New Approaches to Drug Treatment of Alzheimer’s disease
Symptomatic drugs
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), or tau and P-tau depleting agents – passive immunisation – monoclonal antibodies
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
Clinical Trial Unit Griffith University Southport studies
Steadfast study
50 plus age
MMSE 21-26
RAGE inhibitor tablet
Receptor for advanced glycation endproducts – reduce oxidative stress and inflammation
21 months duration
CogRx study
55-85 age
MMSE 18-26
CT1812 Sigma-2 antagonist tablet
Stops binding of Abeta to neurones
LP and MRI
1 month duration
Amaranth study
55-85 age
MMSE 20-30
RBANS <85
CDR 0.5
BACE inhibitor tablet
Stops production of Abeta oligomers
MRI, PET Abeta, PET tau
2 years duration
Abbvie study
55-85 age
MMSE 22-30
RBANS <85
CDR 0.5
Monoclonal antibody against tau
IV infusion 30-90 minutes monthly
2 years duration
MRI, PET Abeta, PET tau
To enquire about these trials and suitability of subjects contact Prof Philip Morris on +61 (0)422545753.