New Drug Treatments for Alzheimer’s disease 2016

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

 

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