The promise of anti-amyloid therapies: A new era in Alzheimer’s treatment

The world is facing an impending tsunami as the number of people developing Alzheimer’s disease continues to grow.

In the U.S. alone, the number currently nears 7 million and is expected to grow to nearly 13 million by 2050.

AD is a progressive neurodegenerative disorder characterized by worsening impairments in memory, language, orientation and executive function. The underlying pathological changes associated with AD are thought to begin up to 20 years prior to symptom onset.

Until recently, the focus of treatment has been symptomatic with modestly effective medications, including cholinesterase inhibitors and memantine. However, we are now at the beginning of a new era with the approval of anti-amyloid therapies that target the protein found in amyloid plaques in the brain, a pathologic hallmark of this disease. That protein is considered by most to be a key pathologic trigger in a cascade of events leading to clinical AD. However, to fully realize the promise of these therapies, several key factors must align: early diagnosis, effective patient management, robust patient support systems and optimization of payment and insurance processes.

Early diagnosis and treatment

Current anti-amyloid treatments, such as lecanemab (Leqembi, Eisai), the first to receive full approval from the FDA, are monoclonal antibodies targeting various forms of beta-amyloid. Lecanemab targets amyloid oligomers. In clinical trials, these medications slow the progression of AD by approximately 30%. However, they have been shown effective only when initiated very early in the course of this disease, either at the stage of mild cognitive impairment or mild dementia. In fact, some evidence suggests these medications may be even more effective when started very early. Therefore, early diagnosis is critical if we are to realize the full potential of new therapies like lecanemab. Unfortunately, in our current state, AD often is diagnosed too late in its course, when patients may no longer be candidates for anti-amyloid therapies.

To address this problem, health care systems must develop ways to promote early recognition and evaluation of cognitive decline. This can include early screening for individuals at risk for cognitive decline, including those with a family history of the disease. Standard screening at Medicare annual wellness visits can be one effective mechanism. We then need to create efficient pathways to facilitate further evaluation and diagnosis by primary care or efficient referral to specialists such as neurologists and geriatricians. The relative shortage of such specialists in many areas will be a barrier, though better use of telemedicine, advanced practice providers and care navigators could help facilitate more efficient evaluations.

For patients potentially eligible for anti-amyloid therapy, access to biomarker studies to confirm the presence of pathologic amyloid is critical. Current barriers include access to lumbar puncture and amyloid positron emission tomography scans. Blood-based biomarkers could potentially eliminate these barriers, though payer coverage is currently limiting.

Navigating patient management: Monitoring for adverse events

While anti-amyloid treatments have been described as game-changing in Alzheimer’s care, they also come with significant challenges and risks. Logistically, use of these medications is complex. In addition to the need for a careful diagnostic evaluation prior to determining eligibility, coordination with pharmacy and infusion centers to allow for biweekly or monthly infusions, and coordination with radiology for frequent safety MRI monitoring are critical. Careful planning and ongoing operational meetings, including representatives of these various departments, can lead to an efficient system of care.

One of the most significant challenges is monitoring and managing adverse events, such as amyloid-related imaging abnormalities (ARIA).

ARIA can manifest as brain swelling or brain bleeds, most often microhemorrhages, though macro-hemorrhages also can occur. While most cases are asymptomatic, some can cause headaches, confusion or other neurologic symptoms. These can even be life-threatening, though this is expected to be relatively rare. Therefore, the importance of a well-organized system to ensure recommended safety MRI monitoring and for addressing the emergence of ARIA or other adverse events cannot be overstated. Fortunately, with appropriate patient and family education, careful coordination with radiology and a clear protocol, this can be managed effectively. The addition of a dedicated nurse navigator, along with a strong relationship with neuroradiology, have been invaluable in our own success.

Patient support and infrastructure

Anticipating strong interest in anti-amyloid treatments in our own region, we formed a multidisciplinary work group several months before the full FDA approval of lecanemab. This allowed us to begin delivering the medication within about a month of full approval and to accommodate well over 100 patients in our first year. The decision to recruit a nurse navigator to oversee this program has been critical. Additionally, we developed a series of educational materials and held a number of professional educational events for primary care, neuro-hospitalists, intensivists and emergency medicine specialists. Shortly after beginning our program, our initial patients and their caregivers asked us to form a support group for patients on lecanemab, which has been highly successful. Despite these initial successes, challenges will remain, particularly with continued growth. As demand continues to steadily grow, we may see constraints on infusion capacity and need to consider partnerships with other infusion centers. We have been unable to exploit home infusion thus far due to payer constraints, though this may change in the future. The development of subcutaneous dosing holds the promise of extending this treatment to patients in more rural areas. We currently have patients driving more than 2 hours each way to receive infusions, but geography is clearly a limiting factor for many.

Optimizing payment and insurance coverage

One of the greatest barriers to accessing anti-amyloid treatments is cost. The total cost of treatment, inclusive of drug cost, infusion fees and MRI monitoring, is substantial and can place a significant financial burden on patients and their families. Furthermore, navigating the complexities of insurance coverage can be a daunting task, both for patients and health care organizations. Working closely with our reimbursement department has been very important. Over time, we have learned what various insurance providers require. Scheduling an additional clinic visit with an advanced care provider to carry out plan-specific requirements, such as a Clinical Dementia Rating, have been useful. However, uneven and varying payer policies and requirements have been, and likely will remain, a barrier to patients for some time. Medicare requires all patients be included in a registry. We have found the CMS registry to be relatively easy to use and are increasingly enrolling interested patients in the Alzheimer’s Network for Treatment and Diagnostics, or ALZ-NET, a more extensive registry.

Conclusion

The advent of anti-amyloid therapies offers new hope in the battle against Alzheimer’s disease, but their success depends on several factors: early recognition, efficient navigation through the diagnostic process and referral to specialty services, and a robust support system for patients and families. For the first time, we have treatments that can change the course of this disease. While we hope that this is just the next step of many more breakthroughs to come, we must now focus on developing effective processes to fully realize the potential of this new class of medication.