Case 3/LC5/LC7 - therapeutics for AD Flashcards
stages of clinical research
- Phase 0: Exploratory Studies NO HUMANS?????
- Involves a small number of participants.
- Focuses on drug metabolism and pharmacokinetics.
- Rarely includes patients; instead, healthy volunteers are often involved.
- Phase I: Safety and Dosage
- Small group of healthy volunteers.
- Primary goal: Assess safety, dosage range, and potential side effects.
- Initial introduction of the intervention into humans.
- Phase II: Preliminary Efficacy
- Larger group, including patients.
- Assesses effectiveness and further evaluates safety.
- Provides initial evidence of the intervention’s efficacy.
- Phase III: Large-Scale Efficacy
- Involves a larger and more diverse patient population.
- Compares the intervention to standard treatments.
- Gathers comprehensive data on safety and efficacy.
- Lower indidence side effects are identified
- Phase IV: Post-Marketing Surveillance
- Conducted after regulatory approval.
- Monitors long-term effects and safety in a larger population.
- Detects rare side effects or complications over an extended period.
symptomatic treatments
- do not affect underlying pathology
- acetylcholine esterase inhibitors - donepezil, rivastigmine, galantamine
- NMDA antagonists - memantine
AChE inhibitors
- Acetylcholinesterase inhibitors (AChE inhibitors) are a class of medications used in the treatment of Alzheimer’s disease (AD).
o These drugs work by increasing the levels of acetylcholine, a neurotransmitter, in the brain. - In Alzheimer’s disease, there is a progressive loss of cholinergic neurons, which are responsible for producing acetylcholine.
- By inhibiting acetylcholinesterase, these drugs slow down the breakdown of acetylcholine, allowing it to accumulate in the synaptic cleft between nerve cells.
- This accumulation enhances cholinergic neurotransmission and temporarily improves cognitive function in some individuals with Alzheimer’s disease
- There can be gastrointestinal side-effects
- Only for mild/moderate AD
- Only a part of this group will responed (3 months we try the treatment)
- Symptoms return after 6 months…
- Effect is modest (studies focus on 6 months treatment)
- Donepezil, rivastigmine and galantamine
- Works best in Lewy-body dementia (PD)
NMDA antagonists
NMDA antagonists are typically used to address the glutamate hypothesis of neurodegeneration.
o The glutamate hypothesis suggests that excessive activation of NMDA receptors by the neurotransmitter glutamate may contribute to the neuronal damage seen in Alzheimer’s disease.
- By modulating NMDA receptor activity, these drugs aim to reduce excitotoxicity and provide neuroprotective effects.
o One such NMDA antagonist used in Alzheimer’s disease is memantine.
- Function through neuroprotection
- For: moderate to severe AD
- Very modest effects
memantine
Memantine is an uncompetitive, low-affinity NMDA receptor antagonist. It works by blocking the excessive influx of calcium ions into neurons, which is associated with excitotoxicity. Only binds when the pore is open –> binds to mg-block
* Target Population: Memantine is approved for the treatment of moderate to severe Alzheimer’s disease. It is often used in conjunction with acetylcholinesterase inhibitors, such as donepezil, for a combined therapeutic approach.
* Clinical Effects: Memantine’s use is associated with modest improvements in cognitive function, activities of daily living, and behavioral symptoms in some individuals with Alzheimer’s disease.
* Safety Profile: Memantine is generally well-tolerated, and its side effects are typically mild. Common side effects include dizziness, headache, and constipation.
aducanumab
Aducanumab (2021) is a monoclonal antibody designed to selectively recognize and bind to beta-amyloid plaques in the brain. –> the first disease-modfying drug
- Leads to plaque clearance with very minor (or no) increases in cognition
- Large controversy after FDA approval
Lifestyle interventions
=non-drug treatments
- Do not change underlying biology
o Rather improve cognitive function and quality of life
- Goal: reducing behavioural and psychological symptoms
o Depression, apathy, sleep deprivation,…
- More effective than pharmacologic interventions for reducing aggression and agitation (=recent study outcome)
- Regular Physical Exercise:
* Engaging in regular aerobic exercise, such as walking, jogging, swimming, or cycling, has been linked to a lower risk of cognitive decline.
* Exercise promotes blood flow to the brain, reduces inflammation, and supports the growth of new neurons (BDNF). - Healthy Diet:
* Adopting a balanced and nutrient-rich diet, such as the Mediterranean or DASH diet, is associated with a lower risk of cognitive decline.
* Diets rich in fruits, vegetables, whole grains, lean proteins, and healthy fats provide essential nutrients for brain health. - Cognitive Stimulation:
* Engaging in mentally stimulating activities, such as puzzles, games, reading, and learning new skills, may help maintain cognitive function.
* Lifelong learning and intellectual challenges are linked to a reduced risk of cognitive decline. - Adequate Sleep:
* Prioritizing good sleep hygiene and ensuring an adequate amount of quality sleep is crucial for overall brain health.
* Sleep is essential for memory consolidation and other cognitive functions. - Social Engagement:
* Maintaining social connections and participating in social activities can contribute to cognitive resilience.
* Social engagement may help reduce feelings of loneliness and support emotional well-being. - Stress Management:
* Chronic stress may contribute to cognitive decline, so adopting stress-reduction techniques such as mindfulness, meditation, yoga, or deep breathing exercises can be beneficial. - Heart-Healthy Habits:
* Managing cardiovascular risk factors, such as hypertension, diabetes, and high cholesterol, is important for brain health.
* What’s good for the heart is often good for the brain, as these risk factors are linked to an increased risk of cognitive decline
Mechanism of action - Mab treatments
- Direct Action:
* Mechanism: Antibodies directly bind to and interact with specific pathological targets in the brain, such as beta-amyloid plaques or tau tangles.
* Purpose: This direct binding can lead to the clearance or neutralization of the pathological proteins, potentially reducing their aggregation and associated neurotoxicity. - Activation of Microglia:
* Mechanism: Antibodies can stimulate the brain’s resident immune cells, called microglia, to become activated. Activated microglia are involved in the clearance of abnormal proteins, such as beta-amyloid.
* Purpose: By promoting microglial activity, antibodies enhance the brain’s ability to recognize and phagocytose (engulf and digest) pathological proteins. This mechanism aims to facilitate the removal of protein aggregates and reduce their impact on neuronal health - Peripheral Sink Mechanism:
* Mechanism: Antibodies introduced into the bloodstream bind to pathological proteins, such as beta-amyloid, in the peripheral circulation (outside the brain) causing a osmotic pressure towards the blood.
* Purpose: The binding of antibodies to peripheral beta-amyloid reduces the concentration of these proteins in the bloodstream, creating a “sink.” This peripheral sink leads to a gradient that promotes the efflux of beta-amyloid from the brain into the bloodstream. As a result, the brain’s beta-amyloid burden is reduced through this clearance mechanism
aducanumab controversy
- Clinical Trials: Biogen conducted Phase 3 trials (EMERGE and ENGAGE) for Aducanumab, a drug aimed at treating Alzheimer’s disease.
- Mixed Results: EMERGE showed a significant reduction in clinical decline, while ENGAGE did not meet its primary endpoint.
3.FDA Approval: Despite mixed results, the FDA granted accelerated approval in June 2021.
- Post-Hoc Analysis: Biogen conducted a post-hoc analysis, combining data from both the unpublished trials to assess overall efficacy.
- Controversy: The use of post-hoc analysis faced criticism for potential biases and overinterpretation of data.
o Clinical Dementia Rating-Sum of Boxes score (scale of 0 to 18)
o Only 0.39 points improvement after 78 weeks of treatment
o Amyloid-related imaging abnormalities (ARIAs) in more than a third of the patients treated with high-dose aducanumab - FDA Decision Impact: The FDA considered the post-hoc analysis in its decision-making process, contributing to the controversy surrounding the drug’s approval. Both the FDA’s stats consultants and drug discovery committee showed skepticism
- Cost and Accessibility Concerns: Aducanumab’s high cost and concerns about accessibility added to the controversy
risk factors
vul in
Amyloid cascade
- Ab plaques
- Tau tangles (10 years)
- Atrophy (5 years)
- Dementia (5 years)
- Prodromal AD = MCI
Anti-Abeta mabs
- Donanemab
- Lecanumab
- Gantenerumab
- Aducanumab
- Primary outcomes of studies: cognition (ADAS-cog) and function (CDR-SOB)
- secondary outcomes: ADL/MMSE/biomarkers/caregiver burden/QoL
- Dose dependent effect of IgG (anti-Ab) on Ab clearance from the brain for lecanumab, donanemab and gantenerumab
- Reduction of 30/40% cognition changes (except for gantenerumab this had no improvements of cognition)
- Normaliziation of biomarkers
o Ptau normalizes
o Amyloid decreases (not completely normal) - Donanemab and lecanumab were very similar but donanemab had less ARIAs (occur due to amyloid clearance through the BBB into the periphery - sink mech.)
- Meta analysis: rate of amyloid clearance in first 12 months = best predictor for cognitive improvement after 18 months (presented at CTAD)
o Gantenerumab buildup of Abs was too slow at the start so the treatment benefits were somehow missed
next gen anti-Abeta mabs
- Shuttle for BBB (TfR1-mediated transcytosis) –> trontinemab
- Less ARIA as other Abs without shuttling
- Faster amyloid clearance
- Subcutaneous administration
- Testing in preclinical AD
- Subtyping of AD (5 subgroups) –> individualized medicine
1. hyperplastic inflamm
2. immune activation
3. RNA dysfunction
4. impairment choroid plexus
5. Impairment BBB
future of therapies
- new targets –> GWAS studies (targets relate to the subtypes)
- immune targets
- Abeta oligomers
- growth facotr interaction
- tau (mab) focus
- second chance for BACE and gamma secretase inhibitors
AD symptoms
- Cognitive dysfunction
o Agnosia : difficulties naming simple objects
o Aphasia : cant produce speaking - Behavioural changes
o Apathy
o Poor judgement - Hallucination/delusions
- Late stages: difficulties in speaking, walking, and swallowing
