AD II Flashcards
Discuss current and future treatments of AD
current treatment for AD (symptomatic)
Cholinesterase inhibitors (donepezil/rivastigmine/galantamine)
memantine
cognitive stimulation therapy/cognitive behavioural therapy
aromatherapy
dance/music
antidepressants
antipsychotics
pain relief
cholinesterase inhibitors
for mild AD
promote cholinergic neurotransmission(loss of cholinergic neurons in AD)
reduces ACh breakdown/cholinergic transmission/increases glutamatergic transmission/increase cognition
memantine
for moderate to severe AD
promotes glutamatergic neurotransmission since there is reduced glutamate uptake by glial cells causing excitotoxicity
reduces NMDAR activation and reduces glutamate excititoxicity
limitation of current treatments
do not slow or alter AD progression
only modest improvements in cognition ~50% individuals
3 therapeutic targets for AD pathology
1) AB - clearest initial causative pathway (19%)
2) Tau - correlates better with cognitive dysfunction than plaques (behind in development) (6%)
3) neuroinflammation (AB/tau plateau (behind in development/broad target) (6%)
amyloid therapies
immunotherapies (increase clearance) - rely on antibodies to treat disease (not neuroinflammation)
vaccine (active immunisation) - introduce peptides to stimulate antibody production to target protein by host immune system
direct antibodies (passive immunisation)
immunotherapy mode of action
1) neutralises target (prevents further binding) by forming antigen-antibody complex which reduces aggregation
2) bind/attract immune cells to degrade target - cause fc-mediated phagocytosis, target freely diffusing AB plaques for clearance by microglia
3) form antigen-antibody complex in blood that acts as a peripheral sink (prevent accumulation in the brain)
AB vaccine
AN1792
synthetic full length AB peptide
phase II stopped in 2002 due to 6% cases have brain inflammation
targetting AB production
y-secretase inhibition (semagacestat) - phase I/II reduced AB phase III worsens cognition/increase in skin cancer via Notch signalling
B-secretase inhibition (Verubecestat) phase II (90% AB reduction) phase II/III worsens anxiety/depression/sleep 2020- rapid atrophy in amyloid rich regions, impored verbal fluency only
Bapineuzumab (pfizer)
recognises the N-terminal AB peptide (not the full length)
Phase I - safe/well tolerated but new microhaemorrhages amyloid-related imaging abnormalities (ARIA) asymptomatic/mild confusion/headaches
phase II/III - halted after no effect in cogntion/function
Solanezumab (Eli Lilly)
recognises soluble monomeric AB peptide
phase I - reduced AB, no improvement in cognition
phase II - small improvement in cognition in mild AD
phase III - non significant trend in mild AD
2020 - increased CSF AB42 (clearance), no change in tau biomarkers
gantenerumab (Roche)
high affinity binding to a conformational epitope on AB fibrils, reduces AB42 to control by PET imaging
FDA - breakthrough therapy designation (failed to show improvements in cognitive decline) - insignificant results
though reduced tau biomarkers/synaptic loss/slowed increase in cognition compared to placebo
why do trials not work
timing of treatment - drugs given when AB already plateaued (overcome with early intervention/prevention trials/DIAN-TU)
poor design of trials and outcome measures are too strict (use more sensitive assessment 3 variations/adaptive trials designs)
Aducanumab (Aduhelm) (biogen)
monoclonal antibody to aggregated AB (oligomeric/fibrillary structures) derived from healthy aged donors
phase Ib/III - major reduction in AB in PET imaging and reduced cognitive decline
phase III (2019) - terminated, no sig improvement in cognition 33% ARIA and cerebral oedema, increase in APOE4 carriers
improved cognitive score and reduced tau pathology
first case of accelerated approval of disease modifying treatment for AD (2021) substantial evidence for effect on intermediate marker (AB removal)
limitation of aducanumab
ICER review claimed inadequate health benefit
rejected by european medicines agency/japan’s healthcare ministry
not covered by medical insurance in the US
phase III showed 33% ARIA (3% death)
biogen withdrew application for full market approval, undergoing phase IV trials (finish ~2026)
Donanemab (Eli Lilly)
humanised version of mouse antibody (fibrillary structure) which recognises form of AB only in plaques
phase II - cognitive improvement in early AD and phosphotau reductions
phase III - 4x more effective at clearing plaques vs 6 months aducanumab
rejected accelerated approval (2023) due to insufficient safety data
more phase III - slowing of cognitive defect/ reduced blood ptau, neuroinflammation
ARIA ~25%, no reduction in tau tangles
2024 - more trials
Lecanemab (Biogen&Eisai)
selectively binds large, insoluble AB protofibrils
phase II (2018) highest dose slowed cognitive decline by 30-47%, reduced amyloid by PET 93%, increased CSF AB
open-label extension - 80% amyloid negative in end and reduced AB tangles
phase III - confirmed positive outcomes, reduced neuroinflammation ARIA ~12.6% 3% deaths
1st full clinical approval in 2023 (FDA approved in July) Jan = accelerated approval
lecanemab prescibing guidelines
Cummings et al., 2023
not taken with coagulants/clotting disorders/stroke/seizures (due to ARIA)
not treated wit acute thrombolytics (aspirin/clopidogrel allowed)
recommened APOE genotyping (detect APOE4 carriers) to discuss risks
recommended MRI monitoring
factors to address when prescribing lecanemab
intravenous therapy for people with early AD (~2 weeks)
$26500 a year
approved in Japan/China
expect UK/europe decision in 2024
final stages of subcutaneous dosing
low success rate
tau therapies
adv: tau tangles correlate better with cognitive dysfunction than AB plaque burden
dis: unlike AB, tau are located in the neurons
E2814 (Eisai)
Roberts et al., 2020 - found in Rohan de silva’s lab UCL
humanised monoclonal IgG1 antibody recognises HVPGG epitope in microtubule binding domain near tau mid-domain (fibrillisation and spread of tau aggregates)
phase II - to end in 2025
DIAN-TU in 2021 to test combined anti-amyloid (lecanemab) and anti-tau (E2814) combnation therapy
neuroinflammation targetting
adv: proposed cause of clinical decline once disease started
dis: enhances glial activation to increase clearance of AB, causes neuronal damage
semaglutide (approved for diabetes)
long-lasting analogue of GLP-1
hormone which stimulates insulin release
does not cross BBB
lowers peripheral blood sugar
reduces peripheral and central inflammation
53% reduced risk of dementia in T2D (norgaard et al., 2022) Novo Nordisk
in mouse AD model, improved glucose uptake/learning/memory/decreased AB plaques and tau tangles (wang et al., 2023)
phase III ongoing
BCG vaccine (tuberculosis)
20% reduced risk of AD
phase II
Mastinib
tyrosine kinase inhibitor in mast cell tumour treatment (particularly dogs)
restores spatial learning/synaptic density in AD mouse (Li et al., 2020)
2023 - positive phase II results which reduce cognitive decline in AD
developments in MND/cancers/MS/Covid-19
NE3107
B-androstenetriol derivative
inhibits pro-inflammatory ERK/NFkB signalling
role on insulin sensitising
phase III - improving/reduce Biomarkers for neurodegeneration/neuroinflammation
PD/traumatic brain injury (in development)
Pegipanermin/XPro1595
2nd gen TNFa type 1 receptor inhibitor which selectively reduces neuroinflammation
no action on type2 receptors in innate immunity/myelination
phase I safety achieved/phase II ongoing (mid 2025)
development in the treatment of cancer
