Surveying the landscape of the newest Alzheimer’s disease medications
The controversy surrounding the U.S. Food and Drug Administration’s (FDA) recent approvals of medications for Alzheimer’s disease (AD) has raised important questions about the medications’ safety and cost, as well as their ability to deliver on improved patient outcomes.
Now’s the perfect time to consider the current landscape of Alzheimer's medications and the challenges faced by healthcare providers, patients and caregivers.
What are the newest medications for the treatment of Alzheimer's disease?
Historically, medications used for AD management addressed symptoms but not the disease process itself. In July 2021, aducanumab (Aduhelm), was the first medication approved by the FDA aimed at treating a proposed cause of AD: beta amyloid plaques (protein clumps that create plaque and disrupt cell function) in the brain. Two other medications aimed at reducing beta amyloid plaques were subsequently approved by the FDA: lecanemab (Leqembi) in 2023 and donanemab (Kisunla) in 2024.
Both aducanumab and lecanemab were initially approved under the FDA’s Accelerated Approval Pathway, which allows the FDA to approve medications for serious conditions where there is an unmet medical need and a medication is shown to have a positive effect on a surrogate marker, in this case a reduction in beta amyloid plaques, that is reasonably likely to provide a clinical benefit to patients, which in this case is slowing the progression of AD.
The accelerated pathway also allows for faster approval of medications, as the effect on surrogate markers may be evident before a clinical impact is observed. Continued or full approval for indications approved under the accelerated pathway is contingent on confirmation in trials with clinical outcomes. For AD, clinical outcomes are typically improved cognitive and functional status. While lecanemab gained full FDA approval in 2023 after submitting trials demonstrating improvement on AD assessments of cognitive and functional status versus placebo, aducanumab was voluntarily withdrawn from the market this year by its manufacturer after the trial program was terminated due to business reasons.
Initially donanemab was submitted under the accelerated pathway but did not receive FDA approval due to the small number of patients in trial data. The application was resubmitted with additional clinical outcomes data, and donanemab subsequently received full FDA approval.
Another important aspect in the approval process for the anti-amyloid antibodies for AD is the role of FDA Advisory Committees. These are panels of independent subject matter experts that render advice on matters the FDA is considering, including medication approvals. FDA advisory committees are convened prior to approval and provide advisement to the FDA about whether a drug should be approved based on safety and efficacy. Although the FDA is not bound to follow the recommendations of its advisory committees, it typically does. In the case of aducanumab, the committee recommended against approval and in an unusual move, the FDA approved aducanumab. Both advisory committees prior to the accelerated and full approvals of lecanemab, and the advisory committee that met prior to the full approval of donanemab, recommended approval.
What are the concerns regarding the evidence evaluating newer Alzheimer's medications?
Concerns for the accelerated approval pathway are primarily related to limited data showing a minimally clinical important difference in outcomes. While there is evidence of reduction in the brain amyloid plaques, there is no long-term data on whether these agents actually slow disease progression or improve quality of life. The trials for these medications are relatively short, lasting only 18 months, which may not be sufficient to determine their long-term effects. Additionally, no trials directly comparing these agents have been performed. Anti-amyloid antibodies do not stop or reverse AD progression. Evidence only shows they slow the rate of cognitive and functional decline.
What are the safety concerns for newer AD medications?
Additional testing is required for AD patients undergoing treatment with anti-amyloid agents. Adverse effects, including brain swelling and bleeding (that also are observed in patients with AD who don’t receive anti-amyloid agents), were observed in anti-amyloid agent clinical trials and are more common in patients with two copies of the APOE gene. In clinical trials, abnormalities were reported in 13-24% of patients receiving anti-amyloid agents as compared with 2-8% of patients receiving placebo. Laboratory testing, including APOE testing, and radiologic imaging are required prior to and during treatment to ensure early detection and prompt management, which are key to ensure a successful recovery.
What are important operational considerations for newer AD medications?
Both lecanemab and donanemab are administered via IV infusion, preferably on an outpatient basis. Lecanemab is administered every two weeks and donanemab is administered once per month. Donanemab has criteria for discontinuing therapy whereas lecanemab is given indefinitely.
The restricted coverage and varying criteria set by commercial payers and government programs like the Centers for Medicare and Medicaid Services (CMS) — which only cover Alzheimer’s medications with full approval (versus accelerated approval) — add complexity to the process. Providers will need to obtain prior authorizations from payers and may need to go through appeals processes to secure coverage. It’s crucial for organizations to stay informed about the specific requirements of each payer, as they can vary among plans.
Organizations should consider the potential administrative burden and resource allocation required for these high-complexity agents. This higher level of complexity for ordering, administering and monitoring of anti-amyloid antibodies as compared with other medications requires frequent monitoring and coordination of care through lab, radiology, pharmacy and revenue cycle management.
It is also important that providers discuss efficacy and safety data and the potential financial burden of these agents with patients and their caregivers.
How should organizations approach formulary decision-making for use of the newer Alzheimer's medications?
While these agents have been shown to reduce brain amyloid plaques and slow the rate of cognitive and functional decline in the short term, their long-term effectiveness and safety are still uncertain. Organizations should carefully consider the available evidence, including surrogate and clinical outcomes, and weigh the risks of potentially serious side effects and cost as part of the formulary decision making process. Since these medications are administered in outpatient facilities, payer formularies should be taken into consideration.
Navigating high-cost medications, such as the anti-amyloid antibodies for AD, can be challenging for healthcare systems, especially in the face of decreasing margins. Strategies for healthcare systems include:
Optimize formularies: Review formularies and assess the cost-effectiveness of different treatment options. This involves evaluating the clinical benefits, potential side effects and cost of each medication. By prioritizing agents that offer the best value for money, healthcare systems can optimize their formularies and allocate resources more efficiently.
Negotiate with manufacturers: Negotiate with pharmaceutical manufacturers to secure more favorable pricing arrangements. This may involve exploring volume-based discounts, value-based agreements or other innovative contracting models.
Use specialty pharmacy services: Specialty pharmacy services can help healthcare systems manage the distribution and administration of high-cost medications. These services often have expertise in navigating insurance coverage, financial assistance programs and patient support services. By partnering with specialty pharmacies, healthcare systems can streamline the process and potentially reduce costs associated with medication administration.
Collaborate with payers: Healthcare systems can collaborate with payers to develop innovative reimbursement models that align with the value and outcomes of high-cost medications. This may involve exploring alternative payment models, such as bundled payments or performance-based reimbursement, which incentivize the delivery of high-quality care while managing costs.
Engage in value-based care: Shifting toward a value-based care model can help healthcare systems prioritize treatments that have demonstrated clinical effectiveness and cost efficiency. By focusing on outcomes and patient-centered care, healthcare systems can make informed decisions about the use of high-cost medications and allocate resources accordingly.
It’s important for healthcare systems to continuously monitor and evaluate the financial impact of high-cost medications on their margins. By implementing a comprehensive approach that combines cost optimization strategies, collaboration with stakeholders and a focus on value-based care, healthcare systems can navigate the challenges posed by high-cost medications while maintaining financial sustainability.
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