Results of a Phase 2A Study of a Novel 5HT4 Agonist for the Treatment of Alzheimer’s Disease J....

Results of a Phase 2A Study of a Novel 5HT4 Agonist for the Treatment of Alzheimer’s Disease

J. Thomas Megerian, MD, PhDExecutive Director, Clinical Research

March 6, 2009

2 2

Rationale for 5-HT4 in Alzheimer’s

• Cognitive dysfunction in Alzheimer’s disease (AD) is due in large part to diminished cholinergic tone, resulting form prominent loss of cholinergic neurons

• 5-HT4 receptor stimulation leads to increases in release / production of acetylcholine (ACh) in the brain

• Activation of 5-HT4 also stimulates growth factors (BDNF) and promotes the alpha-secretase pathway, leading to secretion of the soluble form of amyloid precursor protein (sAPP) and reduced A levels

• sAPP is neuroprotective, increases NGF, enhances memory, and competes with amyloidogenic (toxic) peptides

3

PRX-03140 Increases ACh Release in Hippocampus During Delayed Spontaneous

Alternation in Rats

75

100

125

150

175

200

225

250

8 16 24 32 40 48 56 64 72 80 88

Time (Min)

Pe

rce

nt

of

Ba

se

lin

e H

ipp

oc

am

pa

l A

Ch

Eff

lux

(M

ea

n ±

s.e

.m.)

Vehicle

PRX-3140 1 mg/kg

PRX-3140 5 mg/kg

Pre-Testing Testing Post-TestingBaselineDrug

Injection

p<0.05

*

*

On demand ACh increase; no effect seen in the resting state

4

Amyloid 1-40

* P=0.04 for treated vs. vehicle (n=10); Model: 3 weeks treatment with PRX-03140 i.p.(19 weeks old at study completion)

-)30%(-)12%( -)20%(

0

5

10

15

20

25

30

Vehicle PRX-03140 1 mg/kg PRX-03140 5 mg/kg PRX-03140 10 mg/kg

A

1-4

2 (

pm

ol/

g)

A1-

40(p

mol

/g)

Effect of PRX-03140 on Hippocampal Amyloid 1-40 Levels in Tg2576 Mice

5

• A sub-efficacious dose of PRX-03140 (0.1 mg/kg) plus 0.3 mg/kg donepezil produced even greater efficacy than donepezil alone

• Basis for the Phase 2a trial alone and combined with donepezil

PRX-03140 Enhances an Efficacious Dose of Aricept® in Delayed Spontaneous Alternation in Rats

0

10

20

30

40

50

60

70

Me

an

Pe

rce

nt

Alt

ern

ati

on

VEH PRX 0.03 PRX 0.1 PRX 1.0 DNZ 0.3 DNZ 0.3PRX 0.03

DNZ 0.3PRX 0.1

***††

*

**

Treatment (ip, mg/kg)n=6-9 rats/group

* p< 0.05 vs vehicle** p< 0.01 vs vehicle*** p< 0.001 vs vehicle†† p< 0.01 vs donepezil alone

* p< 0.05 vs vehicle** p< 0.01 vs vehicle*** p< 0.001 vs vehicle†† p< 0.01 vs donepezil alone

Mea

n P

erc

ent

Alt

era

tio

n

Summary of Phase 1 Experience

• Single Ascending Dose Doses from 5 to 250 mg 80 Subjects (20 on Placebo) Ages 18 – 45 Appeared Well Tolerated

• No clearly attributable AE signal above placebo • No effect on QTc

• Multiple Ascending Dose 14 Day MAD Doses from 10 mg to 200 mg No MTD reached Appeared Well Tolerated

• Slight increase in HA, Dizziness over placebo• Repeated Report of Vivid Dreams suggested CNS Cholinergic Action

• Phase 1b 50 mg dose for 10 day in AD Patients Improvement of .3 in Right Frontal EEGAlapha:theta ratio simliar to what has

been seen associated with efficacy of AchEIs.

6

7 7

Randomized, Double-blind, Placebo-controlled, Phase 2a Study To Assess The Effects Of PRX-03140 Alone And In Combination

With Donepezil In Patients With AD

Design• Seventeen US sites • 80 patients • Two weeks dosing

Endpoints• Safety & Tolerability• Donepezil PK• qEEG alpha:theta ratio• Cognitive measures

• ADAS-Cog• Mindstreams CCA• Buschke SRT• Trailmaking A

Screening

Panel 110 mg DNZ + 5 mg 03140/placebo



Panel 410 mg DNZ+ 100 mg 03140/placebo

Panel 510 mg DNZ +200 mg 03140/placebo

Panel 6Monotherapy Arm

50 mg 03140or

150 mg 03140or

placebo

OpenLabel

Extension

6 months

PRX-03140

8

Monotherapy – Significant Difference vs Placebo on Change From Baseline in ADAS-Cog/11

• After two weeks of dosing, mean ADAS-cog change for monotherapy (150mg) was 3.6 points

• Approved Alzheimer’s drugs typically show 3-4 point improvement after 12-24 weeks

• Statistically significant dose-response for 150mg vs. 50mg vs. placebo (p=0.026)

+ 0.9 (3.4)

- 1.0 (5.1)

placebo 50mg PRX-03140 150mg PRX-03140

p = 0.021 for 150mg vs. placebo - 3.6 (5.1)

Mea

n (

±SD

) C

han

ge

in A

DA

S-c

og

Imp

rove

d C

og

nit

ion

-5

-4

-3

-2

-1

0

+1

+2

9

Individual Patient Outcomes: Responses Increase With Dose

CP-018: ADAS-Cog Result by VisitPlacebo

0

5

10

15

20

25

30

35

40

Baseline Day 13

Visit

AD

AS

-Co

g S

core

#601

#607#618

#611

#624

#626

#604, #611

#604#613

#621

#628

CP-018: ADAS-Cog Result by VisitPRX-03140 150 mg

0

5

10

15

20

25

30

35

40

Baseline Day 13

Visit

AD

AS

-Co

g S

core

s

#603

#630#619#609

#612

#617

#615

#625#622


0

5

10

15

20

25

30

35

40

Baseline Day 13

Visit

AD

AS

-Cog

Sco

re

#602

#606#608#610#623

#614#616

#620#627 #629

Improvement

Worsening

No Change

10

PRX-03140 Phase 2a: PRX-03140 + Aricept® Combination ADAS-Cog Results

10

Mea

n (

±SD

) C

han

ge

in A

DA

S-c

og

Imp

rove

d C

og

nit

ion -3.1 (4.9)

placebo

50mg 100mg

-5

-4

-3

-2

-1

0

+1

+2

0 (4.0)

- 2.5 (3.5)

0 (2.9)

5mg

0mg

+1.8 (3.4)

PRX-03140 Dose

200mg25mg

- 3.1 (2.3)

Monotherapy Panels:Effect Sizes (Cohen’s d) Relative to Placebo

• Components:

Immediate Verbal Memory

Delayed Verbal Memory

Immediate Non-Verbal Memory

Delayed Non-Verbal Memory

• Large positive effect for 50 mg/day

(d = 0.99) dose

• Small positive effect for 150 mg/day

(d = 0.44) dose

• No negative effects

MINDSTREAMS MEMORY INDEX

50 150

Dosage (mg/day)

-1

-0.5

0

0.5

1

1.5

Co

he

n's

d

Large

Medium

Small

Small

Medium

Large

Positive Effect

Negative Effect

* p < 0.05 (1-tailed) for drug vs. placebo

*

Monotherapy Panels:Effect Sizes (Cohen’s d) Relative to Placebo

• Components:

Visual Spatial Accuracy


(d = 0.96) dose

• No effect for 50 mg/day dose


MINDSTREAMS VISUAL SPATIAL INDEX

Dosage (mg/day)

-1

-0.5

0

0.5

1

1.5

Co

he

n's

d

Large

Medium

Small

Small

Medium

Large

Positive Effect

Negative Effect

*


50 150

Combination Therapy Panels:Effect Sizes (Cohen’s d) Relative to Placebo

• Components:

Immediate Verbal Memory

Delayed Verbal Memory

Immediate Non-Verbal Memory

Delayed Non-Verbal Memory

• Large positive effects for 25 mg/day

(d = 0.84) and 50 mg/day (d = 1.27)

doses, largest for 50 mg/day

• Small positive effects for 5 mg/day

(d = 0.35) and 100 mg/day

(d = 0.50) doses

• No effect for 200 mg/day dose


MINDSTREAMS MEMORY INDEX

5 25 50 100 200

Dosage (mg/day)

-1

-0.5

0

0.5

1

1.5

Co

he

n's

d

Large

Medium

Small

Small

Medium

Large

Positive Effect

Negative Effect

*


Combination Therapy Panels:Effect Sizes (Cohen’s d) Relative to Placebo

• Components:

Visual Spatial Accuracy


(d = 1.11) dose

• Small positive effects for 5 (d =

0.48) and 200 (d = 0.48) mg/day

doses

• No effect for 25 mg/day and 100

mg/day doses


MINDSTREAMS VISUAL SPATIAL INDEX

5 25 50 100 200

Dosage (mg/day)

-1

-0.5

0

0.5

1

1.5

Co

he

n's

d

Large

Medium

Small

Small

Medium

Large

Positive Effect

Negative Effect

*


15

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

placebo

50mg PRX-03140

150mg PRX-03140- 0.1 (.6)

0.3 (1.2)

PRX-03140 Ph2a Effects on qEEG in AD Patients Consistent with Approved AD Drugs

Alp

ha

: T

het

a R

atio

Ch

ange

Fro

m B

asel

ine

PRX-03140 effect on qEEG is consistent with approved Alzheimer’s drugs, such as donepezil, rivastigmine and tacrine

Positive Trend for Increase in Frontal Alpha: Theta Ratio

0 (.4)

16

PRX-03140 ~ Phase 2a Safety Data

• Appeared well-tolerated in monotherapy and combination

• Monotherapy Well-tolerated at both 50mg and 150mg once daily Only two attributable AEs on drug (heartburn, fatigue) No dose-limiting toxicities or requirement for dose titration No nausea, vomiting, diarrhea or other GI side effects commonly observed

with cholinesterase inhibitors

• Combination with donepezil Well-tolerated from 5mg–100mg once daily Most common AEs at 200mg qd: nausea (n=2), vomiting (n=1)

• Mechanism-based side effects (cholinergic)

• MTD in combination with donepezil: ~200 mg once daily

17

Open Label Extension

• Several subjects experienced subjective improvement resulting in family members petitioning for continuance of therapy during blinded phase

• After verifying objective data that demonstrated improvement in ADAS-Cog a request was made to the FDA to allow for 6 month open label extension for 2 subjects

• Subject 405: 73 year old female, diagnosed with AD for 2 years; baseline MMSE of 22; on 10 mg DNZ for ≈6 months; entered combination arm on 100 mg of 03140

• After 2 weeks, demonstrated a 6 point improvement in ADAS-cog, along with improvements in attention, executive function, visual spatial ability and a global cognitive function summary measure on the Mindstreams Computerized Cognitive Assessment

• Subject 405 has completed 6 months of open label extension. Her MMSE at 6 months was 26, up from 22 at screening

• Daughter states that she is able to play cards again, sign her name again, and has substantial improvements in word-finding ability and semantic memory

• DAW came off of drug for 2 months after the 6 month extension to allow for LFTs to normalize (they had gone up to 2x ULN and remained stable there for 3 months while on therapy)

During this time, MMSE declined to 23, and DAW became more withdrawn, anxious and confused and had clear loss of many cognitive gains she had made.

18


• Subject 615: 66 year old male recently diagnosed with AD, with a baseline MMSE of 20, randomized to 150 mg monotherapy with PRX-03140

• After 2 weeks Demonstrated a 1 point improvement on the ADAS-Cog Trailmaking A test improved from a time of 108 seconds at baseline to 69 seconds

day 15 Improved on multiple (6 out of 7) memory retrieval and storage parameters on the

Buschke SRT, ranging from 2 point improvement on the recall trial to a 23 point improvement on the Long Term Storage Sum of Trials

No change on Mindstreams

• Subject 615 has completed 6 months of open label extension. His MMSE is now 29, up from 21 at screening and continues to show improved memory and mood with daily activities.

19

Summary of Phase 2a Results

• PRX-03140 is well tolerated and appears safe in both monotherapy and in combination therapy with donepezil

• PRX-03140 does not alter the exposure or Cmax of donepezil

• Statistically significant and clinically meaningful improvement in several measures of cognition including ADAS-Cog with PRX-03140 monotherapy after 2 weeks of dosing

• No overall effect on ADAS-cog after 2 weeks in patients already taking donepezil 10mg qd; may require longer term dosing to observe benefit

20

Current Phase 2b Trials

• In our partnership with GSK, we have initiated two separate studies in the USA utilizing PRX-03140

• Monotherapy Trial: PRX-03140 as monotherapy for 3 months and will include a control Aricept arm with an available 3 month extension

• Combination Trial: PRX-03140 as an add-on therapy in patients already taking a stable 10mg dose of donepezil 10mg for at least 4 months; study duration 6 months

21

Acknowledgements“The Patient Is Waiting”

• CEO Elkan Gamzu

• Research and Development Sharon Shacham

• Product Team Leader Ronda Gray-Kaufman

• CMC Sheila Dewitt Richard Yieh

• Quality & Regulatory Kirsten Overoye-Chan Rebecca Warwick Shahidah Mohammad Mike Pacak Jane Chamberlain

• Human Resources Brenda Sousa Martha Bradford

• Clinical Team Julia Kazakin Ralph Mattot Sean McNelis Michael Greeley David Rezendes Anna Zampini Musa Mutyaba Mary Kay Hes

• ADME Simon Jones

• GSK Partners Richard Philipson Bernadette Cummins Richard Keenan Shelagh Wilson Nancy Earle Tim Montague Sarah Derosset

• Financial Team Kim Drapkin Scott Chouinard

22

PRX-03140 ~ Phase 2a Trial Design

• Randomized, double-blind, placebo-controlled, Phase 2a study to assess the effects of PRX-03140 alone and in combination with donepezil in Alzheimer’s patients

• Seventeen US sites, 80 patients, two weeks dosing

• Endpoints: Safety / tolerability, qEEG, exploratory cognitive measures

• Monotherapy - PRX-03140 in patients taking no other cognitive enhancing medications

Doses: 50mg and 150mg vs. placebo once daily, 10 patients per arm (30 total)

• Combination Therapy - PRX-03140 + donepezil Doses: PRX-03140 at 5, 25, 50, 100, 200mg with donepezil 10mg once daily, 10 patients per arm (50

total)

23

Inclusion Criteria

24

PK Summary Combination Therapy

Measured

Drug

Parameter

Treatment0 mg

n=10

5 mg

n=8

25 mg

n=8*

50 mg

n=8*

100 mg

n=8

200 mg

n=8*

Donepezil

Mean Cmax

(ng/mL)

(SD)

Donepezil

Alone

With 3140

55 (27)

55 (19)#

40 (16)

46 (11)

54 (32)

50 (19)

47 (24)

56 (23)

49 (20)

52 (23)

53 (20)

50 (17)

Mean

AUC0-24

(ng*h/mL)

(SD)

Donepezil

Alone

With 3140

1008 (580)

1013 (404)#

793 (339)

894 (256)

1085 (697)

895 (368)

869 (438)

1044 (562)

935 (532)

1033 (475)

1010 (376)

953 (357)

PRX-03140

(Day 7)

Mean Cptrough

(ng/mL)**

(SD)

NA NA 15 (28) 20 (44) 32 (55) 183 (177) 480 (338)

• Coadministration of donepezil (qd; 10 mg) with PRX-03140 (qd; 5, 25, 50, 100 or 200 mg) did not result in clinically relevant pharmacokinetic interaction with donepezil

• Significant interpatient variability in PRX-03140 plasma levels (Day 7, C trough) and overlap of concentrations in lower dose range

•n=7 # placebo (no PRX-3140) ** Excludes samples <LLOQ

25

Exclusion Criteria

26

CP-018 (Monotherapy) ADAS-Cog ResultsPlacebo Group

CP-018: ADAS-Cog Result by VisitPlacebo

0

5

10

15

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35

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Baseline Day 13

Visit

AD

AS

-Co

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#601

#607

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#604, #611

#604#613

#621

#628

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CP-018 (Monotherapy) ADAS-Cog ResultsPRX-03140 150 mg Group


0

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Baseline Day 13

Visit

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-Co

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#603

#630#619#609

#612

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#615

#625#622

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CP-018 (Monotherapy) ADAS-Cog ResultsPRX-03140 50 mg Group


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Visit

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-Co

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#602

#606#608

#610#623

#614

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#620

#627 #629

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PRX-03140 PK Summary Monotherapy Therapy

DayTime

(h)

Dose

(mg)

Mean Cp

(ng/mL)

(SD)

7 Predose

50 100 (120)

150 153 (111)

14

2

50 268 (222)

150 589 (441)

4

50 253 (187)

150 553 (308)

• Ctrough similar for 50 and 150 mg doses

• Three fold increase in dose yields a ~2 fold increase in plasma levels at 2 and 4h

• Significant interpatient variability in plasma levels

30

PRX-03140 Ph2a Effects on qEEG in AD Patients Consistent with Approved AD Drugs

PRX-03140 effect on qEEG is consistent with approved Alzheimer’s drugs, such as donepezil, rivastigmine and tacrine

Positive Trend for Increase in Frontal Alpha: Theta Ratio

Change in Frontal Alpha:Theta Ratio from Baseline

-0.20

0.20.40.60.8

11.21.4

Dose Group

Alp

ha:T

heta

Rat

io C

hang

e

From

Bas

elin

e

placebo

50 mg

150 mg

31

Model Species Dosing Period

Results

Delayed Spontaneous Alternation (dSA)

Rats Acute Significantly improved performance; blocked with 5-HT4 antagonist

Acetylcholine (ACh) release during dSA testing

Rats Acute Significantly increased ACh during dSA, not during rest

Interaction of PRX-03140 and galantamine in dSA

Rats Acute Combination of sub-efficacious doses of PRX-03140 and galantamine significantly improved dSA performance

Interaction of PRX-03140 and donepezil

Rats Acute Combination of PRX-03140 and efficacious dose of donepezil significantly improved dSA performance

Rescue of scopolamine-induced memory deficits

Rats Acute Significantly reduced latency and distance traveled in Morris Water Maze

Morris Water Maze Aged rats 1 wk Significantly reduced latency and distance traveled to find platform

Water version of the Radial Arm Maze

Aged rats 6 wks Significantly improved working and reference memory

Delayed Non-Matching to Position (DNMP)

Aged dogs 18 days Significantly increased working memory

Discrimination and Reversal Learning

Aged dogs 18 days Treated animals performed significantly better in learning tasks compared with control database animals

PRX-03140 – Cognitive Enhancement in Preclinical Models

32

• PRX-03140 shows neuroprotective activity by increasing sAPP and growth factors, while decreasing A1-40/42 in several species

Test Species Dosing Period Results

sAPP secretion in CHO cells stably expressing 5-HT4e

In vitro Acute Dose-dependently increases sAPP secretion with an EC50 = 1-10 nM

Brain sAPP & neurotrophin (NGF & BDNF) levels

Aged rats 6 weeks Showed a trend toward an increase in sAPP, BDNF and NGF levels

CSF A levels Aged dogs 40 days Showed a trend toward a decrease in A1-40andA1-42 levels

Brain sAPP and A levels Aged dogs 2 weeks Showed a trend toward a decrease in insoluble A1-40andA1-42. No effect was observed on sAPP levels.

Brain sAPP and A levels Tg2576 mice 3 weeks Showed a dose-dependent trend toward an increase in sAPP and a decrease in A1-40 and 1-42

Summary of Preclinical Studies of Neuroprotection

33

LogHED (g/kg)

Spontaneous alternation (rats)

Acetylcholine release (rats)

MWM (rats)MWM (aged rats)

Radial arm maze (aged rats)

Learning and DNMP (aged dogs)

sAPP, NGF & BDNF (aged rats)

CSF A (aged dogs)

Brain A (aged dogs)

sAPP, A (tg mice)

Symptomatic and potentially disease modifying doses of PRX-03140 in Human Equivalent Dose Scale

~20 mg

~60 mg

Rat

(Acute)

Dog

(18 days)

Human

(14 days)

Dose1 – 5

mg/kg0.1 – 1 mg/kg

50 mg

Estimated Cmax (ng/mL)

75 – 300 76 – 776 400

Estimated Cavg (ng/mL)

8 – 40 31 – 312 134

34

PRX-03140 Product Profile and Phase 2a

• Brain selective 5HT4 partial agonist, stimulates brain ACh production with minimal effects on gastrointestinal tract

• Can be used alone or in combination with cholinesterase inhibitors (e.g. Aricept®) or disease modifying drugs

• More rapid onset of action and superior tolerability to cholinesterase inhibitors, may be used first line in AD patients

• Randomized, double-blind, placebo-controlled, Phase 2a study to assess the effects of PRX-03140 alone and in combination with Aricept® in Alzheimer’s patients

Monotherapy - PRX-03140 in patients taking no other cognitive enhancing medication; doses of 50mg vs. 150mg vs. placebo once daily, 10 patients per arm (30 total)

Combination Therapy - 10mg Aricept® + PRX-03140 at doses of 5, 25, 50, 100, 200mg, 10 patients per arm (50 total)

3535

CNS Active 5-HT4 Agonist Potential

donepezildonepezil

36

Subject Disposition

131 subjects screenedMale or Female age 60 or greater

Probable Dx of AD by NINDS-ADRDA MMSE = 16 – 26

80 Eligible Subjects

Not Currently Taking Any AD Therapy(minimum washout of 4 weeks)

N= 30 Subject on stable dose of 10 mg Donepezil for 90 days

N = 50

Placebo (n= 10)

PRX-03140 150 mg (n=9)

PRX-03140 50 mg n = 10)

PRX-03140 5 mg (n=8)Placebo (n=2)





1 Subject withdrawn for non-compliance

One Subject Withdrew due to AE (Vomiting)

One Subject Withdrew due to AE ( GERD)

37

Baseline Demographics

ADJUNCTIVE TREATMENT

Demographic 5 mg 25 mg 50 mg 100 mg 200 mg PBO

Gender M/F (%) 25/75 62.5/37.5 75/25 37.5/62.5 75/25 50/50

Age 79.9 76.3 78.4 74.9 79.3 78.7

MMSE 22.4 22.5 21.3 22.6 22.9 23.2

MONOTHERAPY TREATMENT

50 mg 150 mg PBO

Gender M/F (%) 50/50 60/40 60/40

Age 72.6 74.1 76.2

MMSE 23 21.7 21

38

Combination Therapy - No Difference from Placebo on ADAS-Cog/11 After 2 Weeks

1.8(3.4)

-3.1(2.3)

0(4.0)

-2.5(3.5)

0(2.9)

-3.1(4.9)

-3.5-3

-2.5-2

-1.5-1

-0.50

0.51

1.52

Ch

ang

e F

rom

Bas

elin

e

Treatment Group

5 mg25 mg50 mg100 mg200 mgPlacebo

39

EPIX: GPCR Focused Drug Discovery

• G-Protein Coupled Receptors (GPCRs) Large family (≈800) of transmembrane cellular signaling proteins Relevant to many diseases - 40% of top 100 drugs Minimal X-ray structural data available Rational drug design based on ‘usual’ methods not currently possible

• Proprietary Rational Drug Design Platform Unique suite of modeling and optimization algorithms GPCR Models in silico for high-throughput, computer-based screen

• EPIX Structures Guide Discovery and Lead Optimization Models then used to guide rational lead optimization

39

40

EPIX Clinical Portfolio – Internally Discovered

Phase 3 NDA ApprovedPhase 2Phase IIND/

GLP ToxLead

OptimizationLead

DiscoveryTargetProduct

PRX-03140 (5-HT4) Alzheimer's Disease (GSK has exclusive option)Depression

PRX-08066 (5-HT2B) Pulmonary Hypertension w/ COPD

Three Therapeutic Drug Candidates in Phase 2 Development

COPD = Chronic Obstructive Pulmonary Disease

PRX-07034 (5-HT6) Cognitive Impairment

41


• Several subjects experienced subjective improvement resulting in family members petitioning for continuance of therapy during blinded phase

• After verifying objective data that demonstrated improvement in ADAS-Cog a request was made to the FDA to allow for 6 month open label extension for 2 subjects

• Subject 405: 73 year old female, diagnosed with AD for 2 years; baseline MMSE of 22; on 10 mg DNZ for ≈6 months; entered combination arm on 100 mg of 03140

• After 2 weeks, demonstrated a 6 point improvement in ADAS-cog, along with improvements in attention, executive function, visual spatial ability and a global cognitive function summary measure on the Mindstreams Computerized Cognitive Assessment

• Subject 405 has completed 5 months of open label extension. Her MMSE at 4 months was 25, up from 22 at screening

• Daughter states that she is able to play cards again, sign her name again, and has substantial improvements in word-finding ability and semantic memory

42


• Subject 615: 66 year old male recently diagnosed with AD, with a baseline MMSE of 20, randomized to 150 mg monotherapy with PRX-03140

• After 2 weeks Demonstrated a 1 point improvement on the ADAS-Cog Trailmaking A test improved from a time of 108 seconds at baseline to 69 seconds

day 15 Improved on multiple (6 out of 7) memory retrieval and storage parameters on the

Buschke SRT, ranging from 2 point improvement on the recall trial to a 23 point improvement on the Long Term Storage Sum of Trials

No change on Mindstreams

• Subject 615 has completed 6 weeks of open label extension. His MMSE is now 24, up from 20 at screening and continues to show improved memory and mood with daily activities.

43

Mindstreams Computerized Cognitive Assessment Demonstrates Improvement in Memory and Visual

Spatial Index Scores

Results of a Phase 2A Study of a Novel 5HT4 Agonist for the Treatment of Alzheimer’s Disease J....

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