New Expert Guidance for Use of Anti-Amyloids for Early AD

The American Academy of Neurology has released expert consensus guidance on the use of new anti-amyloids to treat early Alzheimer’s disease (AD).

The guideline authors highlight the fact that while these monoclonal antibodies (mAb), which target beta-amyloid, are promising in terms of slowing cognitive and functional decline in early AD, they also carry risks and burdens that should be discussed with patients and caregivers.

“Recent data on lecanemab and other monoclonal antibody infusions targeting amyloid-beta protein make clear that new agents are highly likely to be part of the toolkit for neurologists caring for people with Alzheimer’s disease,” lead guideline author Vijay K. Ramanan, MD, PhD, Department of Neurology at the Mayo Clinic, Rochester, Minnesota, said in a release.

“While the formal evidence base is still evolving, this article was created with expert consensus until there is enough evidence on these therapies to inform evidence-based recommendations.”

The guidance was published online July 26 in Neurology.

Patient Selection Key

Following CLARITY-AD, the phase 3 trial of lecanemab, the agent is now available under US Food and Drug Administration (FDA) accelerated approval, with traditional approval likely imminent and availability of other within-class agents expected in the future.

With this backdrop, the authors note the importance of identifying which patients are most likely to benefit from anti-amyloid treatment. They note lecanemab is potentially indicated for patients with mild cognitive impairment (MCI) or mild dementia due to AD, but current data don’t support its use in presymptomatic AD or in moderate/severe AD dementia.

However, some patients outside of the defined age of 50-90 years or the 22-30-point range on the mini-mental status exam (MMSE) specified in CLARITY-AD may be considered candidates for therapy. This includes younger individuals with sporadic AD who are more likely to have atypical clinical syndromes that can influence cognitive test performance, the authors note.

Strict reliance on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) or neuropsychological assessment items may require extra training or resources, which may not be practical for all settings, they add.

“As such, it will be important for clinicians to consider upfront how best to systematically identify patients who are most likely to benefit from treatment while ensuring that drug usage generally adheres to the conditions under which CLARITY-AD provides evidence of clinical efficacy,” the authors note.

In addition, there needs to be evidence of brain amyloid before initiation of anti-amyloid therapy. In CLARITY-AD, amyloid positivity was determined by either amyloid PET, which is not widely covered by insurance outside of trials, or measurement of cerebrospinal (CSF) biomarkers, which require lumbar puncture, proper sample acquisition, shipment to a qualified lab, and interpretation expertise.

While blood-based biomarkers of AD are being studied and may, in the future, revolutionize screening and treatment monitoring, it is still unclear whether they will have the sensitivity and specificity necessary for use in decision-making for treatment initiation, or whether they are best used as screening tools, the experts note.

Pre-treatment brain MRI is indicated to assess potential cerebrovascular disease and other relevant structural abnormalities to minimize the risk of amyloid-related imaging abnormalities (ARIA), a known side effect of these medications.

In addition, concomitant use of anticoagulants with anti-amyloids is contraindicated because of increased bleeding risk. The experts note that in the CLARITY-AD study, three deaths were linked to lecanemab and at least two of the individuals who died were taking anticoagulants.

In addition, because the apolipoprotein E ε4 allele (APOE ε4) is associated with higher rates of ARIA, particularly among APOE ε4 homozygotes, the experts agree APOE ε4 allele testing should be offered prior to treatment.

“It will be important for clinicians to develop processes for pre-test and post-test genetic counseling regarding the implications of this testing for patients and families, particularly given that there are no other current indications for obtaining APOE allele testing in clinical neurology practice,” the guideline authors write.

They emphasized the need for shared decision-making among clinicians, patients, and caregivers “to ensure alignment of expectations, benefits, risks, and goals of care.”

It’s also important that patients understand the goal of treatment is slowing of decline rather than stabilization or improvement in cognitive functioning, they note.

Some patients may be less enthusiastic about treatment when they weigh the possible side effects, personal financial costs, and logistical burdens associated with treatment, they add.

“Overall, it will be vital for neurology clinicians, patients, and caregivers to engage in nuanced discussions that acknowledge anti-amyloid mAbs are not a cure for AD but could be a reasonable option for seeking additional slowing of disease progression in some patients with early disease and low likelihood of side effects,” they write.

Adapting to the availability of these new therapies will require clinicians to consider several logistical factors, they note. Lecanemab is administered every 2 weeks via intravenous infusion, which takes about an hour.

“Along with facilitating appropriate patient selection and arranging recurring infusions, clinicians must be prepared to respond to ARIA and other potential complications of treatment,” the authors note.

There are also issues of insurance coverage and increased demand. These new drugs, the experts point out, are emerging at a time when communities have variable access to qualified clinicians and dementia care resources, which underscores the need for collaborative care efforts and practice-specific adaptations.

Clinicians will need to engage with eligible patients “to weigh available options, which may be influenced by differential insurance coverage and co-pays, infusion and scan frequency, clinical efficacy, and side effect rates,” the authors write.

The experts also highlight the differences between lecanemab and donanemab, another anti-amyloid that is likely to receive FDA approval in the coming months.

For example, the cohort in the phase 3 TRAILBLAZER-ALZ 2 trial of donanemab was enriched with individuals with intermediate vs high levels of tau burden, which suggests this population may be at an earlier stage of AD and therefore potentially have a better treatment response.

The authors also note the importance of including “a diverse range of participants reflective of real-world clinical neurology” in future trials of anti-amyloids for AD, and that the lack of diversity “has been a clear shortcoming in AD clinical trials to date, which potentially undermines the generalizability of results.”

The authors report no relevant financial relationships.

Neurology. Published online July 26, 2023. Abstract.

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