Is There a Need for New Symptomatic Therapies for Alzheimer’s Disease & What Have We Learned from

Past Trials of Symptomatic Therapies?

George T. Grossberg MD

Samuel W. Fordyce Professor

Department of Neurology & Psychiatry

St Louis University School of Medicine

St Louis , Missouri

USA

DISCLOSURES

Consultant: Accera; Allergan (Forest/Actavis); Avanir; Baxter; Biogen; Genentech; Lundbeck; Novartis; Otsuka; Roche; Takeda

Research Support: Accera; NIH; Noven

Safety Monitoring: Merck; Newron

Presentation Architecture

Prominent Failures of Disease Modifying Therapies

Unmet Needs In Alzheimer’s Disease

Current Symptomatic Therapies and Unmet Needs

Combination Therapy

Future Symptomatic Therapies

Conclusions & Recommendations

Recent Failures of Disease-Modifying/Preventative Therapies

Prominent failures have included:

-- Amyloid aggregation inhibitor- Tramiprosate (Alzhemed)

-- Gamma-secretase inhibitors- R-flurbiprofen; semagacestat

-- Mitochondrial stabilizer- Latrepirdine (Dimebon)

-- Rage inhibitor- PF-04494700

--A-Beta antibodies- Bapineuzumab; solanezumab; crenezumab; gantenerumab

-- IVIg

-- Failures unable to match ADAS-Cog gains of symptomatic therapies

Re-Examination of Symptomatic Therapies

Current FDA-approved symptomatic therapies are based on neuro-transmitter alterations : Acetylcholine & Glutamate

But we see multiple additional neuro-transmitter alterations in AD, including: Serotonin ,Norepinephrine. Dopamine—These pose additional targets for treating AD and its affective and behavioral concomitants

There is also evidence that some current symptomatic therapies may have disease moderating effects

Unmet Needs In Alzheimer’s Disease

Cognitive

Behavioral

Functional

Stress on Caregivers

Delay to Institutionalization

Financial

PlacebowashoutWeeks on therapy

Baseline 6 12 18 Endpoint 30

AD

AS

-Co

g m

ea

n c

ha

ng

e

fro

m b

ase

lin

e

–3

–2

–1

0

1

2

3

4

***

**

***

*

***

***

10 mg/d (n=157)

5 mg/d (n=154)

Placebo (n=162)

*P<.0012; **P<.0007; ***P<.0001 vs placebo.Mean MMSE score = 19.Rogers et al. 1998.

Decline

Improvement

Effects of Donepezil on Cognition:ADAS-Cog

†P<0.05 compared to placebo.Farlow, 2002

s

s

s

s

n

n

n

nl

l

l

l

†

Week 12 Week 18 Week 26

-6

-5.5

-5

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

6-12 mg1-4 mgPlacebo

l

n

s

Rivastigmine RDO Analysis: Mean Change From Baseline on ADAS-Cog

Effects of Galantamine on Behavioral Symptoms: NPI Total Scores

Me

an

(±

SE

M)

chan

ge

in

NP

I sc

ore

fro

m b

ase

lin

e

Baseline 1 2 3 4 5

Placebo

Galantamine 8 mg/d

Galantamine 16 mg/d

Galantamine 24 mg/d

Time (months)

Improvement

Deterioration

n=978.*P < .05 vs placebo.Tariot et al, 2000.

-3

-2

-1

0

1

2

3

4

*

0

5

10

15

20

25

30

35

Increaseddose

Terminatedmedication

Antipsychotics

(n = 55)

Anxiolytics

(n = 33)

Antidepressants

(n = 57)

Reduced

dose

Nursing Home Patients at Week 52

Anand, Koumaras, Hartman 2000.

Effects of Rivastigmine on Psychotropic Medication Use

Effects of Rivastigmine on ADLs:PDS Scores Mean Change from Baseline

PDS = Progressive Deterioration Scale.OC analysis.*P<0.05 vs placebo; **P<0.001 vs placebo.

Corey-Bloom et al, 1998.

–7

–6

–5

–4

–3

–2

–1

0

1

2

Weeks

PD

S S

core

Me

an

Ch

an

ge

fro

m B

asl

ine

*

Improve

Decline

4.54

0 18 26

6-12 mg (n=231)

1-4 mg (n=233)

Placebo (n=235)

12

**

Reprinted with permission from Feldman H et al. Efficacy of donepezil on maintenance of activities of daily living in patients

with moderate to severe Alzheimer’s disease and the effect on caregiver burden. J Am Geriatr Soc. 2003;51(6):737-744.

Donepezil n=111 93 90 84 (111)

Placebo n=110 91 85 87 (110)

Donepezil (observed cases)

IADL, instrumental activities of daily living; PSMS, physical self-maintenance scale

Treatment With a ChEI

Reduces Caregiver Burden

0 4 12 24

P=0.015

P=0.003

Donepezil

Placebo

Me

an

Ch

an

ge

Fro

m

Ba

seli

ne

Tim

e

(min

/d ±

SE

)

80

60

40

20

0

-20

-40

-60P=0.004

Less Time

More Time

Baseline

Aggregate (IADL + PSMS)

Week 24

LOCFWeek

Data on Combination

Therapy for AD

NIH-sponsored analysis of

382 patients over the

course of 15 years

Study supports the benefits

of combination therapy

Atri A et al. Alzheimer Dis Assoc Disorder. 2008;22:209.NIH, National Institute of Health

Results: Cognitive

Performance* Over Time†

Patients receiving combination therapy may experience significantly slower cognitive decline

The data show that the mean deterioration for an untreated patient is 3 to 4 errors per year; combination therapy decreased the deterioration by 2 errors per year

Atri A et al. Alzheimer Dis Assoc Disorder. 2008;22:209.Blessed G et al. Br J Psychiatry. 1968;114:797.

*Based on predictive values from regression models of actual patient data. Actual patient data were used in a

statistical model to generate these predicted values that account for patient differences such as duration of

illness, time entering study, education, and baseline BDS and ADL scores.†Mean cumulative medication treatment time was 1.9 years.‡Blessed Dementia Scale (Information-Memory-Concentration subscale) is a brief mental status best

administered by a physician to assess cognitive impairment.

5

10

15

20

25

30

Pre

dic

ted

Mean

C

og

nit

ion

Sc

ore

s

(nu

mb

er

of

err

ors

)

Years 1 2 3 4

*P<0.05 vs no RX‡P<0.01 vs AChEI†P<0.001 vs no RX§P<0.001 vs AChEI¶P<0.01 vs no RX

Wo

rse

nin

g

Memantine + AChEI

AChEI alone

No treatment

Results: Cognition−BDS‡

†‡

†§†§

†

¶

¶

*

†

Results: Functional

Dependence* Over Time†

• Patients receiving combination therapy may experience less dependence compared with a

ChEI alone and not treatment

Atri A et al. Alzheimer Dis Assoc Disorder. 2008;22:209.Johnson M et al. Alzheimer Dis Assoc Disord. 2004;13;223.Weintraub S. Am J Alzheimers Dis Other Demen. 1986;1:35.

*Based on predictive values from regression models of actual patient data. Actual patient data were used in a

statistical model to generate these predicted values that account for patient differences such as duration of

illness, time entering study, education, and baseline BDS and ADL scores.†Mean cumulative medication treatment time was 1.9 years.‡Weintraub ADL Scale (Weintraub Activities of Daily Living scale) is a 31-item questionnaire on both basic and

instrumental ADLs.

20

40

50

60

70

80

Pre

dic

ted

Mean

L

evel

of

Dep

en

den

ce (

%)

Years 1 2 3 4

*P<0.05 compared with no treatment†P<0.05 compared with AChEI alone

Wo

rse

nin

g

Memantine + AChEI

AChEI alone

No treatment

Results: Function−Weintraub ADL Scale‡

30*

Behavioral Effects of

Combination Therapy

n= 198 186 171 193

n= 197 175 152 189

Tariot P et al. JAMA. 2004;291:317.Cummings JL et al. Neurology. 2006;67:57.

*Statistically significant; †OC analysis; ‡LOCF analysis.

LS, least square; SE, standard error

.4

0

2

4LS

Mean

Ch

an

ge (

SE

)

in T

ota

l N

PI S

co

re

0 12 24 End Point

†P<0.001*

De

cli

ne

Memantine + donepezil

Placebo + donepezil

Memantine + donepezil produced significant improvements in behavior compared with placebo + donepezil.

-2

Imp

rovem

en

t

†P=.010* ‡P=0.002*

Treatment Week

Persistent Treatment With

ChEI and/or Memantine Slows

Clinical Progression of AD

641 AD patients followed over 20 years

Persistent drug treatment produced statistically and clinically significant impact on AD progression as assessed by measures of:

Cognition

ADLs

Global measures

Positive treatment effects even seen in advanced AD Roundtree SD et al. Alzheimers Res Ther. 2009 Oct 21;1:7.

Symptomatic Therapies In The Pipeline: 5-HT 6 Receptor Antagonist- Idalopirdine (Lu AE

58054)

--- 5-HT 6 receptor is G-protein coupled receptor; One of 7 serotonin receptors;

Almost exclusively expressed in the brain. A high affinity selective antagonist of the 5-HT 6 receptor

--- MOA: Idalopirdine potentiates the effects of ChEI’s > increased central (hippocampus and frontal cortex) cholinergic neurotransmission>boost in cognitive processing/performance, but w/o peripheral cholinergic activity.

Also facilitates glutamatergic and monoaminergic signaling and suppresses GABAergic transmission

deJong et al: AAIC Poster, 2013.

Idalopirdine: Phase 2 Study

Primary Objective of the RDBPC study: Effect on cognition (ADAS-Cog) after 24 weeks in donepezil treated (mean of 1.5 yrs) patients with moderate AD

Baseline randomization: N=278 (MMSE 12-19- Mean =17)

Results: ADAS-Cog > 2.5 point difference with drug. P=.004

ADCS-ADL & ADCS-CGIC> NS

Safe and well-tolerated Wilkinson D et al Lancet Neuro 2014

Phase 3 study ongoing. Mild-Mod AD(MMSE 12-22)with ChEI; 10,30,60 mg.

5-HT 7 Receptor Agonists

5-HT 7 receptor agonist 5 carboxamidotryptamine(5-CT) improved novel object discrimination in mice

5-HT 7 receptor stimulation > improved memory in mouse models

5-HT 7 receptor stimulation facilitates memory function and reverses scopolamine-induced memory impairment in mouse models

Freret T et al: Psychopharmacology(Berl.),2014

Meneses A et al: Rev. Neurosci.,2014 & Psychopharmacology, 2014.

Encenicline (EVP-6124): Alpha-7 Nicotinic Receptor Partial Agonist

Nicotine improves concentration, memory and learning via interaction with neuronal nAChRs

Alpha-7 nAChRs are found throughout CNS, but especially the cortex and hippocampus

Pre-synaptic nAChRs, when activated>increased intraterminal calcium and modulate release of glutamate in hippocampus and dopamine(indirect) from pre-frontal cortex and striatum.

Prickaerts J et al: Neuropharmacology, 2012.

Deardorff WJ & Grossberg GT: Expert Rev Neurother. 2015

Encenicline (EVP-6124) Pre-Clinical Data

EVP-6124 restored memory in scopolamine treated rats in an object recognition task

Co-administration of sub-efficacious doses of donepezil and EVP-6124 restored performance on the object recognition task

This supports cholinergic augmentation of memory performance

Prickaerts J et al. Neuropharmacology, 2012.a

Encenicline Phase 1b and 2b Safety & Efficacy Data

Phase 1b study: 4 week, RDBPC ascending dose safety study. Mild-Mod AD on stable ChEI. N=48 > + signals on CogState and NTB. Safe and well-tolerated with ~ 10% GI SE’s (nausea and constipation)

Phase 2b study: 24 week,RDBPC parralel group study in Mild-Mod AD with and w/o ChEI. Four arms-0.3 mg/d,1.0 mg/d,2.0 mg/d, placebo.

-- Results: 2mg/d group at 23 wks- ADAS-Cog 13 stat. signif at 0.0189. CDR-SB,COWAT (oral word association), Cognition & memory composite, executive functions also statistically signif vs placebo. AE (nausea/constipation) prevalence was dose-dependent and in 2mg/d group was higher than placebo, with or w/o background ChEI

Deardorff & Grossberg Expert Rev Neurother 2015

Encenicline-Phase 3 Study

2 large (N=790 each), 26 week, RDBPC trials in Mild-Mod AD(MMSE 14-24) are underway.

Each looks at high vs low dose vs placebo in patients with and w/o stable ChEI dose on board.

Key Efficacy End Points- ADAS-Cog-13 and CDR-SB

--clinicaltrials.gov Accessed July, 2015.

Conclusions and Recommendations-1

Current, FDA-approved, symptomatic therapies (ChEI’s and memantine) are useful in AD.

ChEI’s are most useful if given early and eventually combined with memantine, with benefits seen relative to cognition, behavior, functionality, caregiver strain, delay to institutionalization and decreased use of psychoactive drugs.

Although long-term, placebo-controlled studies are unavailable, naturalistic studies from memory clinics support the long-term use of combination therapy, which may enable patients to stay at home up to 1 yr longer

Conclusions and Recommendations-2

New symptomatic therapies are in development, with the 5-HT 6 receptor antagonist idalopirdine and the alpha-7 nicotinic receptor partial agonist encenicline , being in Phase 3 trials. 5-HT 7 receptor agonists are promising.

For the foreseeable future, combinations of symptomatic therapies, depending on each AD patient’s unique phenotype remain attractive. Combined with lifestyle modification.

Optimal combinations of times to begin various symptomatic therapies and how long to maintain them remain unanswered.

Symptomatic therapies may not be disease modifying, but may be “disease-course modifying”