Amyloid-Targeting Class of Alzheimer Disease Drugs Show Potential, Raise Concerns of Accessibility for Diverse Patients

Although there have been significant advancements in the care and prevention of Alzheimer disease (AD) in recent years, these clinical developments have not been utilized to the fullest potential, with aducanumab, the first approved amyloid-targeting drug, rarely being used.¹

Recently, the FDA converted the accelerated approval of lecanemab to a full traditional approval for the treatment of AD in those with mild cognitive impairment or mild dementia state disease,² whereas donanemab has been submitted for approval to the FDA, with a decision expected by the end of 2023.³

The uptick in the development of drugs utilizing amyloid-targeting monoclonal antibodies has shown promise in slowing cognitive decline, but there have been concerns around not only reimbursement, but whether this new class of therapeutics will widen inequities of care for marginalized patients.

According to the Alzheimer’s Association, more than 6 million Americans are currently living with AD, estimating a projected increase to nearly 13 million by 2050.⁴ In 2023, AD and other dementias are projected to cost the United States approximately $345 billion, potentially rising to nearly $1 trillion by 2050.⁴

Amyloid-β (Aβ) and phosphorylated tau (P-tau) are biomarkers commonly used to measure AD and dementia. In modern drug development of AD, Aβ-targeting monoclonal antibodies have been the first class of therapies to reach clinical trials, with aducanumab being the first to show robust, dose-dependent reductions in amyloid plaque measured by positron emission tomography (PET).⁵

The FDA granted accelerated approval to aducanumab for the treatment of mild cognitive impairment or mild dementia due to AD; however, the decision was met with criticism due to conflicting results in 2 phase 3 clinical trials. The 2 clinical trials were ended early based on “pooled futility analysis,” according to an editorial commentary in JAMA.⁵

In January 2023, lecanemab was the second Aβ-targeting monoclonal antibody granted accelerated approval by the FDA, based on lower Aβ PET scans in a phase 2 study (NCT01767311).⁵ The approval was based on the controlled, randomized CLARITY AD phase 3 clinical trial (NCT03887455), which demonstrated the clinical benefits of the drug for patients. The results showed statistically significant and clinically meaningful declines from baseline to 18 months in the change on the Clinical Dementia Rating-Sum of Boxes.^2,5

However, there were adverse events (AEs) observed in the study, including amyloid-related imaging abnormalities (ARIA).² ARIA is often asymptomatic or tends to have mild reactions but can still lead to life-threating events. According to a study published in JAMA, ARIA is the likely cause of 3 treatment-related deaths in each of the donanemab and lecanemab studies.¹

Weeks after the approval of lecanemab, results from the TRAILBLAZER-ALZ 2 (NCT04437511) demonstrated that donanemab significantly slowed cognitive and functional decline for those with early symptomatic AD that are amyloid-positive, regardless of their baseline level of P-tau.³

The findings showed that donanemab reduced 84% of amyloid plaque compared to only 1% with the placebo at 18 months and across all disease stages, according to the study.³

Although it seems Aβ-targeting antibodies demonstrate successful results, the affordability and accessibility of these drugs will be crucial for patients with AD, research shows.⁶

Currently, patients with Medicare are required to pay the standard 20% co-insurance for lecanemab, but only once the Part B deductible is met. Though this is an improvement in accessibility, the cost is a barrier for individuals who have AD.⁶ Lecanemab is indicated to administer at 10 mg/kg every 2 weeks with prices at $152.89 per mL and $152.88 per mL for the 2 approved formulas, 200 mg/2 mL and 500 mg/5 mL, respectively.⁶

There are also concerns regarding how AEs associated with donanemab may affect its inclusion in the National Coverage Determination, which would require patients to enroll in a registry for monoclonal antibody treatment. Some advocates said that the registry may restrict access to this treatment even further, decreasing the number of patients who would have coverage of these medications under Medicare.⁷

For donanemab, patients who are traditional Medicare beneficiaries with no supplemental coverage would be “expected to pay 20% of the estimated $78,700 per patient treatment costs, including imaging and outpatient visits, associated with donanemab, which would total more than $15,000,” the authors of a study published by JAMA wrote.⁷ The potential for high out-of-pocket costs could potentially widen the gap for access, and the required trips to physicians for infusion and advanced imaging capacity is likely to create additional barriers to access, according to the study.⁷

The authors of the study wrote there are concerns for individuals residing in more rural areas, those who do not qualify for Medicaid, those who do not have reliable transportation, and those of ethnically and racially diverse backgrounds.⁷

According to a survey conducted by the Kaiser Family Foundation, between 2010 and 2021, Hispanic individuals were more than 2.5 times more likely to be uninsured compared to White individuals while Black individuals are 1.5 times more likely to be uninsured.⁸

In fact, as reported by JAMA, neuroimaging centers are typically placed in predominantly White neighborhoods, which disproportionally affects those who are from varying racial and ethnic backgrounds.⁹

In clinical trials of these Aβ-targeting antibodies, there was a lack of representation among individuals who are Native American, Alaskan Native, Asian, Black, or Hispanic, according to the authors of a JAMA article.⁹ These limitations further exclude the efficacy and safety findings in these populations, which may affect the likelihood of prescribing among these patients.⁹

Further investigation into these populations, as well as policies regarding the accessibility and availability of Aβ-targeting antibodies are useful for the full scope of how beneficial these drugs will be in the future. However, it is likely that Aβ-targeting antibodies will continue to change the treatment landscape of AD.^4,7,9

References

1. Widera EW, Brangman SA, Chin NA. Ushering in a new era of Alzheimer disease therapy. JAMA. 2023. doi:10.1001/jama.2023.11701
2. Gallagher A. FDA converts lecanemab-irmb to full approval for treatment of Alzheimer disease. Pharmacy Times. July 6, 2023. Accessed July 27, 2023. https://www.pharmacytimes.com/view/fda-converts-lecanemab-irmb-to-full-approval-for-treatment-of-alzheimer-disease
3. Hunter E. Study: donanemab significantly reduces cognitive, functional decline associated with Alzheimer disease. Pharmacy Times. July 18, 2023. Accessed July 27, 2023. https://www.pharmacytimes.com/view/study-donanemab-significantly-reduces-cognitive-functional-decline-associated-with-alzheimer-disease
4. Alzheimer’s Association. Alzheimer’s disease facts and figures. Accessed July 27, 2023. https://www.alz.org/alzheimers-dementia/facts-figures
5. Rabinovici GD, La Joie R. Amyloid-targeting monoclonal antibodies for Alzheimer disease. JAMA. 2023. doi:10.1001/jama.2023.11703
6. Gbadebo O. Anti-amyloid monoclonal antibody drugs continue to show promise treating Alzheimer disease. Pharmacy Times. July 24, 2023. Accessed July 27, 2023. https://www.pharmacytimes.com/view/anti-amyloid-monoclonal-antibody-drugs-continue-to-show-promise-treating-alzheimer-disease
7. Rosenthal MB. Novel Alzheimer disease treatments and reconsideration of US pharmaceutical reimbursement policy. JAMA. 2023. doi:10.1001/jama.2023.11702
8. Artiga S, Hill L, Damico A. Health coverage by race and ethnicity, 2010-2021. Kaiser Family Foundation. December 20, 2022. Accessed July 27, 2023. https://www.kff.org/racial-equity-and-health-policy/issue-brief/health-coverage-by-race-and-ethnicity/
9. Manly JJ, Deters KD. Donanemab for Alzheimer disease—who Benefits and who is harmed? JAMA. 2023. doi:10.1001/jama.2023.11704