dementias advances in treatment

Update on biological treatments for dementia

Professor Roy Jones

RICE (The Research Institute

for the Care of Older People),

Royal United Hospital, Bath;

University of Bath;

University of Bristol

Disclosures

I serve on scientific advisory boards and receive honoraria for lectures and chairing symposia for major pharmaceutical and other companies involved in research to find treatments for Alzheimer’s disease and related conditions .

The research institute also receives research support grants from various Pharmaceutical or Biotech companies, the NIHR and charitable foundations

Research to find new treatments

Since 1987 we have been involved at RICE in studies

of more than 50 compounds for the potential treatment

of dementia (mainly Alzheimer’s disease) and memory

impairment

Five drugs have been licensed, four of which are still in

use and available in the UK, and all were studied in

clinical trials at RICE

No new drugs have been marketed since 2002 and

more that 120 drugs have failed to post positive results

in phase III late-stage trials

Drugs for Alzheimer’s disease

Cholinesterase inhibitors (acts on acetyl choline)

[ Tacrine (Cognex) — 1993 ]

Donepezil (Aricept) — 1997

Rivastigmine (Exelon) — 1998

Galantamine (Reminyl) — 2000

NMDA receptor antagonist (acts on glutamate)

Memantine (Ebixa) — 2002

2016: another year of disappointments

The disappointing:idalopirdine (Lundbeck/Otsuka)

5-HT6 serotonin receptor antagonist for add on therapy to

cholinesterase inhibitors

Phase III trial (STARSHINE) in mild to moderate AD added to

donepezil did not meet primary or secondary endpoints but

safe and well tolerated (September 2016)

Two similar phase III trials (STARBEAM and STARBRIGHT)

just completed

Press release (yesterday): the 3 studies failed to

demonstrate efficacy (as observed in the positive clinical

phase II study) sufficient to support a regulatory submission.

Lundbeck’s share price “dived”.

(Pfizer’s 5-HT6 receptor antagonist PF-05212377 also failed last

year so this approach may not be effective)

The pathological cascade in ADOverproduction of Aβ

Abnormal APP metabolismReduced Aβ clearance

Ageing

Unknown factors

AD-mutations(APP, PS1, PS2 genes)

Risk-genes(apolipoprotein E) Amyloid-β

accumulation

Activation of neurotoxic cascadesDecreased neurotrophic support

Fibrillary AβAβ oligomers

Hyperphosphorylation of tau

Amyloid plaques

Neuritic plaques

Dementia

Synaptic dysfunctionAxonal dysfunction

Collapse of cytoskeleton

Neurofibrillary tangles

Glial activationInflammation

Oxidative stressMitochondrial dysfunction

Adapted from Forlenza O, et al. BMC Medicine 2010; 8: 89.

The disappointing: amyloid immunisation

Solanezumab (Eli Lilly)– Issues of efficacy in 2 similar studies (EXPEDITION 1 and 2) but

reanalysis (both by Lilly and independently) of combined data

from the studies suggested a 34% effect on cognition in milder

patients (patients not confirmed as amyloid positive)

– Further study (EXPEDITION 3) in 2100 patients with mild AD

and confirmed as amyloid positive (Florbetapir PET scan or CSF

analysis) finished last year

Results announced November 2016. Unfortunately the

study was negative and although there were trends in

both primary cognitive and secondary endpoints the

effects were small and Lilly will not seek approval for the

drug in mild AD (some pre-dementia studies may still

proceed)

The irresponsible!Anti-tau therapy:LMTM (TauRx)

LMTM is a reduced form of methylene blue: it and related

compounds have been in clinical trials for some years (with a

proposed mechanism that blocks tau hyperphosphorylation)

In 2016 three trials (2 in AD and 1 in FTD) reported negative results

The UK company press release led on a purported benefit in a sub-

group (of unstated size) which suggested the drug had positive

results but only in participants not receiving standard AChEI therapy

Immediately after this one of our patients refused to start donepezil

“to wait for this better drug that won’t work if you’re on a current drug”

The company have carried out a “cohort analysis” (not based on the

randomised data) that shows an apparent effect of active AND

placebo (a low 4mg dose of drug given to try and mask unblinding

because the drug turns urine blue) in those not on AChEI therapy

This comparison has been called at best, wrong and at worst, bogus

What can we learn from these and other failures?

Why the failure with solanezumab?

Wrong dose: dose finding for trials was limited and based on

plasma data. Dose may be too low (? could be increased in

ongoing studies with solanezumab in preclinical AD). Future

dose finding likely to be based on CSF exposure and kinetics

The Aβ bound in plasma may actually get into the brain with the

drug

Subjects in Expedition 3 may have had a heavier amyloid load

than Expedition 1 and 2 due to amyloid PET scan positivity

being determined visually

Worth analysing individual patient data for level of amyloid load

and efficacy

The drug targets the wrong type of amyloid or needs to be

given even earlier or the amyloid hypothesis is wrong or

insufficient for therapeutic success

Development of better animal models of Alzheimer’s disease



Ageing

Unknown factors


Risk-genes(apolipoprotein E/TREM2) Amyloid-β

accumulation




Amyloid plaques

Neuritic plaques

Dementia







Development of improved mouse models of AD(MODEL-AD)

In January 2017, the US National Institute of Aging

(NIA) funded a 5-year $25m dollar programme to

generate and characterise mouse models using late-

onset AD genetic variants that most faithfully

represent human disease

Aim to develop 8 models/year and going beyond

amyloid and tau

Starting with apoE4 and R47H variant of TREM2,

then add for example microglial transporter ABCA7

and immune gene interleukin-1 receptor accessory

protein (IL1RAP)

Models will be freely available

MODEL-AD: Model Organism Development & Evaluation for late-onset AD

Alzheimer’s disease occurs on a continuum of severity from

No (Alz disease)Mild (Alz disease)Marked impairment (Alz dementia)

*MCI = Mild Cognitive Impairment due to AD or Prodromal AD

% of end-stage AD

100

60

20

0

80

40

40 50 7060 80

Asymptomatic(pre-clinical)

phase

Symptomatic(pre-dementia)

phase

Dementiaphase

Onsetof MCI*

Clinical diagnosisof AD

Estimated start of amyloid deposition

Age (years)

Degree of cognitive

impairment

AD Diagnosis Marching Leftward

Standard

diagnosis

Dubois

research criteria:

“early AD”

Modified

Dubois criteria:

“earlier AD”

Presymptomatic

AD

No symptoms,

biomarker

evidence

of amyloid

dysregulation

Very mild

symptoms

+ amyloid

biomarker

Episodic

memory

impairment

+ any

biomarker

Dementia

Onset of ADpath

Courtesy of B Winblad From Aisen PS. Alzheimers Res Ther. 2009

Do biomarkers help?

Amyloid protein is reduced and total tau and p-tau are increased in CSF in AD

Sunderland et al. JAMA 2003; 289: 2094–2103

CSF -amyloid1-42 CSF tau

Alzheimer’s disease

(n=131)

Alzheimer’s disease

(n=131)

Controls

(n=72)

Controls

(n=72)

pg

/ml

pg

/ml

CSF – cerebrospinal fluid

Issues with biomarkers

Availability and expense of MRI and PET scanners and

amyloid imaging agents (and scans may need to be

repeated)

Need for CSF testing (and may need to be repeated)

Standardising CSF biomarkers has improved and is

likely to become more widely used

Acceptance by regulators of biomarker data in

registration of new drugs (seems more likely especially

for FDA in US)

If drugs are registered using biomarkers, will this

restrict their prescription only to patients who have had

biomarkers measured?

Treatment of Alzheimer’s disease

166 people with prodromal or mild AD, recruited from a number of centresFurther larger studies are ongoing including at RICE

Sevigny J et al, Nature 2016, 537, 50-56

Aducanumab update

Initially 1,3,& 10mg/kg studied but high adverse effects at

10 so 6mg/kg added and reduced amyloid (florbetapir

PET) at 1 year

ARIA-E (oedema) common and increased with dose and

apoE4 status (5% 1&3, 43% 6 and 55% 10 for carriers,

9% 3, 22% 6, 17% 10): discontinuation low & 56%

continued, some at a lower dose. 89% occur early in

treatment and one third asymptomatic

Two phase III studies in progress in mildly symptomatic

patients

AD Secondary Prevention Studies

• API (Alzheimer’s Prevention Initiative): $100m prevention trial

of outwardly healthy people at high genetic risk of AD using

antibody crenezumab (Genentech) – large Columbian kindred

and those with familial AD mutations from US

• DIAN (Dominantly Inherited Alzheimer Network) using

gantenerumab, solanezumab & BACE inhibitor in 160 people

aged 30+ with FAD mutation from US, UK, Australia, Spain

and Germany

• A4 (Anti Amyloid in Asymptomatic AD) - a trial of those who

are amyloid biomarker positive

• Positive results from these studies will provide support for the

amyloid hypothesis

AAmyloid Protein

-Amyloid Deposits

Beta Secretase Gamma Secretase

Beta Amyloid Peptide A

A-peptide Production

Beta Amyloid Fibrils

A

Passive immunisation

Active immunisation

Prevent amyloid

aggregation

Secretase Inhibitors

-secretase (BACE-1) inhibitors

Verubecestat (MK8931;BACE1 inhibitor)

– phase II/III study (EPOCH) in 1960 subjects with mild to

moderate AD. Safety cohort of 200 treated for at least 3

months completed 2013 and study allowed to continue –

main results ?2017/8.

– APECS trial in amnestic Mild Cognitive Impairment due to AD

(n=1500) results due 2019

E2609 (Eisai/Biogen; BACE-1 inhibitor) – phase III

studies in early AD (FDA Fast Track Status)

Others include HPP854 (High Point Pharmaceuticals,

ph1 MCI/mild AD), RG7129 (Roche, ph1); AZD3293

(Astra Zeneca, phase 1)



Ageing

Unknown factors


Risk-genes(apolipoprotein E) Amyloid-β

accumulation




Amyloid plaques

Neuritic plaques

Dementia







Anti-tangle (anti-tau) approaches to therapy

Increasing interest in anti-tau treatments since tau (and tau

PET imaging) reflects the state of a person’s disease and

cognition more than amyloid

Altering or blocking tau hyperphosphorylation

– Unsuccessful so far

Enhancing clearance of aggregates with antibodies or

drugs

– Tau is a potential target for active or passive immunotherapy and

data from mice supports this approach

– A number of immunisations targeting tau have now entered

early clinical trials (eg current phase I study at RICE with

ACImmune’s active antibody will complete this year)

RVT-101(Inteperdine; Axovant)

5-HT6 serotonin receptor antagonist (like 2

recently failed compounds)

3 studies in AD, DLB & Parkinson’s disease

dementia (PDD)

– MINDSET: 6 month phase 3 study in AD added to

stable donepezil therapy measuring cognition and

ADLs

– HEADWAY: phase 2 study in DLB with global

primary measure and hallucinations as secondary

– October 2016: small 3 month study in AD, DLB

and PDD looking at effects on gait

Slide of Professor Clive Holmes

Xanamem (Actinogen, Australian company) blocks

enzyme that activates cortisone into active ‘stress

hormone’ cortisol, which is very active in hippocampus

and frontal cortex.

XanADu phase II study in mild AD about to start

40mg daily of pimavanserin a

selective 5HT2A partial inverse

agonist was well tolerated over 6

weeks of treatment

After solanezumab: where should Alzheimer’s research go?

(see www.alzforum.org/news/

Slide of Professor Clive Holmes

http://www.alzforum.org/news/conference-coverage/aruk-roundtable-where-now-alzheimers-disease-research

Image courtesy of Howard Fillit, ADDF

The future?

• Understand more about oligomeric Aβ

• Look at pathways from the new genetic approaches such as GWAS

(as in US MODEL-AD mouse model development)

• Tau clearly has a central role in Aβ neurotoxicity and needs further

investigation

• Consider multiple pathologies beyond amyloid and tau that are in

the AD brain early on – hypertension, diabetes, inflammatory

disease, Lewy bodies, hippocampal sclerosis, TDP43 deposits,

vascular disease

• Consider 2 or more approaches in combination

• Consider adaptive clinical trial designs

• Improve trial efficiency, combine phases of development, enable early

stopping, test candidate drugs in parallel etc

• European Prevention of Alzheimer’s Dementia (EPAD) will use this to

test treatment in the pre-symptomatic phase (proof of concept trials)

1

Goal 1: Prevent and effectively treat

Alzheimer’s disease by 2025

If this is to be achieved by finding a

suitable drug treatment, then that

drug should already be in Phase II

testing!

Thank you

dementias advances in treatment

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