J. Thomas Megerian, MD, PhD Executive Director, Clinical Research March 28, 2008

Transcription

1 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 28, 2008

2 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 2

3 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 (5-HT2B) Pulmonary Hypertension w/ COPD PRX (5-HT6) Cognitive Impairment Depression PRX (5-HT4) Alzheimer's Disease (GSK has exclusive option) COPD = Chronic Obstructive Pulmonary Disease 3

4 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 (sappα) and reduced Aβ levels sappα is neuroprotective, increases NGF, enhances memory, and competes with amyloidogenic (toxic) peptides 4 4

5 PRX Increases ACh Release in Hippocampus During Delayed Spontaneous Alternation in Rats Percent of Baseline Hippocampal ACh Efflux (Mean ± s.e.m.) Baseline Pre-Testing Testing Post-Testing Drug Injection Time (Min) * * Vehicle PRX mg/kg PRX mg/kg p<0.05 On demand ACh increase; no effect seen in the resting state 5

6 Effect of PRX on Hippocampal Amyloid β1-40 Levels in Tg2576 Mice 30 Amyloid β 1 40 Aβ1 40(pmol/g) ( 12%) ( 20%) ( 30%) 5 0 Vehicle PRX mg/kg PRX mg/kg PRX mg/kg * P=0.04 for treated vs. vehicle (n=10); Model: 3 weeks treatment with PRX i.p. (19 weeks old at study completion) 6

7 PRX Enhances an Efficacious Dose of Aricept in Delayed Spontaneous Alternation in Rats Mean Percent Alteration Mean Percent Alternation * p< 0.05 vs vehicle ** p< 0.01 vs vehicle *** p< vs vehicle p< 0.01 vs donepezil alone ** * *** VEH PRX 0.03 PRX 0.1 PRX 1.0 DNZ 0.3 DNZ 0.3 PRX 0.03 Treatment (ip, mg/kg) n=6-9 rats/group DNZ 0.3 PRX 0.1 A sub-efficacious dose of PRX (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 7

8 Summary of Phase 1 Experience Single Ascending Dose Doses from 5 to 250 mg 80 Subjects (20 on Placebo) Ages 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. 8

9 Randomized, Double-blind, Placebo-controlled, Phase 2a Study To Assess The Effects Of PRX 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 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 Panel 6 Monotherapy Arm 50 mg or 150 mg or placebo Open Label Extension 6 months PRX

10 Monotherapy Significant Difference vs Placebo on Change From Baseline in ADAS-Cog/11 Improved Cognition Mean (±SD) Change in ADAS-cog -5-4 p = for 150mg vs. placebo 3.6 (5.1) (5.1) (3.4) 0 +1 placebo 50mg PRX mg PRX 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 weeks Statistically significant dose-response for 150mg vs. 50mg vs. placebo (p=0.026) 10

11 Individual Patient Outcomes: Responses Increase With Dose CP-018: ADAS-Cog Result by Visit Placebo CP-018: ADAS-Cog Result by Visit PRX mg ADAS-Cog Score #611 #604 Baseline Day 13 Visit #621 #624 #618 #607 #626 #604, #611 #613 # 6 # ADAS-Cog Scores Baseline Day 13 Visit #612 #615 #603 #625 #622 #609 #619 #630 #617 CP-018: ADAS-Cog Result by Visit PRX mg Improvement #602 No Change ADAS-Cog Score #616 #614 #608 #606 #623 #610 #620 #627 #629 Worsening 0 Baseline Day 13 Visit 11

12 PRX Phase 2a: PRX Aricept Combination ADAS-Cog Results Improved Cognition Mean (±SD) Change in ADAS-cog (4.9) 0mg placebo +1.8 (3.4) 5mg 3.1 (2.3) 0 (4.0) 25mg 50mg PRX Dose 2.5 (3.5) 100mg 0 (2.9) 200mg 12

13 Mindstreams Computerized Cognitive Assessment Demonstrates Improvement in Memory and Visual Spatial Index Scores 13

14 PRX Ph2a Effects on qeeg in AD Patients Consistent with Approved AD Drugs Positive Trend for Increase in Frontal Alpha: Theta Ratio Alpha : Theta Ratio Change From Baseline (.4) (.6) 0.3 (1.2) placebo 50mg PRX mg PRX PRX effect on qeeg is consistent with approved Alzheimer s drugs, such as donepezil, rivastigmine and tacrine 14

15 PRX ~ 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 15

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 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 16

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 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. 17

18 Summary of Phase 2a Results PRX is well tolerated and appears safe in both monotherapy and in combination therapy with donepezil PRX 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 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 18

19 Upcoming Phase 2b Trials In our partnership with GSK, we will be initiating two separate studies in the USA utilizing PRX Monotherapy Trial: PRX as monotherapy for 3 months and will include a control Aricept arm; 3 month extension is available Combination Trial: PRX 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 19