Current Scenario of amyloid beta hypothesis in clinical trials

1. Amyloid β hypothesis and
current scenario of clinical trials
Muhammad Jamal
PhD Fellow
University of Karachi.

2. Alzheimer’s Disease
 Alzheimer’s disease is an
irreversible, progressive brain
disorder that slowly destroys
memory and thinking skills,
and eventually the ability to
carry out the simplest tasks. In
most people with
Alzheimer’s, symptoms first
appear in their mid-60s.

3. Amyloid-β Hypothesis
 Researchers proposed that when amyloid-β clumps together to form deposits in
the brain, it triggers neurodegenerative processes that lead to the loss of memory
and cognitive ability that is observed in Alzheimer’s disease. Amyloid-β is therefore
an obvious therapeutic target — if you can deal with the peptide, then you can
treat the condition.
 The aggregation of amyloid-β is thought to trigger a cascade of disease-causing
processes such as inflammation, tau-tangle formation, synapse dysfunction and cell
death.

4. Beta secretase and Gamma secretase

6. Flurizan and Semagacestat
 Gamma Secretase inhibitor
Myriad had taken a sort-of kind-of gamma-secretase inhibitor (Flurizan) into the clinic,
and failed dismally.
But Eli Lilly’s semagacestat (LY450139) has long been the most advanced pure
gamma-secretase inhibitor.
It inhibits the enzyme directly, and had shown dose-dependent lowering of amyloid
formation in humans.
There were side effects noted from Notch, mostly in the GI tract, but the profile was
still good enough to go on into Phase III two years ago. And now we have the results.

7. Nothing. Worse than nothing – they saw real declines in cognitive
function compared to the placebo group.
 insult to injury – that the drug was associated with a greater risk of skin cancer.

8. March,2019 Aducanumab
 Biogen and Eisai have
announced that they’re
halting Phase III trials
of aducanumab, their anti-
amyloid antibody, after the
monitoring committee
judged that further
treatment would be futile.

9. January, 2019 Crenezumab

10. April, 2018 Azeliragon

11. November, 2016 Solanezumab

12. Gantenerumab

13.  4 Anti-Aβ mAbs have failed 9 big Ph3 trials
 3 γ-Secretase inhibitors showed cognitive worsening
 4 BACE inhibitors showed cognitive worsening
Long live the amyloid hypothesis...

14. Thank you