ND - L5 Flashcards
Topics discussed?
developing AD therapeutics
why major clinical trials have failed
more drugs
Type of AD therapeutics? (7)
secretase inhibitors Abeta degrading enzymes oligomerisation inhibitors tau inhibitor change biometal concentrations Abeta immunisation tau immunisation
Why are gamma secretases bad? Example
has other substrates, not specific
Semagacestat - lowered Abeta but phase 3 showed worsening (NOTCH)
BACE inhibitors?
MK-8931 in phase 2/3
BACE has large active site –> large compounds required
problems with specificity as well
oligomerisation inhibitors?
Tramiprosate
maintins Abeta in non-fibrillar form
failed to improve cognition in Phase 3
Tau inhibitor?
being looked into
need to be careful
Change biometal concentrations? (2)
clioquinol (old drug) - modulates am path in mice
PBT2 - small trial look promising, GFC
Abeta immunisation?
immunise AD mouse model (APP transgenic) with Abeta antigen
results in reduction in amyloid plaques and Abeta levels
Active vaccination example?
AN1792
no significant differences
meningoencephalitis (6%)
5 years later - amyloid plaque lower but no improved survival
Two examples of passive immunisation?
Bapineuzumab - epitope AB1-5
binds soluble and fibrillar Abeta
phase 3 failed
Solanezumab - epitope AB16-24 (middle)
binds soluble Abeta
reversed memory deficits without affecting brain Abeta load
phase 3 endpoints not met
Tau immunisation?
immunogen
works slightly in mice
Why have the major clinical trials failed?
Abeta and tau mediated injury are happening in cognitively normal people
need biomarkers!
Describe the biomarkers signal graph(s)
-
How do you measure amyloid levels?
positron emission tomography
florbetapir –> gamma rays
don’t yet have definitive change
more drugs?
Aducanumab
mAb targets aggregated forms of amyloid beta (sol and insol)
first to reduce amyloid and improve cognition
BUT ARIA
