New Treatments Are Changing the Future of Alzheimer Disease

Recent FDA approvals and new scientific understandings have given patients and practitioners renewed hope for the future of Alzheimer disease (AD), which has long presented a challenge. As new treatments finally reach the public, pharmacists will play a growing role in counseling and ensuring patient access.

AD was first identified by Alois Alzheimer, a physician in Germany, when a woman named Auguste Deter was admitted to the institution where he worked. Alzheimer asked Deter to recall basic facts about her life and tested her understanding of where she was. Deter frequently responded, “I have lost myself, so to say,” according to the Alzheimer Society of Canada.¹

Deter spent 5 years in the institution before her death, by which point her cognitive abilities had significantly declined. Alzheimer then studied her brain, finding that certain regions had shrunk and noting 2 significant deposits: plaques and tangles. Alzheimer concluded that Deter had a rare form of dementia and theorized that the plaques and tangles were related to the disease, opening the door for new research.¹

For the next 70 years, AD was still believed to be a rare form of dementia, and fewer than 150 scientific articles were published. However, an editorial published by American neurologist Robert Katzman in 1976 opened researchers’ and health care practitioners’ eyes to the widespread devastation of AD, which Katzman called a “major killer.”¹ Crucially, he wrote that AD is the most common cause of dementia, the fourth leading cause of death in the US, and a major public health challenge across the entire world. These observations changed the perspective on AD.¹

Various organizations and individuals began organizing in the following years, funding huge amounts of research. More than 45,000 articles have since been published, reviewing the disease’s causes, effects, and potential treatments and cures. A cure for AD has yet to be found, but several treatments to manage the symptoms have been tested and approved, giving hope to the individuals and caregivers affected.¹

“Having an armamentarium that’s fully stocked is the best option for physicians treating this disease,” Pamela Spicer, a neuroscience expert and therapy area director at Citeline, said in an interview. “Right now, we basically have 2 drug targets that address dementia symptoms, and then we have this anti-amyloid antibody [and] these newer ones entering the market, the full potential of which really has yet to be seen. So, newer treatment options would provide a variety but ideally address the disease in various ways, and hopefully we can do that in clinically meaningful ways.”

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Researchers now understand that AD is primarily observed in older adults, with a prevalence of 43.8 million in 2016. Importantly, this represents a 116% increase since 1990, when 20.3 million patients were affected. Data suggest that the number of people affected by dementia will reach 150 million by 2050.²

“We used to think Alzheimer disease was a dementia, and that’s it,” Sharon Cohen, MD, medical director at the Toronto Memory Program, said in an interview. “Now we know clinically, people go through a presymptomatic stage, then the mild cognitive impairment stage, then the dementia stage with mild, moderate, and severe dementia. So, the clinical continuum is quite broad.”

Pathologically, AD is characterized by an accumulation of abnormal neuritic plaques and neurofibrillary tangles in the brain2, just as Alois Alzheimer originally postulated. These changes in the brain are also accompanied by a loss of neurons. Researchers have proposed 2 hypotheses based on this knowledge²:

“Biologically, there’s also a complex continuum where the first changes are accumulation of amyloid in the brain, then tau and other protein becomes abnormal, hyperphosphorylated, and starts injuring the brain. Neuroinflammation is part of that injurious process as well,” Cohen said. “And then you get neurodegeneration with progressive loss of neurons and connections between neurons, and the synapses disappear. So being able to target specific stages, both clinically and biologically, allows for precision medicine.”

Traditionally, treatments for AD have focused primarily on symptom management because by the time of diagnosis, the pathological process in the brain has been present for more than a decade. As researchers have gained better understandings of the disease’s pathophysiology; however, new treatments have emerged to target these underlying pathways.

“We’re at the dawn of a new era in the treatment of Alzheimer disease,” Martin Tolar, MD, PhD, the founder, president, and CEO of Alzheon, said in an interview. “We actually do understand the underlying pathogenesis, and there have been a number of different approaches tried, in particular against the 2 main hallmarks of the disease…which is the amyloid plaque and the tau tangles.”

Additionally, improvements in diagnostic testing using imaging and biomarkers have allowed clinicians to detect preclinical and presymptomatic stages of AD, opening up the opportunity for earlier treatment.

“The best biomarker is the phosphorylated tau protein,” Tolar explained. “Tau is the [neuronal] scaffolding protein…and when the cells are injured, it starts to phosphorylate. And then when [the cells] die, it’s released in the [cerebrospinal fluid] and then in plasma, where we can record it and we can actually detect it.”

The 3 FDA-approved treatments for AD are lecanemab (Leqembi; Eisai and Biogen), donanemab (Kisunla; Lilly), and aducanumab (Aduhelm; Biogen), which is being discontinued as of November 1, 2024.³ Although the approvals have been met with much excitement, the clinical trials have also faced many questions and some controversy, particularly in the case of aducanumab.

Lecanemab was initially granted accelerated approval by the FDA in January of 2023, before being converted to a traditional approval in July of that same year, based on confirmatory study results. The treatment’s ability to reduce amyloid plaques in the brain was demonstrated in Study 301 (NCT03887455), a multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolling 1795 patients.⁴

Treatment was initiated in patients with mild cognitive impairment or mild dementia and confirmed presence of amyloid beta pathology. Treatment was randomized 1:1 to either placebo or lecanemab 10 mg/kg, once every 2 weeks.⁴

According to the results, patients receiving lecanemab experienced a statistically significant and clinically meaningful reduction of decline from baseline to 18 months on the primary end point, which was the Clinical Dementia Rating Scale Sum of Boxes score, compared with placebo. Investigators also saw statistically significant differences between treatment groups for all secondary end points, including the Alzheimer’s Disease Assessment Scale Cognitive Subscale 14, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment.⁴

The most common adverse effects were headache, infusion-related reactions, and amyloid-related imaging abnormalities (ARIA). ARIA typically present as temporary swelling in areas of the brain and usually resolves over time, although it may be accompanied by small spots of bleeding in or on the surface of the brain. Symptoms of ARIA can occur and include headache, confusion, dizziness, vision changes, and nausea.⁴

On July 2, 2024, the FDA approved donanemab-azbt as the first and only amyloid plaque-targeting therapy using a limited-duration treatment regimen based on amyloid plaque removal. This could represent a significant step forward because, previously, a major question surrounding the treatments for AD was whether it was possible to halt treatment once progress was made.⁵

“Current medications for Alzheimer disease do not show much improvement or slowing of symptoms, unfortunately, so this is a big win,” Nikhil Palekar, MD, director of the Stony Brook Center of Excellence for Alzheimer’s Disease and director of the Stony Brook Alzheimer’s Disease Clinical Trials Program, said in an interview. “It’s a first step, but it’s a big win for the field, for our patients, and families struggling with Alzheimer.”

In the TRAILBLAZER-ALZ 2 (NCT04437511) phase 3 study, participants who were in the least advanced stages of disease saw the greatest benefits with donanemab, although treatment also significantly slowed clinical decline in a large population including patients with high tau levels. Individuals treated with donanemab who had less advanced disease showed a 35% slowing of decline compared with placebo on the integrated Alzheimer’s Disease Rating Scale, which measures memory, thinking, and daily functioning. In the overall population, the response to treatment was also statistically significant at 22% slowing of decline.⁵

In the overall patient population, donanemab reduced amyloid plaques by an average of 61% at 6 months of treatment, 80% at 12 months, and 84% at 17 months compared with the start of the study. Once patients were confirmed to have minimal levels of amyloid plaques, they were able to complete treatment with donanemab and switch to placebo for the remainder of the study.⁵

“Unfortunately, we do not have any medications at this point that can [halt disease progression or reverse illness], but [donanemab] will slow the progression down in quite a significant way, which will allow patients to remain functional for a longer period of time,” Palekar explained. “And this is really important because this will also allow them to be able to have the opportunity to participate in other clinical trials that are coming up targeting other molecules or proteins that are also implicated in Alzheimer disease.”

Donanemab is administered intravenously every 4 weeks, with 700 mg for the first 3 doses followed by 1400 mg thereafter. Like lecanemab, ARIA can occur.⁵

Although aducanumab was approved before lecanemab and donanemab, its controversial approval and lack of Medicare funding has resulted in the recent announcement that it will be discontinued in November 2024.³

“The approval process for aducanumab specifically was very strange,” Spicer said. “For one, the FDA worked unusually closely with Biogen during the review process, and the agency went against the advisory committee recommendation in its approval.”

The FDA approved aducanumab in June 2021, representing a first-of-its-kind treatment and the first therapy targeting the underlying pathophysiology of AD. Three separate studies with 3482 participants evaluated the efficacy of aducanumab, but 2 of the studies—EMERGE (NCT02484547) and ENGAGE (NCT02477800 )—quickly came under fire for their contradictory results. Although they had identical study designs and the same primary end point, differing study protocols and premature termination of both trials may have led to their contradictory results, in which the high-dose treatment arm in the EMERGE study was the only arm among both trials to demonstrate cognitive improvement.⁶

Biogen performed extensive subgroup analyses to try and explain these different results, with 2 potential reasons. Firstly, it was noted that there were more individuals who had a rapid decline in the ENGAGE trial than in the EMERGE trial, and removing these outliers from the data set made the results of the 2 trials more compatible. Second, a smaller number of participants in the ENGAGE trial had received the higher doses of the drug.⁷

Spicer noted that when the label was first released, it did not specify in which stage of the disease the drug should be initiated. In earlier stages of its development, she said investigators were using anti-amyloid antibodies in patients with more severe moderate stages of disease before learning that these drugs work best in earlier stages. She also noted that the original label had no requirement for the drug to be used in patients with confirmed amyloid pathology.

“It just makes sense that you have this anti-amyloid drug, and it should be used in patients who have amyloid, and we now have the tools to measure that [in vivo],” Spicer said. “It was a little surprising that the label didn’t stipulate that one way or another, even though that was part of the clinical program.”

Regardless of explanations provided by the company, questions and controversy lingered. In April of 2022, Medicare officials announced that they would only cover aducanumab for individuals who receive it as part of a clinical trial.⁸ Physicians and entire medical centers also announced that they would not be administering the drug due to concerns about its safety and adverse effects, including ARIA.⁹

Now, with the removal of aducanumab from the market approaching in November 2024, clinicians are looking to learn lessons from its disastrous approval process. In addition to the high expense of clinical trials for the treatment of AD, designing these trials presents many challenges.

In an open letter published in the journal of the Alzheimer’s Association, authors pointed out that many trials, including the ENGAGE and EMERGE trials, are conducted across many medical centers in different countries with many clinical evaluators, most of whom are not members of the team conducting the study so as to avoid bias. As a result, many participants have incomplete long-term follow-up data, which is crucial to properly evaluate the end points.⁷

Other barriers include limited patient awareness of clinical trial availability, lack of clear diagnosis criteria, and infrequent trial referrals. Although all clinical research is expensive and time-consuming, AD research is particularly complicated, pricey, and slow.¹⁰ Still, researchers hope that the lessons learned from aducanumab can be applied to future studies, allowing for more successful treatments for this complicated disease.

“After decades of failures, we do have a good understanding of the biology, we understand what’s driving Alzheimer disease, and how to find the patients [and] when to treat patients,” Tolar said. “There are a number of companies that are now developing treatments that can be much more effective. It’s really the dawn of a new era in therapeutics for Alzheimer disease.”

New Treatments Are Changing the Future of Alzheimer Disease

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References

The history behind Alzheimer’s disease. Alzheimer Society. Accessed August 28, 2024. https://alzheimer.ca/en/about-dementia/what-alzheimers-disease/history-behind-alzheimers-disease

Sidhu J, Lui F, Tsao JW. Alzheimer Disease. StatPearls [internet]. Updated February 12, 2024. Accessed August 28, 2024. https://www.ncbi.nlm.nih.gov/books/NBK499922/#:~:text=Pathophysiology,basal%20forebrain%20and%20the%20neocortex

Aduhelm. Accessed August 28, 2024. https://www.aduhelm.com/#:~:text=Patients'%20last%20infusion%20date%20must,review%20in%20the%20PATH%20program

FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. News release. FDA. July 6, 2023. Accessed August 29, 2024. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval

Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA Netw. 2023;330(6):512-527. doi:10.1001.jama.2023.13239

Brockmann R, Nixon J, Love BL, Yunusa I. Impacts of FDA approval and Medicare restriction on antiamyloid therapies for Alzheimer’s disease: patient outcomes, healthcare costs, and drug development. Lancet Reg Health Am. 2023;20:100467. doi:10.1016/j.lana.2023.100467

Kuller LH, Lopez OL. ENGAGE and EMERGE: truth and consequences? Alzh & Demen. 2021;17(4):692-695. doi:10.1002/alz.12286

Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. Centers for Medicare & Medicaid Services. April 7, 2022. Accessed August 29, 2024. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&NCAId=305

Belluck P. Cleveland Clinic and Mount Sinai Won’t Administer Aduhelm to Patients. New York Times. July 14, 2021. Accessed August 29, 2024. https://www.nytimes.com/2021/07/14/health/cleveland-clinic-aduhelm.html

Goldman D, Malzbender K, Lavin-Mena L, Hughes L, Bose N, Patel D. Key Barriers for Clinical Trials for Alzheimer’s Disease. USC Schaeffer. August 17, 2020. Accessed August 29, 2024. https://healthpolicy.usc.edu/research/key-barriers-for-clinical-trials-for-alzheimers-disease/