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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.

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results of a phase 2a study of a novel 5ht4 agonist for the treatment of alzheimer s disease

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 ResearchMarch 6, 2009

rationale for 5 ht4 in alzheimer s
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

prx 03140 increases ach release in hippocampus during delayed spontaneous alternation in rats
PRX-03140 Increases ACh Release in Hippocampus During Delayed Spontaneous Alternation in Rats

*

*

p<0.05

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

slide4

Ab1-40(pmol/g)

Effect of PRX-03140 on Hippocampal Amyloid b1-40 Levels in Tg2576 Mice

Amyloid b 1-40

(-12%)

(-20%)

(-30%)

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

(19 weeks old at study completion)

prx 03140 enhances an efficacious dose of aricept in delayed spontaneous alternation in rats
PRX-03140 Enhances an Efficacious Dose of Aricept® in Delayed Spontaneous Alternation in Rats

***

††

* p< 0.05 vs vehicle

** p< 0.01 vs vehicle

*** p< 0.001 vs vehicle

†† p< 0.01 vs donepezil alone

**

*

Mean Percent Alteration

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
summary of phase 1 experience
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.
slide7

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

Panel 6

Monotherapy Arm

50 mg 03140

or

150 mg 03140

or

placebo

Screening

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

Panel 1

10 mg DNZ + 5 mg 03140/placebo

Panel 2

10 mg DNZ + 25 mg 03140/placebo

Open

Label

Extension

6 months

PRX-03140

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

monotherapy significant difference vs placebo on change from baseline in adas cog 11
Monotherapy – Significant Difference vs Placebo on Change From Baseline in ADAS-Cog/11

-5

p = 0.021 for 150mg vs. placebo

- 3.6 (5.1)

-4

-3

-2

Improved Cognition

Mean (±SD) Change in ADAS-cog

- 1.0 (5.1)

-1

+ 0.9 (3.4)

0

+1

150mg PRX-03140

50mg PRX-03140

placebo

+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)
individual patient outcomes responses increase with dose

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Individual Patient Outcomes: Responses Increase With Dose

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Improvement

No Change

Worsening

prx 03140 phase 2a prx 03140 aricept combination adas cog results
PRX-03140 Phase 2a: PRX-03140 + Aricept® Combination ADAS-Cog Results

-5

-4

- 3.1 (2.3)

-3.1 (4.9)

-3

- 2.5 (3.5)

-2

Improved Cognition

Mean (±SD) Change in ADAS-cog

-1

0 (2.9)

+1.8 (3.4)

0 (4.0)

0

25mg

50mg

100mg

200mg

0mg

+1

placebo

+2

5mg

PRX-03140 Dose

10

slide11

Large

Medium

Small

Small

Medium

Large

Monotherapy Panels:

Effect Sizes (Cohen’s d) Relative to Placebo

MINDSTREAMS MEMORY INDEX

  • 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

Positive Effect

1.5

*

1

0.5

Cohen's d

0

-0.5

-1

Negative Effect

50

150

Dosage (mg/day)

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

slide12

Large

Medium

Small

Small

Medium

Large

Monotherapy Panels:

Effect Sizes (Cohen’s d) Relative to Placebo

MINDSTREAMS VISUAL SPATIAL INDEX

  • Components:
    • Visual Spatial Accuracy
  • Large positive effect for 150 mg/day (d = 0.96) dose
  • No effect for 50 mg/day dose
  • No negative effects

Positive Effect

1.5

*

1

0.5

Cohen's d

0

-0.5

-1

Negative Effect

50

150

Dosage (mg/day)

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

slide13

Large

Medium

Small

Small

Medium

Large

Combination Therapy Panels:

Effect Sizes (Cohen’s d) Relative to Placebo

MINDSTREAMS MEMORY INDEX

  • 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
  • No negative effects

Positive Effect

1.5

*

1

0.5

Cohen's d

0

-0.5

-1

Negative Effect

5

25

50

100

200

Dosage (mg/day)

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

slide14

Large

Medium

Small

Small

Medium

Large

Combination Therapy Panels:

Effect Sizes (Cohen’s d) Relative to Placebo

MINDSTREAMS VISUAL SPATIAL INDEX

  • Components:
    • Visual Spatial Accuracy
  • Large positive effect for 50 mg/day (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
  • No negative effects

Positive Effect

1.5

*

1

0.5

Cohen's d

0

-0.5

-1

Negative Effect

5

25

50

100

200

Dosage (mg/day)

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

prx 03140 ph2a effects on qeeg in ad patients consistent with approved ad drugs

placebo

50mg PRX-03140

150mg PRX-03140

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

Positive Trend for Increase in Frontal Alpha: Theta Ratio

0.4

0.3

0.3 (1.2)

0.2

0.1

Alpha : Theta Ratio Change From Baseline

0

- 0.1 (.6)

0 (.4)

-0.1

-0.2

-0.3

  • PRX-03140 effect on qEEG is consistent with approved Alzheimer’s drugs, such as donepezil, rivastigmine and tacrine
prx 03140 phase 2a safety data
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
open label extension
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 extension18
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
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
current phase 2b trials
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
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

Acknowledgements“The Patient Is Waiting”
prx 03140 phase 2a trial design
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)
pk summary combination therapy
PK Summary Combination Therapy
  • 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
cp 018 monotherapy adas cog results placebo group
CP-018 (Monotherapy) ADAS-Cog ResultsPlacebo Group

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prx 03140 pk summary monotherapy therapy
PRX-03140 PK Summary Monotherapy Therapy
  • 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
prx 03140 ph2a effects on qeeg in ad patients consistent with approved ad drugs30
PRX-03140 Ph2a Effects on qEEG in AD Patients Consistent with Approved AD Drugs

Positive Trend for Increase in Frontal Alpha: Theta Ratio

  • PRX-03140 effect on qEEG is consistent with approved Alzheimer’s drugs, such as donepezil, rivastigmine and tacrine
summary of preclinical studies of neuroprotection
Summary of Preclinical Studies of Neuroprotection
  • PRX-03140 shows neuroprotective activity by increasing sAPPa and growth factors, while decreasing Ab1-40/42 in several species
slide33

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

sAPP, Ab (tg mice)

Brain Ab (aged dogs)

CSF Ab (aged dogs)

sAPPa, NGF & BDNF (aged rats)

Learning and DNMP (aged dogs)

Radial arm maze (aged rats)

MWM (aged rats)

MWM (rats)

Acetylcholine release (rats)

Spontaneous alternation (rats)

LogHED (mg/kg)

~20 mg

~60 mg

prx 03140 product profile and phase 2a
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)
combination therapy no difference from placebo on adas cog 11 after 2 weeks

-

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3

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Change From Baseline

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

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epix gpcr focused drug discovery
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

epix clinical portfolio internally discovered
EPIX Clinical Portfolio – Internally Discovered

Three Therapeutic Drug Candidates in Phase 2 Development

Product

Target

Lead Discovery

Lead Optimization

IND/GLP Tox

Phase I

Phase 2

Phase 3

NDA

Approved

PRX-08066

(5-HT2B)

Pulmonary Hypertension w/ COPD

Cognitive Impairment

PRX-07034

(5-HT6)

Depression

(5-HT4)

Alzheimer's Disease (GSK has exclusive option)

PRX-03140

COPD = Chronic Obstructive Pulmonary Disease

open label extension41
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
open label extension42
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.
slide43
Mindstreams Computerized Cognitive Assessment Demonstrates Improvement in Memory and Visual Spatial Index Scores