#AAIC21 – Expert Group Publishes Guidance on Aduhelm’s Use

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by Marisa Wexler MS |

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A panel of experts has crafted guidance for clinical use of Aduhelm (aducanumab), the first targeted treatment for Alzheimer’s disease recently granted accelerated approval by the U.S. Food and Drug Administration (FDA).

The recommendations include criteria for determining those patients most appropriate for this once-monthly infusion treatment, and for monitoring safety with its use. The guidelines are in the report “Aducanumab: Appropriate Use Recommendations,” published in The Journal of Prevention of Alzheimer’s Disease.

“Aducanumab [Aduhelm] has been approved. In the coming months and years, it will be given to tens of thousands of patients,” said Jeffrey Cummings, MD, a professor of neurology at the University of Nevada Las Vegas and founding director of the Cleveland Clinic Lou Ruvo Center for Brain Health, who co-authored the guidelines. “We felt that there was a need for appropriate use recommendations so that the drug could be used properly and safely.”

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Cummings and other experts discussed the recommendations at the 2021 Alzheimer’s Association International Conference, held late last month in Denver and online.

“We see these recommendations as a first step. We’re going to learn so much over the next months and years. These criteria will need revision, for sure,” Cummings said. “But we felt that they were urgently needed for the immediate application, because the drug is here, and people need to know how to use it safely.”

Aduhelm was developed by Biogen and Eisai, but neither company was involved in the creation of these use guidelines.

“I don’t even think they knew this was happening,” Cummings said.

Eligible patients and amyloid checks

A major focus of the recommendations concerns determining those patients who are suitable for Aduhelm — and those who are not.

This has been an issue of contention in the Alzheimer’s community: The FDA initially approved Aduhelm for all with this disease. But controversy followed, and the agency soon updated its label to limit treatment initiation to people with mild cognitive impairment (MCI) or early Alzheimer’s, the group studied in its clinical trials. The update has generally been welcomed across the Alzheimer’s community.

The recommendations list several standardized tests available to detect early cognitive impairment, such as the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA).

Experts also stressed that clinicians need to engage their patients in open and honest conversations about cognitive difficulties they are experiencing. Changes in cognition are usually noticeable in people with MCI or early Alzheimer’s — to themselves and to those around them — even as they continue to go about their normal day-to-day life.

In its label, the FDA does not require patients be tested for the presence of amyloid plaques before initiating treatment. Amyloid plaques are atypical clusters of proteins in the brains of people with Alzheimer’s, and are thought to drive the disease. Aduhelm works by breaking up these plaques.

Experts on the panel thought testing for amyloid plaques should be “absolutely mandatory,” and their existence determined before starting with Aduhelm.

“The mechanism through which aducanumab works is the removal of [amyloid] plaques. Without the target being present, there is no point in administering the drug,” said Liana Apostolova, MD, an Alzheimer’s researcher and a neurology professor at Indiana University.

In Aduhelm’s clinical trials, the presence of amyloid plaques was confirmed in patients using positron emission tomography (PET), a type of imaging technology that can visualize plaques in the brain. PET, while a useful technology, is expensive, and the experts noted that it is not available in many locations.

As an alternative to PET, these clinician-researchers recommended testing patient’s cerebrospinal fluid (CSF) — the fluid that surrounds the brain and spinal cord — for evidence of amyloid. CSF is typically collected via a needle inserted into the lower spine, a procedure called a lumbar puncture or spinal tap.

“The trials were done with amyloid PET. However, not all practices have availability to offer that to participants, and it’s still not covered by insurance,” Apostolova said, adding that CSF testing “is a very good proxy for the presence of amyloid in the brain, and can be reliably used and is covered by insurance.”

Safety monitoring

Over a third of trial participants given Aduhelm at therapeutic doses experienced an adverse event called amyloid-related imaging abnormalities (ARIA), which is characterized by the abnormal fluid accumulation (swelling) in the brain, as detected by MRI.

In most cases, ARIA doesn’t cause overt symptoms, but in those it does, symptoms include nausea, confusion, headache, and troubled vision. In rare cases, ARIA can cause severe symptoms, like seizures.

Because of the high risk of ARIA with Aduhelm’s use — reported in 41% of trial patients treated at its approved dose, with 10% showing symptoms — the panel recommended that people undergo an MRI prior to initiating treatment, followed by regularly scheduled MRIs. An MRI should also be performed if patients report symptoms indicative of ARIA while on Aduhelm.

In those with symptomatic ARIA, or with moderate to severe ARIA even in the absence of symptoms, experts recommend pausing treatment, then regular testing to see if the ARIA resolves. ARIA usually resolves in roughly one to four months; should it do so, patients and their care team can then decide on resuming treatment.

Severe ARIA symptoms, like seizures or stroke-like syndromes, should lead to treatment discontinuation, the recommendations state.

Patients with mild ARIA and no symptoms can continue using Aduhelm, the panel recommends, while undergoing MRIs and other tests to monitor its resolution.

An individual’s risk of ARIA is affected by genetics, specifically by APOE status. The APOE gene has several forms, and one of them — called the E4 variant — is roughly associated with a doubling of ARIA risk, the experts said.

Notably, this variant is also linked with an increased risk of developing Alzheimer’s. As such, discussions concerning this genetic variant, and deciding whether to be tested for it, affect not just for the person with Alzheimer’s, but also their biological relatives.

In light of this, the experts favored thorough discussions with patients and their loved ones about the potential benefits and risks of genetic testing for APOE status, so informed decisions can be made. If testing is desired, it should be provided.

“People need to know if they want to know, but it is a nuanced issue,” Cummings said.

In addition to ARIA, the experts also recommend “vigilance for all potential side effects in patients treated with aducanumab with special attention to headache, falls, and diarrhea.”

Managing patient expectations, diversity

In general, the panel stressed the importance of frank and honest discussions with patients and their care teams, in order to ensure realistic expectations.

“Those considering aducanumab therapy should understand that the expected benefit is slowing of cognitive and functional decline; improvement of the current clinical state is not anticipated,” they wrote.

Frank discussion of what is unknown about this new medicine was also noted. One widely acknowledged flaw in Aduhelm’s clinical trials was the vast majority of participants being white — a common trial problem that, the experts agreed, the broader scientific field needs to do more to address.

With a lack of ethnic and racial minorities in clinical trials, it’s impossible to know whether people of certain backgrounds respond to a treatment differently. For example, the E4 variant in APOE is not associated with an increased risk of Alzheimer’s among people of African ancestry, so the relevance of this genetic variant with regard to ARIA risk in Black people on Aduhelm is unclear.

Additionally, minorities across the U.S. commonly experience stigma and discrimination in healthcare settings. Stigmas around cognitive impairment can be especially profound, and pose an obstacle to these people getting potentially helpful treatment.

As such, the experts recommend “that clinicians strive to engage diverse patients in diagnosis and treatment discussions, with the goal of achieving equity among diverse groups in the use of aducanumab.”