Imaging biomarkers play a crucial role in the development, approval, and use of disease-modifying drugs for Alzheimer’s disease

With Alzheimer’s disease (AD) contributing to 60%-70% of the 55 million people living with dementia worldwide, the quest for solutions that slow, or even stop, the underlying disease processes has been a long, sometimes arduous, journey. Beyond the traditional lifestyle recommendations such as physical activity, a healthy weight, and avoiding smoking, people at risk of AD have had few pharmaceutical options until the approval by the US FDA of aducanumab (ADUHELM™) in mid-2021 and now the approval of lecanemab (LEQEMBI™) earlier this month. Both are disease-modifying drugs (DMDs) targeting amyloid beta plaques in the brain, a hallmark of AD.
These landmark approvals have:
Although the FDA approval of Aduhelm was controversial for many reasons, the better risk/benefit profile of Leqembi (and possibly of donanemab) could improve uptake and approvals of DMDs in the future, particularly in countries that did not grant approval for Aduhelm.

AD management is benefitting from broad development.

In fact, DMDs represented 83.2% of the 143 drugs being developed for AD as of January 2022. These therapies aim to address amyloid, tau, neuro-inflammation, and oxidative stress, all identified as contributors to AD. As a result, the future of AD therapies looks promising, offering greater patient choice and the potential for synergistic combinations of drugs to maximize outcomes. This is particularly important given the heterogeneity in AD pathology, presentation, and progression and could advance personalized medicine in this space. It is expected that personalized, combination drug therapy working against a range of targets will become the preferred approach. Crucial to a personalized approach is having relevant information to choose the right treatment for the right patient at the right time.

One thing is certain — DMDs will be part of the future of AD management, and the entire patient pathway for DMD in AD requires due diligence for the maximum benefit with the lowest risk. This pathway encompasses early disease detection, identification of eligible patients, and monitoring of both efficacy and side effects. Biomarkers, including imaging biomarkers, will play an important part in this pathway, especially to overcome lingering skepticism about Aduhelm’s efficacy and concerns about its safety profile.

Detect AD as soon as possible.

Because changes in the brain can begin decades before the presentation of clinical symptoms in AD, symptom-based diagnoses actually occur very late in the disease course. However, early diagnosis can be complex, especially when symptom-based diagnosis is already fraught with challenges. AD tends to be a “disease of exclusion” in clinical practice, ruling out other possibilities such as normal aging and other causes of dementia. With Leqembi and other DMDs, the hope is that they will slow progression when given to people with early-stage AD. By extending the milder stages of the disease, people with AD could gain more years of independence.
However, although 70% of the brain amyloid was removed in the phase 3 Leqembi trial, the rate of cognitive decline declined by only 27%. That is why some studies are investigating whether intervention before amyloid plaques can accumulate to a detrimental level could prevent cognitive decline. Brain PET scans to detect the presence of amyloid or tau, cerebral spinal fluid analysis, and emerging blood biomarkers will be key for objective, early diagnosis and could guide the use of amyloid-targeting DMDs for the patients who would benefit the most.

Identify appropriate, eligible patients.

The Leqembi label states that it should only be used with patients with early or mild AD and with confirmed presence of amyloid beta pathology, matching the patients included in the clinical trials. With the increasing use of imaging and other biomarkers as entry criterion in late-phase clinical trials for other DMDs, these biomarkers will also likely be important in clinical practice. Nearly half of the trials used amyloid PET for imaging biomarkers, highlighting its role in determining patient eligibility.
However, eligibility for Leqembi currently goes beyond just the presence of amyloid plaque. The primary safety concern with Leqembi is the occurrence of amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. Studies have shown the frequency of ARIA to be higher when the APOE4 gene is present. In addition, the three people who died due to suspected ARIA-related complications during the extended trial of Leqembi were taking anticoagulant drugs. It is believed that these drugs might have worsened the bleeding in the brain.
Therefore, in addition to meeting the label requirements, clinicians should consider genetic markers, contraindicated medical conditions, and the patient’s drug profile when prescribing Leqembi and other drugs in the same class. This holistic approach increases in importance when one takes into account the burden of infusions, varying efficacy, risk of side effects, and cost of treatment (at least US $25,000 a year). In the United States, the Centers for Medicare and Medicaid Services (CMS) has declined to cover Aduhelm under federal insurance plans unless the person was enrolled in a clinical trial, and Leqembi is currently covered under the same ruling. This leaves some patients paying the full cost out of pocket, increasing the importance of the best patient-drug match. Imaging and other biomarkers, even with their potential cost, will provide critical input into the most appropriate patients, their safety, and whether the drug is working as intended.
PET Amyloid Report from our cPET™ application (WIP: not cleared for clinical use)

Closely monitor efficacy and safety.

The heterogeneity of AD necessitates close monitoring of patients on amyloid-reducing DMDs, for optimal dosage and objective measurements of effectiveness. Endpoints related to cognitive decline can be subjective, vary between clinicians, and fail to capture changes in underlying pathology. Objective biomarkers such as imaging can be more accurate; for example, amyloid and tau PET scans were used to measure amyloid and tau accumulation, key endpoints in the phase 3 Leqembi trial.
Regarding safety, the most common reported side effects of Leqembi were infusion-related reactions, headache, and ARIA.
In clinical trials of amyloid-targeting therapies for AD, the incidence of ARIA has ranged from 0% to 42%. Compared with the 35% of patients who experienced ARIA with edema or effusions (ARIA-E) in clinical trials of Aduhelm, only 12.6% of patients receiving Leqembi experienced them (and 27% with donanemab). ARIA-E with Leqembi:
ARIA with microhemorrhages and superficial siderosis (ARIA-H) were experienced by 17.3% of the patients receiving Leqembi in the phase 3 clinical trial (compared with 9.0% in the placebo group).
The risk of ARIA depends on patient characteristics, the therapy’s mechanism of action, length of treatment, and dosage. Although most cases of ARIA in clinical trials (67-90%) of AD treatments were asymptomatic, headache, visual disturbance, dizziness, nausea and vomiting, and confusion have been reported. The most severe cases can require hospitalization, and the potential for a long-lasting impact on clinical course, including cognitive decline, and response to treatment is currently unknown. ARIA typically resolves after halting the medication, and the first few months represent the critical time period in which ARIA can occur.

Provide appropriate care across the patient pathway.

As genetic testing becomes more mainstream and celebrities like Chris Hemsworth shine the spotlight on genetic risk factors for AD, the public is likely to consider early access to DMDs an imperative when faced with a heightened genetic risk of cognitive decline. Aduhelm and Leqembi are the first drugs to enter this space, and with additional DMDs in development, neurologists and radiologists will be tasked with incorporating them into their AD armamentarium.
Each new DMD provides greater clarity about who would benefit, at the lowest risk, and helps prepare the health system, including establishing referral and diagnosis pathways as well as imaging and infusion infrastructure. Changes to reimbursement models for AD therapies could also improve uptake of new DMDs.
Given the challenging presentation and imaging characteristics of AD and ARIA, the right tools are needed to provide the best care for patients on DMDs. A technology-enabled imaging and diagnostic support tool can be an advantage for accurate patient management. Objective identification, measurement, and detection of changes in amyloid plaques or tau accumulation, micro-bleeds, and brain swelling can differentiate neurology and radiology practices in terms of the care provided and patient safety. Detailed, clear reporting can ease concerns from physicians, patients, and caregivers alike concerning the benefits and risks of new drugs.

Will you be attending ECR 2023?

Stop by our booth, EXPO X1 in the Artificial Intelligence Exhibition (AIX) area AI-36, for a demonstration of our artificial intelligence (AI)–enabled software solution that was designed to support entire patient care pathways, including early detection, differentiation of diagnosis, treatment planning, and monitoring.