Alzheimer’s Disease: New Therapies and Management Strategies

Payers and manufacturers will have to effectively collaborate to manage costs, ensure access, and improve outcomes in this patient population.

The most common cause of dementia in older adults, Alzheimer’s disease (AD), is an irreversible, progressive brain disease that deteriorates memory and cognition.1 The cause of AD is thought to be abnormal build-up of protein around brain cells. Amyloid protein deposits form plaques around brain cells and tau protein deposits form tangles within brain cells.2

Kathryn Canaday, Pharm.D. Vice President, Pharmacy and Clinical Drug Management Medical Mutual of Ohio

The initial symptoms of AD may manifest differently across the patient population, though memory problems are typically one of the first signs.1 Other symptoms can include decline in other aspects of thinking, vision and spatial issues, and impaired reasoning or judgment.1 Mild cognitive impairment can be an early sign of AD; however, not all individuals with mild cognitive impairment will develop AD.1 As the disease progresses, individuals with AD will have increasing difficulty completing everyday tasks and may become repetitive, get lost easily, lose items, or find simple concepts confusing. Emotion dysregulation may increase as AD progresses as well.1, 2

Diagnosis of AD is challenging because brain changes can occur long before clinical symptoms manifest or are detected.3 The progression of AD occurs in three phases: preclinical, mild cognitive impairment, and dementia; dementia is further stratified into mild, moderate, and severe stages. The preclinical phase includes potential biological changes in the brain, but no symptoms. In the mild cognitive impairment phase, mild symptoms manifest that most likely do not interfere with daily activities and may go unnoticed and undiagnosed. Progression through the dementia phase is determined by the interference with everyday activities on a continuum from some to many to most being unable to be completed. Factors including age, genetics, and sex can influence how quickly patients progress through the phases of disease.3

Diagnosis of AD currently includes a combination of symptom reporting, cognitive testing, and a series of lab testing, such as CT scans, MRIs, or PET scans, that work to rule out other conditions that may potentially contribute to cognitive changes.1-3 PET scans provide analysis of proteins from cerebrospinal fluid. While no validated blood biomarkers are currently known for AD, three cerebrospinal fluid biomarkers, including Aβ42, total tau protein, and phosphorylated tau, can be used as biomarkers for diagnosis.3

Recommended diagnosis per the International Working Group includes both the presence of biomarkers and specific phenotypes common to AD for confirmed diagnosis.3 Despite this recommendation, biomarker data is not commonly used in clinical practice. MRI is often used to show contrast between gray and white matter.1, 3

More than 6 million adults in the U.S. age 65 or older have AD. If population trends continue and the U.S. population continues to age, the number of those living with AD will increase significantly over the next decade.1 The vast majority of AD cases occur in individuals 65 or older, which is described as late-onset AD. Early-onset AD occurs in individuals between ages 30 and 65 but is very rare. After initial diagnosis, the life expectancy of individuals with AD can average four to eight years; some patients with AD may live up to 20 years after diagnosis, with more than 40% of that time spent in the severe stage.1 In the late progression of AD, nonmemory symptoms such as immobility, difficulty swallowing, and malnutrition become prevalent, which impact activities of daily living, correlate with significant morbidity, and decrease autonomy and quality of life.3 Caregiver burden in this stage is significant, as it is estimated that more than 11 million Americans provide unpaid care for patients with AD and associated dementias.3 AD carried a cost burden of $321 billion in 2022, in addition to an estimated $271 billion in unpaid caregiving.4

Current Treatment Landscape

Treatment and management of AD is dynamic, multifactorial, and multidisciplinary. Currently, there are three FDA-approved cholinesterase inhibitors — donepezil, galantamine, and rivastigmine — and an N-methyl-D-aspartate-antagonist, memantine.3, 5 These approved treatments are all similarly associated with improvement above baseline on cognitive measures on the AD Assessment Scale cognitive subscale.3 Galantamine and oral rivastigmine are indicated for mild to moderate AD, while donepezil and transdermal rivastigmine are indicated for mild, moderate, or severe AD.3, 5 Memantine can be added to a treatment regimen if a patient progresses to severe AD while on these drugs, and in some cases, the combination of donepezil-memantine is used as a monotherapy. Current standard treatment for AD focuses on symptom improvement; thus, effectiveness will decrease over time as the disease progresses.3, 5 Currently, there is no cure for AD. Two FDA-approved medications target the fundamental pathophysiology of the disease, and others are under review.5

In June 2021, the FDA approved aducanumab (ADUHELM®, a monthly intravenous immunoglobulin gamma 1 monoclonal antibody) for the treatment of AD.6 The accelerated approval of aducanumab was based on a post-hoc analysis of the EMERGE trial, which found reduction of amyloid plaques for the primary surrogate endpoint in patients treated with high-dose aducanumab. The FDA concluded that the reduction in amyloid plaques is likely to provide clinical benefit.6, 7 In July 2021, the FDA approved a label revision clarifying the indication to include initiation in patients with mild cognitive impairment or mild dementia stage of disease, as this was the population in which aducanumab was initiated in clinical trials. Along with the accelerated approval, the FDA required an additional trial to evaluate the safety and efficacy of aducanumab, to be completed by 2030.6, 7 In 2021, the Institute for Clinical and Economic Review (ICER) concluded that the health-benefit price benchmark range for aducanumab is $3,000 to $8,400 per year, compared to the list price of $56,000.8

Lecanemab (Leqembi™)

In January, the FDA approved lecanemab-irmb (Leqembi™) for the treatment of AD.9 This approval makes lecanemab the second of a new category of approved AD medications that target the pathophysiology. The FDA granted lecanemab accelerated approval based on the results of a phase 2b randomized, controlled clinical trial confirming the drug’s clinical benefit.9 In the phase 2b study of 856 patients with AD, treatment was initiated in patients with mild cognitive impairment or mild dementia disease stage and confirmed presence of amyloid beta pathology.10 The patients randomized to receive treatment with lecanemab experienced significant dose- and time-dependent reduction in amyloid beta plaque.10 Patients receiving 10 mg/kg of lecanemab every two weeks had a statistically significant reduction in brain amyloid plaque from baseline to week 79, while those receiving placebo had no reduction of amyloid beta plaque.10 Results from a phase 3 study of 1795 patients randomized to receive lecanemab or placebo showed the mean change from baseline CDR-SB score was less in patients receiving lecanemab than placebo (1.21 vs. 1.66, respectively).11 A further sub-study of 698 patients showed greater reductions in brain amyloid burden with lecanemab, compared to placebo.11 Treatment with lecanemab comes with a warning for amyloid-related imaging abnormalities (ARIA).9

Table 1. Alzheimer’s Disease Pipeline

Abbreviations: DHP CCB = dihydropyridine calcium-channel blockers; GLP-1 = glucagon-like peptide 1; IV = intravenous; NDRI = norepinephrine and dopamine reuptake inhibitors; NMDA = N-methylD-aspartate; NSAIDs = nonsteroidal anti-inflammatory drugs; SC = subcutaneous

An expansive pipeline shows promising treatment opportunities for AD on the horizon.

Treatment Advances/Updates

An expansive pipeline shows promising treatment opportunities for AD on the horizon. In January, the FDA declined to grant accelerated approval to donanemab, which would have been the third amyloid-targeting therapy indicated for early AD.12 The FDA noted that approval would require safety data on at least 100 patients who have taken donanemab continuously for at least a year. There is an ongoing phase 3 trial (TRAILBLAZER-ALZ 2), which may provide the required data for the traditional approval pathway.12 Previously, donanemab was investigated investigated for safety and efficacy in the TRAILBLAZER-ALZ, TRAILBLAZER-ALZ 2, and TRAILBLAZER-ALZ 3 studies. It was assessed head-to-head with aducanumab in the TRAILBLAZER-ALZ 4 study.13 Results from TRAILBLAZER-ALZ showed significant reduction in the primary outcome of change in Integrated AD Rating Scale from baseline (-6.86 donanemab vs. -10.6 placebo) (32%) at 76 weeks.13 In the TRAILBLAZER-ALZ 4 trial, after six months, donanemab achieved completed amyloid plaque clearance (<24.1 Centiloids) in 37.9% of patients versus 1.6% in aducanumab-treated patients.14

Gantenerumab, a fully human anti-amyloid antibody, failed to meet primary and secondary endpoints in the phase 3 GRADUATE clinical trials, and development of this molecule has been discontinued. The pipeline (Table 1) shows a more expansive pipeline in this category.

Payer Impact

Strategic management and policymaking by the Centers for Medicare & Medicaid Services (CMS) will be key moving forward, as analysts suggest 96% of the market for AD treatments in the pipeline are in the Medicare population.15 Cost effectiveness of new AD treatments is an important starting point for setting value-based prices. An important negotiation point for payers and manufacturers may be performance warranties, which help to apportion risk associated with initial treatment.15 Subscription payment plans may be a useful tool to address affordability as more novel therapies for AD become available.15 As seen in other disease states with innovative therapies, different value-based agreements may be a solution for a variety of costly treatment options in this space.15 However, in order to be effective, they would require efficient care models for screening and treatment. Payers and manufacturers will have to effectively collaborate to manage costs, ensure access, and improve outcomes in this patient population.16

References

1. “What is Alzheimer’s Disease?” National Institute of Health, 8 July 2021, https://www.nia.nih.gov/health/what-alzheimers-disease.

2. “Alzheimer’s Disease.” Cleveland Clinic, https://my.clevelandclinic. org/health/diseases/9164-alzheimers-disease.

3. Hill, Angela. “Alzheimer Disease and the Evolving Treatment Landscape.” American Journal of Managed Care, 12 Sept. 2022, https://www.ajmc.com/view/alzheimer-disease-and-the-evolvingtreatment-landscape.

4. “The Economic Costs of Alzheimer’s Disease.” Joint Economic Committee Democrats, 6 July 2022, https://www.jec.senate.gov/ public/index.cfm/democrats/issue-briefs?id=02F4CADC-954F4E3B-8409-A4213E3C0759.

5. “How is Alzheimer’s Disease Treated?” National Institute of Health, 8 July 2021, https://www.nia.nih.gov/health/how-alzheimers-diseasetreated.

6. “FDA Grants Accelerated Approval for Alzheimer’s Drug.” U.S. Food & Drug Administration, 7 June 2021, https://www.fda.gov/newsevents/press-announcements/fda-grants-accelerated-approvalalzheimers-drug.

7. “FDA’s Decision to Approve New Treatment for Alzheimer’s Disease.” U.S. Food & Drug Administration, 7 June 2021, https:// www.fda.gov/drugs/news-events-human-drugs/fdas-decisionapprove-new-treatment-alzheimers-disease.

8. “ICER Publishes Final Evidence Report and Policy Recommendations on Aducanumab for Alzheimer’s Disease.” Institute for Clinical and Economic Review, 5 Aug. 2021, https://icer.org/news-insights/ press-releases/icer-publishes-final-evidence-report-and-policyrecommendations-on-aducanumab-for-alzheimers-disease/.

9. “FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment.” U.S. Food & Drug Administration, 6 Jan. 2023, https:// www.fda.gov/news-events/press-announcements/fda-grantsaccelerated-approval-alzheimers-disease-treatment.

10. Swanson, Chad, et al. “A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Ab protofibril antibody.” Alzheimer’s Research & Therapy, 17 Apr. 2021, https://pubmed.ncbi.nlm.nih. gov/33865446/.

11. Van Dyck, Christopher, et al. “Lecanemab in Early Alzheimer’s Disease.” New England Journal of Medicine, 5 Jan. 2023, https:// www.nejm.org/doi/full/10.1056/NEJMoa2212948.

12. Shapiro, Lindsay. “FDA Rejects Accelerated Approval Application for Donanemab.” Alzheimer’s News Today, 24 Jan. 2023, https:// alzheimersnewstoday.com/news/accelerated-approval-deniedalzheimers-therapy-donanemab.

13. Mintun, Mark, et al. “Donanemab in Early Alzheimer’s Disease.” New England Journal of Medicine, 6 May 2021, https://www.nejm.org/ doi/full/10.1056/NEJMoa2100708.

14. “Lilly Shares Positive Donanemab Data in First Active Comparator Study in Early Symptomatic Alzheimer’s Disease.” Eli Lilly and Company, 30 Nov. 2022, https://investor.lilly.com/news-releases/ news-release-details/lilly-shares-positive-donanemab-data-firstactive-comparator.

15. Lin, Pei-Jung, et al. “Preparing the health-care system to pay for new Alzheimer’s drugs.” Alzheimer’s & Dementia, 18 Aug. 2020, https:// europepmc.org/article/med/32808733.

16. Hung, Anna, et al. “Addressing Challenges in Payment and Access to Treatments for Early-Stage Alzheimer’s Disease.” Duke Margolis Center for Health Policy, 2020, https://healthpolicy.duke.edu/sites/ default/files/2020-03/duke_alzheimerissuebrief-2020.pdf.