What could be targeted when attempting to develop therapeutics for Alzheimer’s disease?
- APP
- beta and gamma secretases
- interfere with cleavage of APP i.e. limit production of Aβ
- stop formation of oligomers
What is the Aβ balance sheet?
- synthesis – clearance = load
- catabolise (increase)
- transport (increase)
- deposition (decrease)
- targeting proteases targets the synthesis
- targeting formation of oligomers = affecting the load of a particular Aβ species
- so basically we want to decrease synthesis and increase clearance
Why target secretases?
- pharmaceutical companies like targeting enzymes: they have an active site that can be targeted, develop a compound that fits into that active site, agonist, or an antagonist
What are gamma secretase inhibitors?
Semagacestat:
- dose-dependently lowered plasma, CSF and brain Aβ in animals and lowered plasma and CSF Aβ in humans
- two Phase III trials showed semagacestat did not slow Alzheimer’s disease progression and caused WORSENING of clinical measures of cognition and the ability to perform activities of daily living
- PS1= presenilin-1, NCT = nicastrin, PEN-2, presenilin enhancer 2, APH-1 = anterior pharynx-defective phenotype 1 (makes up gace)
- phase III are enormously expensive (100s of millions of dollars)
Why are gamma secretase inhibitors a problem?
- side effects
- non selective
- many substrates
- NOTCH is an important protein - interfering with notch can cause cancers
gamma secretase inhibitors cleave a number of other proteins in the body
- still trying to make gamma secretase inhibitors
What are β-secretase inhibitors?
- are in early stages of clinical development
- are in early stages of clinical development
- the Merck drug MK-8931 is going through Phase 2/3 (dec 2013)
- structure of β-secretases has been solved - makes it easier to target
- active site has two aspartates
- aspartyl protease
- large active site (unusual for aspartyl proteases)
- difficult to make compounds that fit into the active site
- good safety profile so far
How can alpha-secretases be used therapeutically?
- enhancing their activation
- they cleave part way through Aβ and believed this is a non-toxic form
What is the Alzheimer’s disease vaccine?
approach: immunise AD mouse model (APP transgenic) with the Aβ antigen
result: reduction in amyloid plaques and Aβ levels
What do antibodies need to do for the vaccine to work?
cross the blood brain barrier
What active vaccination has been trialled?
- AN1792
- AN 1792 is aggregated Aβ42 peptide antigen
- phase IIa trial, mild-to-moderate AD patients immunised with AN 1792
- no significant differences between antibody responder and placebo groups in a variety of behavioural tests
- in addition, the trial was interrupted due to meningoencephalitis in 6% of immunised patients (thought to be associated with T-cell activation)
- 80 patients from phase I randomised, placebo controlled trial with AN 1792 were assessed in a long-term follow up for clinical and/or post-mortem neuropathological examination
- while mean Aβ load (amyloid plaque) 5 years after immunisation was lower in AN 1792 group than unimmunised controls, no evidence of improved survival or of improvement in time to severe dementia
- while active Aβ42 immunisation cleared amyloid plaques in AD patients, this had no effect on progression of neurodegeneration
What passive immunisation has been trialled?
Bapineuzumab
- humanised monoclonal antibody to epitope Aβ1-5
- binds both soluble and fibrillar Aβ
- reduced amyloid burden in transgenic mice
- less than promising results from Phase I and II trials
- in Phase III trials it failed in AD patients with or without the ApoE4 allele
Solanezumab
- humanised monoclonal antibody to Aβ16-24 that preferentially binds soluble Aβ
- in AD mouse model it reversed memory deficits without affecting brain Aβ load
- phase II trials, solanezumab increased plasma and CSF levels of Aβ40 and Aβ42, an indication that plaque load in the brain was decreased
- it had no effect on behavioural outcomes (ADAS-Cog test)
- Advanced to placebo-controlled Phase III trials in mild-to-moderate AD subjects
- in both trials, the primary endpoints, both cognitive and functional, were not met
- secondary analysis of pooled date of the failed solanezumab trials showed a modest slowing in cognitive decline in patients with mild AD
What else can be immunised against?
- Tau
- tau-targeted immunisation impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice
immunogen: 12 amino acid peptide human tau sequence (ass 395-406), comprising phosphorylated Ser396/Ser404 epitope
three different groups
I = before onset
II = moderate
III = advanced tau pathology
saw decreased tau-pathology in mice models
What are oligomerisation inhibitors?
Tramiprosate (homotaurine)
- sulfated glycosaminoglycan mimetic
- maintains Aβ in a non-fibrillar form and reduce Aβ42-induced cell death
- in transgenic mice, tramiprosate treatment significantly reduced amyloid plaque load and soluble and insoluble Aβ40 and Aβ41 levels in the brain
- failed in several clinical trials, including a definitive Phase III study, to improve cognitive performance
How can we target Aβ:metal interactions?
Metal-protein attenuating compounds (MPACS)
Clioquinol
- “old” drug used an oral anti amebic antibiotic
- chelates Zn2+ and Cu2+
- crosses the blood brain barrier
- modulates amyloid pathology in APP transgenic mice
- efficacious in a small phase II human trial
PBT2: follow up MPAC to clioquinol
What were the MPAC clinical trial results?
- Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial (2008)
- takes a dive in Phase 2 alzheimer’s trial (2014)
2008 trial was too small
doesn’t mean drug doesn’t work just means have to do a better trial
So what kinds of therapeutics have been developed?
- vaccines
- anti-oxidants
- neuroprotectants
- alpha-secretase activator
- anti-inflammatory
- tau aggregation inhibitor
Why have the major clinical trials failed?
- side effects
- badly designed trials
- correct diagnosis
- depending on the phase of Alzheimer’s disease you want to act on you need to make sure that is when your drug acts and that your trial contains those patients
- Aβ amyloid deposition: uncertain whether steady increase over life or rapid in the years prior to prodrome
- Around 50 years the Alzheimer’s disease process starts (pre-symptomatic)
- Amnestic MCI starts ~10 years earlier (70 years)
- 80 years: peak age of onset (incidence) for dementia
problem with trials to date is that they have been treating people in late stages of AD progression (even if mild to moderate phenotype)
When do you treat for AD?
- deposition occurs much earlier i.e. when people are still cognitively normal
- need to be able to measure amyloid in living people e.g. with PET
- can therefore measure the amyloid load
- Thioflavin T radioactive - binds amyloid and can be used for imaging purposes
- can help indicate Braak staging
- PET is great but also quite expensive
another option
- a blood-based predictor for neocortical Aβ burden in Alzheimer’s disease: results from the AIBL (australian imaging biomarkers and lifestyle) study
- take blood every 18 months from age 60 of about 1000 patients, look at blood of patients who did or did not develop Alzheimer’s
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