New Drug Treatments for Alzheimer’s disease 2016
Abstract
For the past 20 years there has been little new in treatments for Alzheimer’s disease. However, knowledge of the neuropathology of this disease has increased significantly. Now we are on the cusp of an explosion of new drug treatment approaches to this condition. Currently a large number of worldwide clinical trails testing new drugs for Alzheimer’s disease are underway. In three year’s time the treatment landscape will have changed dramatically. This presentation provides an update on recent pathological understandings of Alzheimer’s disease and the role of biomarkers that inform new drug interventions directed to modifying disease processes. Examples will be provided of promising new drugs undergoing larger clinical trails.
Prof Philip Morris
New Approaches to Drug Treatment of Alzheimer’s Disease 2016
Prof Philip Morris
MBBS, BSc med, PhD
FRANZCP, FAChAM (RACP), DAmBPN
Distinguished Fellow and Board Director, PRCP
President, Australian and New Zealand Mental Health Association
Bond University, Robina Queensland, Australia
www.drphilipmorris.com
Dementia is becoming the greatest medical problem for ageing populations in developed and developing countries
Alzheimer’s disease is the most common cause of dementia
350,000 Australians currently suffer from Alzheimer’s disease
One million projected to be diagnosed by 2050
Is early identification of memory and associated cognitive problems key to effective treatment and prevention of further deterioration?
Risk factors for Alzheimer’s Disease
Age – older age, greater risk
Genes
Older onset – APO e4/4 genotype
Younger onset – chromosome mutations 1, 14, 21
Inflammation – TNF, amyloid plaques attract immune cells, NSAIDs protect against Alzheimer risk
Cardiovascular risk factors, diabetes and obesity – increase risk
Hormones – females have higher prevalence, but HRT not protective
Mood disorders – depression a risk factor
Anxiety disorders – PTSD a risk factor
Head injury – repeated LOC a risk factor
Diet – low saturated fat, high antioxidant foods and fish oil protective
Alcohol – in moderation protective
Education – higher levels protective
Mental and social activity – may be protective
Physical activity and fitness – protective
Marital status – marriage reduces risk
The prevalence of Alzheimer’ disease is increasing as populations age
But the incidence is falling in developed countries
Over half of Alzheimer’s disease burden worldwide might be attributed to potentially modifiable risk factors
These estimates do not take into account the association between risk factors
Seven potentially modifiable risk factors that have consistent evidence of an association with Alzheimer’s disease – diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment
Population-attributable risk (PAR) of Alzheimer’s disease
Worldwide – low educational attainment 19%
Developed countries – physical inactivity 21%
Combined (adjusted) worldwide and developed countries – PAR 30%
9·6 million attributable cases of 33·9 million cases
Alzheimer’s disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg. physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression
(Norton S et al. Lancet Neurology 2014, 13 (8): 788-794)
Current Medication Approaches
Nootropic = cognitive enhancing drug or protecting higher brain function against external traumatic factors
Alzheimer’s disease (AD) – symptomatic versus neuroprotective or disease modifying approaches to treatment
All Alzheimer’s disease drugs (AD drugs) so far are symptomatic
Cholinesterase inhibitors – enhance cholinergic function
Donepezil – a cholinesterase inhibitor
Galantamine – a cholinesterase inhibitor and nicotine receptor modulator
Rivastigmine – a cholinesterase and butyrylcholinesterase inhibitor
Memantine – a NMDA low affinity non-competitive receptor antagonist – protect against excessive Ca2+ influx
Other potential nootropics include nicotine, selegiline, vitamin E, ginkgo bilboa, piracetam, HRT, anti-inflammatory drugs, statins, folic acid
Souvenaid
A ‘medical food’
A daily milkshake (200ml) made of selected nutrients that support synapse formation and function
Evidence base –
Two controlled trials in mild Alzheimer’s disease showed a modest beneficial effect on memory performance
One controlled trail in moderate Alzheimer’s disease showed no effect on cognitive performance
One controlled trial in prodromal Alzheimer’s disease showed benefit in preventing memory decline
Stage of Illness
No disease
Pre-clinical (10-15 years)
Prodromal – MCI form of Alzheimer’s disease (2-5 years)
Alzheimer’s disease – mild, moderate, severe (10 years)
Amyloid beta protein builds up from pre-clinical to declared Alzheimer’s disease stages
Increasing tau protein deposition heralds clinical deterioration later in progression
Biomarkers in Alzheimer’s disease
APOe 4 genotype risk and inherited gene mutations
MRI – focal atrophy of medial temporal lobe and hippocampus
CSF – low amyloid beta levels, raised tau and P-tau levels
PET glucose cerebral metabolism – reduced activity in medial temporal, parietal, posterior cingulate and precuneus regions
PET amyloid ligand studies – increased amyloid beta burden
PET tau ligand studies – increased tau protein burden
QEEG and evoked potentials
Using biomarkers to identify pre-clinical Alzheimer’s disease, subjects for trials, and targets for drug interventions
New Approaches to Drug Treatment
A few new symptomatic drugs are being developed – mainly 5HT6 receptor antagonists – none yet available
New approaches – disease modifying agents
Amyloid beta depleting methods – vaccines and passive immunisation – monoclonal antibodies [mAB] (eg. aducamumab, solanezumab, bapineuzumab, crenezumab), and eluting agents
Agents that prevent amyloid beta accumulation (beta-site amyloid precursor protein cleaving enzyme inhibitor – BACE inhibitors), or the amyloid beta oligomer’s toxic action on synapses (eg. CT1812 CogRx)
Tau depleting agents – agents that prevent tau accumulation, or inhibit tau aggregation (eg. TAI – LMTX – modified methylene blue)
Anti-inflammatory agents (anti-Tumour Necrosis Factor eg. etanercept, masitinib – sigmoid1mu-receptor action)
Microglial activators
Aducamumab
Monoclonal antibody derived from B cells of ‘super-elderly’ individuals
Targets aggregated forms of amyloid beta and soluble oligomers and insoluble fibrils in the amyloid plaque
Study tested four doses of monthly infusions of aducamumab versus placebo over 54 weeks in 165 PET scan amyloid positive subjects with prodromal or mild Alzheimer’s disease
Results showed a dose-dependent reduction of PET amyloid burden, and a dose-dependent improvement in cognitive function (MMSE and Clinical Dementia Rating [CDR])
Drop-out rates were high – 17-38% in active treatment and 25% in placebo groups
Most common adverse event (usually asymptomatic) was Amyloid-related imaging abnormalities (ARIAs) – mainly vasogenic edema
Results prompted FDA ‘fast-track’ approval for a much larger study
Tau aggregation inhibitors (TAIs) – Methylthioninium (LMTX)
Placebo controlled study of two doses of LMTX over 60 weeks in 891 subjects with mild and moderate Alzheimer’s disease
Either as add-on to usual anti-dementia drug therapy (majority of subjects), or as mono-therapy (minority of subjects)
No benefit as an add-on drug
Clear benefit as a mono-therapy on slowing decline in ADAS-cog and ADAS-ADL scores
Slower rate of progression of brain atrophy as measured by size of lateral ventricles on MRI scan
Safety profile benign
No difference in ARIAs between active and placebo groups
A follow-up study on 220 subjects with behavioural version of Fronto-Temporal Dementia (bv-FTD) did not show any benefit
We await further Alzheimer’s disease trails
The Future?
Combined drug treatment will probably be required for Alzheimer’s disease – analogy from AIDS and various cancer chemotherapy regimes that use multiple drug approaches depending on staging of disease
A possible approach in biomarker confirmed Alzheimer’s disease would depend on the stage and include –
A symptomatic drug (cholinesterase inhibitor and memantine)
An amyloid beta clearing agent (active or passive immunization)
An amyloid production reducing agent (BACE inhibitor)
A drug to block the effects of amyloid oligomers on neuronal synapses
A tau clearing agent
A tau production reducing agent
A tau aggregation inhibitor, and
An anti-inflammatory agent