Pharmaceutical treatments have been at a standstill, but promising drugs are on the horizon.
More than 5 million people in the United States have Alzheimer disease (AD), and that number is expected to triple by 2050.1,2
Although AD is the third-leading cause of death in those 65 years and older, just $900 million is dedicated to research. In 2020, the annual cost of AD and other forms of dementia is estimated at $350 billion.
All drugs approved by the FDA to treat AD are symptomatic therapies that work on the acetylcholine or glutamate neurotransmitters. The standard medical treatment for AD includes cholinesterase inhibitors and a partial N-methyl-D-aspartate antagonist that ameliorate cognitive and memory deficits.3 There are no treatments that delay, prevent, or stop disease progression.
AD is a progressive neurodegenerative disorder most commonly found in older individuals. It is marked by behavioral and cognitive impairment symptoms that are characterized by difficulty completing familiar tasks and memory loss.2,4
Based on our understanding, development of AD occurs through several mechanisms in the brain. In AD, the accumulation and deposition of amyloid plaques develop deep in the hippocampus. Whether these plaques cause AD or are a by-product remains to be determined. Second, formation of neurofibrillary tangles involving the tau protein lead to neuronal injury, and the progressive loss of neurons results in cognitive impairment.4
Biogen has submitted a biologics license application to the FDA for its antiamyloid antibody, aducanumab, this year, and the FDA has accepted the application with priority review. If approved, aducanumab would be the first AD medication in 16 years.5,6
This human immunoglobulin monoclonal antibody has a high affinity for an epitope on β-amyloid. Although the data are optimistic, the journey to approval has not been easy. After a successful phase 1 trial, the phase 3 trials EMERGE and ENGAGE showed mixed results. Although these trials were set up to be identical, EMERGE showed benefit, and ENGAGE did not replicate those results. After a futility analysis showed little treatment efficacy, the trials were discontinued in 2019.5,7
These 2 studies compared high- and low-dose aducanumab and a placebo over 78 weeks. The high-dose EMERGE cohort experienced a 22% improvement in the primary outcome of an adjusted mean clinical dementia rating sum of box (CDR-SB) scores compared with the baseline. By contrast, the low-dose EMERGE group, as well as the high- and low-dose cohorts in the ENGAGE study, experienced no statistically significant change in CDR-SB outcomes.5,7
However, in October 2019, Biogen presented a more complete analysis of its EMERGE and ENGAGE trials, this time showing that “sufficient exposure to high-dose aducanumab reduced clinical decline across multiple clinical end points.”5,6
Biogen explained the different results by attesting that because the ENGAGE trial began enrolling first and recruitment remained ahead of EMERGE, more patients in EMERGE were affected by the protocol amendments, which resulted in a higher number of patients exposed to the highest dose in EMERGE versus ENGAGE. Clinical benefit was associated with the degree of exposure to aducanumab. A protocol adjustment during the study increased the mean dose of aducanumab, a move associated with better outcomes, and because of the stages in enrollment, patients in the EMERGE trial were more likely to receive the higher dose.5,7
In March, Biogen launched its redosing study, called EMBARK.6 The study enrolled participants who were formerly enrolled in Biogen’s stage 3 trial of aducanumab. An effective treatment to slow the progression of AD would be a huge milestone.
Limitations to Research
Developing new drugs for AD can be tricky. Many modalities of the disease remain unknown. Study end points often depend on subjective measures and scales that may be influenced by patient self-reporting or reviewer bias. For example, in many clinical trials, we are looking at objective lab end points or mortality, but in AD, end points depend on scales, such as the activities- of-daily living inventory for mild cognitive impairment and CDR-SB.8
The question remains, when is it OK to lower the bar and meet an unmet patient need? There are other examples of medications that have failed trials but have had positive patient impact, such as AstraZeneca’s Lynparza.
Despite some setbacks, the AD frontier remains active. There are multiple drugs in the AD pipeline, with many targeting amyloid plaques and tau proteins.
What Can Pharmacists Do?
Pharmacists should stay abreast of current research. Not a lot has changed as far as pharmaceutical treatment over the past decade, but many promising drugs are on the horizon. Second, early identification remains a priority. Screening patients and identifying AD earlier can have a lasting treatment impact. Finally, there are a host of lifestyle factors that are shown to reduce the risk of AD.9 Pharmacists should promote healthy lifestyle choices, such as cardiorespiratory activity, cognitive engagement, diet, and exercise.
Joanna Lewis, PharmD, MBA, has worked in a variety of practice settings, most recently as a coordinator at Duke University Hospital in Durham, North Carolina.