lecture 24 Flashcards
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
