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”