Donepezil is the generic name for Aricept ™, approved over 25 years ago for “dementia of the Alzheimer’s type.” Two recent papers suggest that it may be “disease-modifying,” depending on how that term is defined [one cannot find a hard definition on the FDA website.]
Dr. J. Cummings, an eminent dementia researcher (active with lecanemab now), wrote a definition in 2009: “…Disease modification can be defined as treatments or interventions that affect the underlying pathophysiology of the disease and have a beneficial outcome on the course of AD [Alzheimer’s Disease]…”
Aducanumab, Aduhelm ™, was FDA approved in 2021 with some controversy about its beneficial outcomes for patients. A National Institute of Aging (NIA) website states: “Medications that target the underlying causes of a disease are called disease-modifying drugs or therapies. Aducanumab is the only disease-modifying medication currently approved to treat Alzheimer’s…”
Donepezil’s effectiveness has never been dramatic; the same NIA website says: “…These drugs may help reduce or control some cognitive and behavioral symptoms….” It’s class of drugs is known as cholinesterase inhibitors (ChEI aka AChEI for acetylcholinesterase). That biochemical pathway seems to be involved, but for some reason was not considered part of the pathophysiology and the drugs were not considered disease modifying. [???]
France stopped state funding for donepezil use in AD (along with three others) in 2018. The BMJ translated a French journal: “The days are over when support for patients and their struggling caregivers was based on drugs raising false hopes.” And no one wants expensive new drugs that might raise false hopes.
However, a Cochrane Review 2018, 30 studies with >8K patients, states: “There is moderate-quality evidence that people with… dementia due to Alzheimer’s disease … with donepezil experience small benefits in cognitive function, activities of daily living and clinician-rated global clinical state…” A 2022 review in Down Syndrome dementia did show two positive donepezil studies, but unclear how many negative studies (only six of 364 studies identified were further reviewed).
This year July 2022, Zuin et al published an observational study of >1500 patients in a US database, concluding: “Our results, obtained from the National Alzheimer’s Coordinating Center…, suggest that older people with dementia who are prescribed AChEIs have a slower decline in cognitive performance and a reduced mortality (by approximately 40%) after a follow-up of almost eight years.”
This parallels a series of longitudinal Swedish studies by Wattmo et al, looking at donepezil and similar drug therapy, including three year outcomes 2016, or short-term drug response effects on time to nursing home placement, 2018. In the latter paper, ~800 patients, they concluded: ” Patients who exhibit a positive short-term response to ChEI can expect to stay in their own home for 3-8 months longer…”
Last year, Apr 2021, another research group looked at AChEIs, >11K subjects on meds, evidently a different Swedish database, and found that: “ChEIs are associated with cognitive benefits that are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia.”
Let’s go back to Cummings’ “disease modifying” definition for a bit. In many diseases, the pathophysiology is not known precisely, like cancer development. Some effective cancer therapies don’t even target fundamental carcinogenesis pathophysiology (PD-1 pathway, anti-angiogenesis, CAR-T cells), yet are approved for prolonging survival.
Does donepezil or other AChEIs, on the market for decades, fulfill the second part of the definition, about having a “beneficial outcome on the course of AD”? No one claims that they halt progression or death, but “real-world” studies like those cited above show that they may slow or delay cognitive decline and time to death.
The FDA, on a website, states that aducanumab or “…Aduhelm is the first treatment directed at the underlying pathophysiology of Alzheimer’s disease, the presence of amyloid beta plaques in the brain…” i.e. improving brain imaging. Written by Dr. P. Cavazzoni, an FDA director, she explains that Aduhelm is on the Accelerated Approval Program, since it “…is expected to lead to a reduction in the clinical decline…”
[Overt Editorializing: One might say that expecting a reduction in clinical decline implies that a reduction had not been clearly demonstrated.]
The CMS (Medicare), in coming to their Aduhelm funding decision, was not so sure about the pathophysiology part, making this statement: “In sum: the etiology of AD is unknown and may be multifactorial; clinical diagnosis is poor (Beach 2012, Knopman 2001) and can be improved by biomarkers, but to a degree that is debated; the role of Aꞵ as cause vs marker of disease remains controversial.”
The European Medicines Agency were also recommending against aducanumab, and the company withdrew its application earlier this year, 2022, for marketing in the EU. The Japan Health Ministry had also refused approval, even though Japanese company Eisai was involved.
Before aducanumab, several other monoclonal antibodies showed an effect on amyloid imaging, as did agents known as BACE inhibitors, but no others were brought forward for approval, since the measurable impact on patients evidently did not meet efficacy criteria.
For patients and families, tangible, significant improvements in a patient’s life, or a family’s caregiving, seems to be the most important criteria, whether or not there are changes in beta amyloid or other imaging results.
[BTW, the cost of donepezil is currently ~ one dollar/day, according to one website, so $365/year, whereas the lowered price of Aduhelm is quoted ~ $28,000/year.]
Many serious human disease conditions are not treated with just a single agent, [childhood leukemia typically takes at least five) even though development of new agents is usually one at a time. However, the concept that one agent was not enough resulted in the first combination chemotherapy trials in childhood leukemia being published over 60 years ago, by Dr. J. Burchenal and colleagues.
Yet very few combination trials are seen in AD. Of 205 trials recruiting (or haven’t yet started, searched 10/19/22 on ClinicalTrials.gov), the US has only one for AD therapy that is a combination trial: Eisai’s lecanemab and Eisai’s own anti-tau therapy E2814.
This isn’t counting any combinations of vitamins, senolytics, a DIAN-TU head to head study of monoclonals, or behavioral therapies. Even this year, though, there are published studies of various agents while subjects are on donepezil. Otherwise, there are no new trials for combinations of AChEIs, BACE inhibitors, tau agents or other anti-beta amyloid monoclonal antibodies.
Dr. H. Fillit, co-founder of the Alzheimer’s Drug Discovery Foundation, did write of the need for innovations in clinical trials past Aduhelm, June 2022, but seemed to leave out AChEIs in combinations. He did mention other therapies, including repurposed meds, and is providing investigational leadership. But will the ideas translate into clinical trials?
If donepezil and other AChEIs are even partially disease modifying, and an agent like aducanumab (or other anti-beta amyloid antibodies like donanemab, Sept 2022) can change amyloid PET scans, where are the combination clinical trials? There seems to be a need for an augmentation to the current infrastructure, and an accelerant. Will the NIA, academia, or non-profits take a role for more and varied trials?