Download EPIX 5-HT6 Program for Obesity

Results of a Phase 2A Study of a Novel
5HT4 Agonist for the Treatment of
Alzheimer’s Disease
J. Thomas Megerian, MD, PhD
Executive Director, Clinical Research
March 6, 2009
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 (sAPPa) and
reduced Ab levels
• sAPPa is neuroprotective, increases NGF, enhances memory,
and competes with amyloidogenic (toxic) peptides
2
2
PRX-03140 Increases ACh Release in
Hippocampus During Delayed Spontaneous
Alternation in Rats
Percent of Baseline Hippocampal
ACh Efflux (Mean ± s.e.m.)
*
Vehicle
PRX-3140 1 mg/kg
PRX-3140 5 mg/kg
250
*
225
200
175
150
125
p<0.05
100
75
8
16
24
Baseline
32
Drug
Injection
40
48
56
Pre-Testing
64
72
Testing
80
88
Post-Testing
Time (Min)
 On demand ACh increase; no effect seen in the resting state
3
Effect of PRX-03140 on Hippocampal
Amyloid b1-40 Levels in Tg2576 Mice
Amyloid b 1-40
30
AAb1-40(pmol/g)
b 1-42 (pmol/g)
25
(-12%)
(-20%)
(-30%)
PRX-03140 1 mg/kg
PRX-03140 5 mg/kg
PRX-03140 10 mg/kg
20
15
10
5
0
Vehicle
* P=0.04 for treated vs. vehicle (n=10); Model: 3 weeks treatment with PRX-03140 i.p.
(19 weeks old at study completion)
4
70
60
Mean Percent Alternation
Mean Percent Alteration
PRX-03140 Enhances an Efficacious Dose of
Aricept® in Delayed Spontaneous Alternation in Rats
50
* p< 0.05 vs vehicle
** p< 0.01 vs vehicle
*** p< 0.001 vs vehicle
†† p< 0.01 vs donepezil alone
***
††
**
*
40
30
20
10
0
VEH
PRX 0.03
PRX 0.1
PRX 1.0
DNZ 0.3
DNZ 0.3
PRX 0.03
DNZ 0.3
PRX 0.1
Treatment (ip, mg/kg)
n=6-9 rats/group
• 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
5
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
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 1
10 mg DNZ + 5 mg 03140/placebo
Panel 6
Monotherapy Arm
50 mg 03140
or
150 mg 03140
or
placebo
Panel 2
10 mg DNZ + 25 mg 03140/placebo
Panel 3
10 mg DNZ + 50 mg 03140/placebo
Panel 4
10 mg DNZ+ 100 mg 03140/placebo
Panel 5
10 mg DNZ +200 mg 03140/placebo
7
Open
Label
Extension
6 months
PRX-03140
7
Mean (±SD) Change in ADAS-cog
Improved Cognition
Monotherapy – Significant Difference vs Placebo on
Change From Baseline in ADAS-Cog/11
-5
p = 0.021 for 150mg vs. placebo
-4
- 3.6 (5.1)
-3
-2
- 1.0 (5.1)
-1
+ 0.9 (3.4)
0
+1
placebo
50mg PRX-03140
150mg PRX-03140
+2
• 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)
8
Individual Patient Outcomes:
Responses Increase With Dose
CP-018: ADAS-Cog Result by Visit
Placebo
40
35
35
#621
#624
25
#618
#626
#607
#604, #611
#613
#
6
#628
0
1
20
15
#611
#604
10
5
0
Baseline
ADAS-Cog Scores
40
30
ADAS-Cog Score
CP-018: ADAS-Cog Result by Visit
PRX-03140 150 mg
30
#612
25
20
#615
#603
#625
#622
#609
#619
#630
#617
15
10
5
0
Baseline
Day 13
Day 13
Visit
Visit
CP-018: ADAS-Cog Result by Visit
PRX-03140 50 mg
Improvement
40
ADAS-Cog Score
35
30
No Change
#602
25
20
15
10
5
#616
#614
Worsening
#606
#608
#623
#620
#627
#610
#629
0
Baseline
Day 13
Visit
9
Mean (±SD) Change in ADAS-cog
Improved Cognition
PRX-03140 Phase 2a: PRX-03140 + Aricept®
Combination ADAS-Cog Results
-5
-4
- 3.1 (2.3)
-3.1 (4.9)
- 2.5 (3.5)
-3
-2
-1
+1.8 (3.4)
0
25mg
0mg
+1
+2
0 (2.9)
0 (4.0)
50mg
placebo
5mg
PRX-03140 Dose
10
100mg
200mg
Monotherapy Panels:
Effect Sizes (Cohen’s d) Relative to Placebo
MINDSTREAMS MEMORY INDEX
Positive Effect
1.5
1
*
Large
Cohen's d
Medium
0.5
• 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
• Small positive effect for 150 mg/day
(d = 0.44) dose
0
Small
-0.5
Medium
Large
-1
50
150
Dosage (mg/day)
* p < 0.05 (1-tailed) for drug vs. placebo
Negative Effect
• No negative effects
Monotherapy Panels:
Effect Sizes (Cohen’s d) Relative to Placebo
MINDSTREAMS VISUAL SPATIAL INDEX
Positive Effect
1.5
*
Cohen's d
1
• Components:
Visual Spatial Accuracy
Large
• Large positive effect for 150 mg/day
(d = 0.96) dose
Medium
• No effect for 50 mg/day dose
Small
• No negative effects
0.5
0
Small
-0.5
Medium
Large
-1
50
150
Dosage (mg/day)
* p < 0.05 (1-tailed) for drug vs. placebo
Negative Effect
Combination Therapy Panels:
Effect Sizes (Cohen’s d) Relative to Placebo
MINDSTREAMS MEMORY INDEX
Positive Effect
1.5
*
Large
1
Cohen's d
Medium
0.5
Small
Small
Medium
• No effect for 200 mg/day dose
Large
• No negative effects
-0.5
5
25
50
100
Dosage (mg/day)
* p < 0.05 (1-tailed) for drug vs. placebo
200
• 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
0
-1
• Components:
Immediate Verbal Memory
Delayed Verbal Memory
Immediate Non-Verbal Memory
Delayed Non-Verbal Memory
Negative Effect
Combination Therapy Panels:
Effect Sizes (Cohen’s d) Relative to Placebo
MINDSTREAMS VISUAL SPATIAL INDEX
Positive Effect
1.5
*
Large
• Large positive effect for 50 mg/day
(d = 1.11) dose
Medium
• Small positive effects for 5 (d = 0.48)
and 200 (d = 0.48) mg/day doses
1
Cohen's d
• Components:
Visual Spatial Accuracy
0.5
Small
• No effect for 25 mg/day and 100
mg/day doses
0
Small
-0.5
Medium
Large
-1
5
25
50
100
Dosage (mg/day)
* p < 0.05 (1-tailed) for drug vs. placebo
200
Negative Effect
• No negative effects
PRX-03140 Ph2a Effects on qEEG in AD
Patients Consistent with Approved AD Drugs
Alpha : Theta Ratio Change From Baseline
Positive Trend for Increase in Frontal Alpha: Theta Ratio
0.4
0.3
0.3 (1.2)
0.2
0.1
placebo
0
50mg PRX-03140
-0.1
0 (.4)
- 0.1 (.6)
150mg PRX-03140
-0.2
-0.3
 PRX-03140 effect on qEEG is consistent with approved Alzheimer’s
drugs, such as donepezil, rivastigmine and tacrine
15
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
16
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.
17
Open Label Extension
• 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.
18
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
19
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
20
Acknowledgements
“The Patient Is Waiting”
• Clinical Team
• CEO


Elkan Gamzu


• Research and Development


Sharon Shacham

• Product Team Leader



Ronda Gray-Kaufman

• CMC


• ADME
Sheila Dewitt
Richard Yieh






Kirsten Overoye-Chan
Rebecca Warwick
Shahidah Mohammad
Mike Pacak
Jane Chamberlain





• Human Resources


Simon Jones
• GSK Partners
• Quality & Regulatory

Julia Kazakin
Ralph Mattot
Sean McNelis
Michael Greeley
David Rezendes
Anna Zampini
Musa Mutyaba
Mary Kay Hes

Brenda Sousa
Martha Bradford
Richard Philipson
Bernadette Cummins
Richard Keenan
Shelagh Wilson
Nancy Earle
Tim Montague
Sarah Derosset
• Financial Team


21
Kim Drapkin
Scott Chouinard
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)
22
Inclusion Criteria
23
PK Summary
Combination Therapy
Measured
Drug
0 mg
5 mg
25 mg
50 mg
100 mg
200 mg
n=10
n=8
n=8*
n=8*
n=8
n=8*
55 (27)
40 (16)
54 (32)
47 (24)
49 (20)
53 (20)
With 3140
55 (19)#
46 (11)
50 (19)
56 (23)
52 (23)
50 (17)
Mean
Donepezil
1008 (580)
793 (339)
1085 (697)
869 (438)
935 (532)
1010 (376)
AUC0-24
Alone
With 3140
1013 (404)#
894 (256)
895 (368)
1044 (562)
1033 (475)
953 (357)
NA
NA
15 (28)
20 (44)
32 (55)
183 (177)
480 (338)
Paramete
r
Mean Cmax
(ng/mL)
(SD)
Donepezil
Treatment
Donepezil
Alone
(ng*h/mL)
(SD)
PRX-03140
Mean
Cptrough
(Day 7)
(ng/mL)**
(SD)
•
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, Ctrough) and overlap of
concentrations in lower dose range
•n=7
# placebo (no PRX-3140) ** Excludes samples <LLOQ
24
Exclusion Criteria
25
CP-018 (Monotherapy) ADAS-Cog Results
Placebo Group
CP-018: ADAS-Cog Result by Visit
Placebo
40
35
#621
ADAS-Cog Score
30
#624
25
#618
#626
#607
20
15
10
#604, #611
#613
#601
#611
#604
5
#628
0
Baseline
Day 13
Visit
26
CP-018 (Monotherapy) ADAS-Cog Results
PRX-03140 150 mg Group
CP-018: ADAS-Cog Result by Visit
PRX-03140 150 mg
40
ADAS-Cog Scores
35
#612
30
25
20
#615
#603
15
#625
#622
#609
#619
#630
#617
10
5
0
Baseline
Day 13
Visit
27
CP-018 (Monotherapy) ADAS-Cog Results
PRX-03140 50 mg Group
CP-018: ADAS-Cog Result by Visit
PRX-03140 50 mg
40
ADAS-Cog Score
35
#602
30
25
20
15
10
5
#616
#614
#606
#608
#623
#610
#620
#627
#629
0
Baseline
Day 13
Visit
28
PRX-03140 PK Summary
Monotherapy Therapy
Day
7
Time
Dose
(h)
(mg)
Mean Cp
(ng/mL)
(SD)
50
100 (120)
150
153 (111)
50
268 (222)
150
589 (441)
50
253 (187)
150
553 (308)
Predose
2
14
4
•
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
29
PRX-03140 Ph2a Effects on qEEG in AD
Patients Consistent with Approved AD Drugs
Positive Trend for Increase in Frontal Alpha: Theta Ratio
Change in Frontal Alpha:Theta Ratio from Baseline
Alpha:Theta Ratio Change
From Baseline
1.4
1.2
1
0.8
0.6
0.4
0.2
0
-0.2
placebo
50 mg
150 mg
Dose Group
 PRX-03140 effect on qEEG is consistent with approved Alzheimer’s
drugs, such as donepezil, rivastigmine and tacrine
30
PRX-03140 – Cognitive Enhancement in
Preclinical Models
Model
Species
Dosing
Period
Results
Delayed Spontaneous
Alternation (dSA)
Rats
Acute
Significantly improved performance; blocked with 5HT4 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 scopolamineinduced 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
31
Summary of Preclinical Studies of
Neuroprotection
Test
Species
Dosing Period
Results
sAPPa secretion in CHO cells stably
expressing 5-HT4e
In vitro
Acute
Dose-dependently increases sAPPa secretion with
an EC50 = 1-10 nM
Brain sAPPa & neurotrophin (NGF &
BDNF) levels
Aged rats
6 weeks
Showed a trend toward an increase in sAPPa, BDNF
and NGF levels
CSF Ab levels
Aged dogs
40 days
Showed a trend toward a decrease in Ab1-40 and
Ab1-42 levels
Brain sAPPa and Ab levels
Aged dogs
2 weeks
Showed a trend toward a decrease in insoluble Ab140 and Ab1-42. No effect was observed on sAPPa
levels.
Brain sAPPa and Ab levels
Tg2576 mice
3 weeks
Showed a dose-dependent trend toward an increase
in sAPPa and a decrease in Ab1-40 and 1-42
•
PRX-03140 shows neuroprotective activity by increasing sAPPa and growth factors, while
decreasing Ab1-40/42 in several species
32
Symptomatic and potentially disease modifying doses of
PRX-03140 in Human Equivalent Dose Scale
Rat
Dog
Human
(Acute)
(18 days)
(14 days)
1–5
mg/kg
0.1 – 1
mg/kg
50 mg
Estimated
Cmax (ng/mL)
75 – 300
76 – 776
400
Estimated
Cavg (ng/mL)
8 – 40
Dose
sAPP, Ab (tg mice)
Brain Ab (aged dogs)
CSF Ab (aged dogs)
sAPPa, NGF & BDNF (aged rats)
31 – 312
134
Learning and DNMP (aged dogs)
Radial arm maze (aged rats)
MWM (aged rats)
MWM (rats)
Acetylcholine release (rats)
Spontaneous alternation (rats)
LogHED (mg/kg)
33
~20
mg
~60
mg
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)
34
CNS Active 5-HT4 Agonist Potential
donepezil
35
Subject Disposition
131 subjects screened
Male 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)
Subject on stable dose of 10 mg Donepezil for 90 days
N = 50
N= 30
Placebo (n= 10)
PRX-03140 5 mg (n=8)
Placebo (n=2)
PRX-03140 50 mg n = 10)
PRX-03140 25 mg (n=7)
Placebo (n=2)
PRX-03140 150 mg (n=9)
1 Subject withdrawn for non-compliance
PRX-03140 50 mg (n=8)
Placebo (n=2)
One Subject Withdrew due to AE ( GERD)
PRX-03140 100 mg (n=8)
Placebo (n=2)
PRX-03140 200 mg (n=7)
Placebo (n=2)
One Subject Withdrew due to AE (Vomiting)
36
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
23
21.7
21
MMSE
37
Change From Baseline
Combination Therapy - No Difference from
Placebo on ADAS-Cog/11 After 2 Weeks
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
-3.1
-3.1
(2.3)
(4.9)
-2.5
(3.5)
0
0
(4.0)
(2.9)
1.8
(3.4)
Treatment Group
38
5 mg
25 mg
50 mg
100 mg
200 mg
Placebo
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
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
Unique suite of modeling and optimization algorithms
GPCR Models in silico for high-throughput, computer-based screen
• EPIX Structures Guide Discovery and Lead Optimization
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Models then used to guide rational lead optimization
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EPIX Clinical Portfolio – Internally Discovered
Three Therapeutic Drug Candidates in Phase 2 Development
Product
Target
Lead
Lead
IND/
Discovery Optimization GLP Tox
PRX-08066
(5-HT2B)
Pulmonary Hypertension w/ COPD
PRX-07034
(5-HT6)
Cognitive Impairment
(5-HT4)
Depression
Alzheimer's Disease (GSK has exclusive option)
PRX-03140
COPD = Chronic Obstructive Pulmonary Disease
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Phase I
Phase 2
Phase 3
NDA
Approved
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 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
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Open Label Extension
• 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.
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Mindstreams Computerized Cognitive Assessment
Demonstrates Improvement in Memory and Visual
Spatial Index Scores
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