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Third Generation Cholinesterase Inhibitors To Treat Alzheimer’s

If you’ve been in the loop, you’d have heard about Axovant Sciences, the company that aimed to treat dementia with intepirdine, nelotanserin and RVT-104.

Despite countless failed trials with intepirdine, we reckon there may still be hope left for Axovant and dementia patients.

In this article, we will be talking about the potential of third generation cholinesterase inhibitors to treat Alzheimer’s.

Table of contents

    History Of Cholinesterase Inhibitors (ChEIs)

    Let us first dive into the history of cholinesterase inhibitors (ChEIs) for dementia and the rationale for implementing them into Alzheimer’s treatment pipeline.

    ChEIs are a group of drugs that

    1. Block the normal breakdown of acetylcholine (ACh) into acetate and choline and
    2. Increase both the levels and duration of actions of acetylcholine found in the central and peripheral nervous system.

    The acetylcholinesterase inhibitors have a variety of indications. Most commonly, their use is in treating neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Lewy body dementia.

    Different physiological processes in these degenerative disorders destroy cells that produce ACh and reduce cholinergic transmission in different regions of the brain.

    The cholinesterase inhibitor drugs inhibit AChE activity and maintain the ACh level by decreasing its breakdown rate.

    This is to maintain the activity of acetylcholine at cholinergic synapses. (Source: Cholinesterase Inhibitors – StatPearls – NCBI Bookshelf)

    Fun fact: The first ChEI for Alzheimer’s disease, tetrahydroaminacridine (tacrine), was licensed in 1993 in the US, Canada, and parts of Europe.

    Why Are Acetylcholinesterases Bad For The Brain?

    Studies dating as far back as 1996 have shown that acetylcholinesterases accelerate the assembly of beta-amyloid into long, unbranched fibrils.

    Such accumulation of beta-amyloid into fibrils is a hallmark of Alzheimer’s disease.

    According to this annual report, Axovant claims that RVT-104 is a combination of a peripheral muscarinic receptor antagonist and high-dose rivastigmine.

    RVT-104 serves as a potential treatment for patients with Alzheimer’s Disease or Lewy Body Dementia, with the aim to inhibit the activity of acetylcholinesterase in the brain.

    How Is RVT-104 Better Than RVT-101?

    RVT-101 (Intepirdine) was the blockbuster new drug by Axovant that bombed in 2017 due to failed clinical trials.

    RVT-101 (Intepirdine) is a selective 5-HT6 receptor antagonist created for the treatment of Alzheimer’s disease and dementia with Lewy bodies, or DLB. This drug, however, failed to delight.

    As a potent antagonist of the serotonin (5‐hydroxytryptamine) subtype 6 (5‐HT6) receptor, intepirdine has been shown to boost synaptic acetylcholine transmission in preclinical models of cognitive impairment and could improve cholinergic deficiency in DLB patients.

    Because the 5‐HT6 receptor is found almost exclusively in the central nervous system, targeting this receptor may provide benefits over AChEIs by reducing the risk for adverse peripheral effects.

    (Source: An international, randomized, placebo‐controlled, phase 2b clinical trial of intepirdine for dementia with Lewy bodies (HEADWAY‐DLB) – PMC)

    Hence, we can see that intepirdine may have solely focused on increasing ACh and perhaps efficiency of transmission, leading to its failure.

    However, Axovant is now moving towards RVT-104, a third generation AChEI, which is able to block acetylcholinesterase’s activity, potentially preventing the enzyme from inducing the assembly of beta-amyloid fibrils that we see so much in Alzheimer’s, while simultaneously salvaging the remaining acetylcholine in the brain.


    We hope our in-depth analysis of AChEIs was able to provide some encouragement for you and your family in battling Alzheimer’s.

    In the past, treatment plans for Alzheimer’s were seemingly bleak, with no chance of success.

    In recent times however, a few potentially groundbreaking drugs have been making their mark in the world of pharmacotherapy.

    We shall continue plugging into the research, and hope to produce more informative articles on dementia related treatments, with the purpose to educate and encourage.

    FAQ on Third Gen ChEIs

    FAQ #1: What Are The Existing Third Gen ChEIs?

    The existing ChE inhibitors include donepezil, rivastigmine, and galantamine (Giacobini & Linville, 1998).


    These drugs work by inhibiting the enzyme AChE, which is responsible for degrading acetylcholine (ACh) into acetate and choline.


    By inhibiting AChE, these drugs increase the availability of ACh in the brain. More ACh helps alleviate cognitive symptoms associated with Alzheimer's Disease (Cummings, 2004).

    FAQ #2: Why Are They Called Third Gen Cholinesterase Inhibitors?

    Third generation cholinesterase inhibitors are not explicitly defined in the provided literature.


    However, they are mentioned in Giacobini & Linville, 1998 as improved versions for existing cholinesterase inhibitors.


    Specific to Alzheimer's Disease, these third generation inhibitors refer to novel agents that can potentially target multiple factors involved in the disease.


    For example, a drug that can target both acetylcholinesterase (AChE) and Aβ-cleaving enzymes may result in a better outcome.

    FAQ #3: 8 Benefits From Using Third Gen ChEIs?

    The benefits of cholinesterase inhibitors (ChEIs) in the treatment of Alzheimer's disease include:

    1. Improvement in cognition, behavior, activities of daily living, and global functioning in mild-to-moderate AD patients (Farlow, 2004).
    2. Reduction of caregiver stress and delay of time to nursing home placement (Farlow, 2004).
    3. Modest but significant therapeutic benefit in the treatment of mild-to-moderate AD (Farlow, 2004).
    4. Slower decline on measures of functional impairment and cognitive measures than those taking placebo (Cummings, 2004).
    5. Improvement in measures of functional impairment and cognitive measures in patients with mild cognitive impairment (Cummings, 2004).
    6. Delayed move to institutionalized care when initiated in the early stages of disease (Sabbagh et al., 2006).
    7. Improvements across the key symptom domains of activities of daily living, behavior, and cognition (Sabbagh et al., 2006).
    8. Potential for disease-modifying properties (Cummings, 2004).

    FAQ #4: Limitations Of Third Gen ChEIs In Treating Alzheimer's

    While ChE inhibitors have shown benefits in the treatment of Alzheimer's Disease, they have limitations. The limitations of cholinesterase inhibitors (ChEIs) include:

    1. Limited disease-modifying properties: ChEIs do not cure AD, but only treat the symptoms of the disease (Cummings, 2004).
    2. Adverse side effects: ChEIs can cause side effects such as nausea, vomiting, and diarrhea (Cummings, 2004).
    3. Limited efficacy in severe dementia: Galantamine, a ChEI, has shown a significant risk reduction for severe dementia, suggesting a specific effect on beta-amyloid and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) (Farlow, 2004). However, it is not a positive allosteric modulator of alpha7nAChR, which may indicate a more complex mechanism of action (Farlow, 2004).
    4. Lack of improvement in neuropsychiatric symptoms: Current network meta-analysis suggests that ChEIs may not improve neuropsychiatric symptoms, such as agitation and aggression (Cummings, 2004).
    5. Limited consensus on the choice of drugs and dosages: There is no consensus on the choice of ChEIs and their doses at different stages of AD, highlighting the need for more effective and safer treatments (Cummings, 2004).
    6. Need for multi-target inhibitors: Since AD is a multifactorial disease, the drug discovery road map ahead has to be multi-target inhibitors to target multiple factors involved in the disease (Cummings, 2004).