why the Approval?
The drug reached its endpoint; after 12 months at the higher dose (10 mg/kg), nearly one-half of all patients no longer had positive amyloid positron emission tomography (PET) scans.6 Scharre explains that the swelling, which was resolved in most patients, could be a consequence of beta-amyloid being pulled through the blood vessels. “But is it harming anything? We don’t really know,” Scharre says. “Right now, with this drug, we have mild help for early patients with early symptoms.”

For a disease as common and as devastating as Alzheimer’s, the potential of disease modification could be historic. According to an FDA spokesperson, “The Agency concluded that there was substantial evidence that Aduhelm reduces amyloid-beta plaques in the brain, and further concluded that the reduction in amyloid-beta plaques was reasonably likely to predict clinical benefit, meeting the requirements for an accelerated approval.” The agency also heard from members of the patient community and believed this treatment could address an unmet need. In the United States, Alzheimer’s kills more people than breast and prostate cancers combined. Like many cancer drugs, Aduhelm doesn’t offer a cure; it offers the possibility of more time.

Finding the Right Patients for Aducanumab
“The aducanumab trials included patients at the early stages of Alzheimer’s. At this stage, patients are likely still functioning mostly independently but are likely having memory lapses, things like forgetting words or the location of objects,” says Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation. “While it’s true that age is the leading risk factor for Alzheimer’s, age is not the determinant of who would benefit from this treatment. That should be based on a patient’s clinical presentation—that they are in the early stages of the disease, plus results from a PET scan confirming the presence of amyloid in the brain.”

The recently narrowed FDA recommendation may help providers select potential patients, but the real challenge will be identifying these patients before it’s too late.

A Call for Early Detection
It’s clear from the clinical trials that patients who did benefit were a subset of a very specific group: those with early signs of cognitive decline or early Alzheimer’s with positive amyloid PET scans. Some have cited this as reason to reject approval. Others have cited it as a flag signaling the need for earlier detection. “My hope is that this will cause people to seek out their primary care doctor or a neurologist and enter into the medical arena for preventive care,” says Paul Wright, MD, senior vice president and system chair of Nuvance Health Neuroscience Institute. “We’re very good at delivering sick care in this country, but we can improve how we deliver true health care, where we try to do everything possible to prevent diseases from occurring.”

Meanwhile, at Ohio State University, Scharre has developed SAGE, a self-administered digital-form brain test. Patients can take the test at home on a yearly basis, or however often is needed. Their doctor receives and reviews the results and can track changes over time. “Of the millions of patients with Alzheimer’s, they all had to go through this early stage; we just aren’t identifying them. If we could identify this early group, there would be lots of patients who could potentially be helped by an antiamyloid agent,” Scharre says.

What’s Next for Providers, Patients, and Caregivers?
As with any treatment, providers will need to assess each patient individually and consider risk vs reward. “At the end of the day, this is now a potential treatment that providers and patients will have to consider, but that consideration should include a consideration of the risks as well as the benefits of pursuing it,” Alexander says. Like many researchers, Alexander worries this may pave the way for approval of other amyloid-targeted drugs: “It’s important to consider the broader amyloid cascade hypothesis and especially the evidence to support or refute the validity of amyloid as a surrogate endpoint for Alzheimer’s.”

Others are hopeful that this approval will lead the way for a new era of disease-modifying drugs. “Now, we have this drug that gets rid of amyloid, researchers are also working on one that gets rid of tau,” Scharre explains. “Potentially, you could combine these with a drug that mitigates inflammation and so forth. We could combine disease-modifying therapies; then I think we will see some significant impact on patients.”

In July, the Centers for Medicare & Medicaid Services launched an analysis to “determine whether Medicare will establish a national Medicare coverage policy for monoclonal antibodies targeting amyloid for the treatment of Alzheimer’s.”11 The independent investigation into the FDA regulatory process is ongoing. Across the Atlantic, the European Medical Association is reviewing the drug for approval.

Throughout the controversy, it’s imperative to remember the individuals, families, and communities touched by this devastating disease. Whatever the fate of aducanumab may be, its publicity will hopefully increase awareness and early screenings of patients with Alzheimer’s, opening the door to further advancements and future promise for providers, patients, and caregivers alike.

— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She’s written for both consumer and professional medical magazines as well as popular newspapers. Her writing can be found in Practical Pain Management, Endocrine Web, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communication consultant for nonprofits focused on improving community health.

References
1. FDA grants accelerated approval for Alzheimer’s drug. FDA website. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug. Published June 7, 2021.

2. Biogen; Eisai. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf. Accessed June 29, 2021.

3. Alzheimer’s Association. Beta-amyloid and the amyloid hypothesis. https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf. Updated March 2017. Accessed June 30, 2021.

4. Makin S. The amyloid hypothesis on trial. Nature. 2018;559(7715):S4-S7.

5. Biogen and Eisai to discontinue phase 3 ENGAGE and EMERGE trials of aducanumab in Alzheimer’s disease. Biogen website. https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials. Published March 21, 2019. Accessed June 30, 2021.

6. Schneider L. A resurrection of aducanumab for Alzheimer’s disease. Lancet Neurol. 2020;19(2):111-112.

7. Facts and figures. Alzheimer’s Association website. https://www.alz.org/alzheimers-dementia/facts-figures. Accessed July 9, 2021.

8. Biogen; Eisai. Highlights of prescribing information. https://www.biogencdn.com/us/aduhelm-pi.pdf. Updated July 2021. Accessed July 9, 2021.

9. Mahase E. Three FDA advisory panel members resign over approval of Alzheimer’s drug. BMJ. 2021;373:n1503.

10. Alexander GC, Knopman DS, Emerson SS, et al. Revisiting FDA approval of aducanumab [published online July 28, 2021]. N Engl J Med. doi: 10.1056/NEJMp2110468.

11. CMS opens National Coverage Determination analysis on treatment for Alzheimer’s disease. Centers for Medicare & Medicaid Services website. https://www.cms.gov/newsroom/press-releases/cms-opens-national-coverage-determination-analysis-treatment-alzheimers-disease. Published July 12, 2021.