The Opportunity: c-ibs and pain relief with confidence YKP10811

Transcription

1 The Opportunity: c-ibs and pain relief with confidence YKP

2 TABLE OF CONTENTS Profile Summary Clinical Data Mode of Action Pharmacologic Profile Safety and Toxicity Profile ADME Overview vs. Competitors Other Important Information 2

3 PROFILE SUMMARY KEY POINTS Broader efficacy (upper and lower GI motility) Potential indications; Constipation, c-ibs, Gastroparesis, Functional dyspepsia SUPPORTING FACTS Upper & Lower GI motility increase confirmed (rat & dog) Upper GI efficacy confirmed (rat & dog) Lower GI motility confirmed by the method used in clinical assessment (dog manometry) Compared to other IBS drugs, YKP10811 demonstrated consistent and robust efficacy in multiple preclinical models of GI motility across the species (GI expert s comments) cf) Prucalopride: weak upper GI efficacy in clinical trial Visceral pain relief Acute stress-induced visceral pain relief - Confirmation on efficacy in multiple visceral pain models TNBS/PRS induced colorectal hypersensitivity (rat) Rectal Sensation/Volume (dog) cf) Prucalopride: no effect on visceral hypersensitivity in clinical trial Long term efficacy Partial agonist activity (less likely to cause desensitization) No tachyphylaxis observed in animal model CV safety No QTc prolongation observed in dogs and rats No agonist activity at other 5-HT receptor subtypes (No agonist activities with 5-HT 1B/1D, 5-HT 2A and 5-HT 2B ) -> No CV Risk 3

4 CLINICAL DATA: PHASE 1 Phase Ia (SAD): Completed Subjects: Results: 40 healthy subjects (4 cohorts) Well-tolerated up to 90 mg / No significant changes in ECG, vital signs, hematology, clinical labs Most AEs are mild or moderate and comprise primarily GI symptoms, reflecting the enterokinetic properties of YKP10811 Phase Ib (MAD): Completed Subjects: Results: 41 healthy subjects (4 cohorts) Well-tolerated up to 45 mg of consecutive dosing for 9 days (QD); Steady-state reached on Day 8 No serious or severe AEs (most frequent AEs: headache and diarrhea) No significant changes in ECG, vital signs, hematology, clinical labs Over 50% of subjects experienced loose stool at dose level of 15~30 mg (Improved AE profile compared to prucalopride) YKP10811 Prucalopride Dose At clinical efficacy dose 2mg Bowel Movement Sign Diarrhea (57%) Diarrhea (42%) Adverse Event Abdominal pain (0%), Headache (14%) Abdominal pain (75%), Headache (25%) 4

5 CLINICAL DATA: PHASE 1 (continued) Food Effect Study: Completed Subjects: 14 healthy subjects 45 mg (QD) administered (N =14 cross-over) in fasted/fed males and females Results: Cmax reduced, Tmax delayed, AUCs comparable Most common AEs related to drug treatment: headache, diarrhea No significant changes in ECG, vital signs, hematology, clinical labs 5

6 CLINICAL DATA: POC (in progress) Proof of Concept in Chronic Constipation Patients: In progress Subjects: 66 Chronic constipation patients (4 groups, Placebo / 10mg / 20mg / 30mg ) Objective: To evaluate the effects of multiple doses of YKP10811 on gastric and colonic transit in chronic constipation patients. To determine the dose levels of YKP10811 for further pharmacodynamic study Study Design: Single-Center, Randomized, Parallel Group, Dose Response, Multiple Administration, Double-Blind, Placebo-Controlled Study Parameters: Scintigraphic assessment of gastric, small bowel and colonic transit of solids Bowel movement diary Pharmacokinetic assessments at 9 time points Safety assessment by vital signs, clinical labs, ECGs, physical examination, and AEs. (Results will be available at the end of 2013) 6

7 MODE OF ACTION 1 In vitro receptor binding and functional assay YKP10811 demonstrated highly selective binding to 5-HT 4 receptors. (no significant binding to 165 receptors and enzymes at 1 µm of YKP10811) YKP10811 is a specific and selective partial agonist for the 5-HT 4 receptor. (Tegaserod has 5-HT 1D agonist activity implicated in CV ischemia.) YKP10811 Tegaserod Receptor Binding Functional assay Functional assay Binding agonist antagonist agonist antagonist 5-HT 1B NA 5-HT 1D NA NA 5-HT 2A 5-HT 2B 5-HT 4e NA 7 N.A.: not applicable

8 PHARMACOLOGIC PROFILE SUMMARY YKP10811 has efficacy in upper as well as lower GI tract YKP10811 Prucalopride Tegaserod Colon Transit Active (rat 1 po) Active (dog 0.3 po) N/A Active (dog 0.3 po) Lower GI Motility Colonic Manometry Contractions Defecation Active (dog 0.3 po) Active (dog 3 po) Active (dog 0.3 po) Active (dog 0.3 po) Active (dog 0.3 po) Active Upper GI Motility Gastric Emptying Gastric Emptying in a diseased canine model Active (rat 1 po) Active (dog 0.3 po) Active (dog 0.1~0.3 po) N/A N/A Not Active (mouse/rat 0.3 ip) Not Active (dog 0.3 po) Not Active (dog 0.3 po) Visceral Pain TNBS-induced colorectal hypersensitivity PRS-induced colorectal hypersensitivity Active (rat 10 po) Active (rat 30 po) N/A N/A Active (rat 5 po) Active (rat 5 po) Long Term Efficacy TNBS-induced colorectal hypersensitivity (7d) No tachyphylaxis (rat 30 po) N/A Tachyphylaxis (rat 5 po) TNBS: 2,4,6-trinitrobenzene sulfonic acid, PRS: Partial Restraint Stress 8

9 PHARMACOLOGIC PROFILE 1 Lower GI motility test YKP10811 significantly accelerated colon transit in dogs (at concentration as low as 0.3 mg/kg, po) 3 Six sections of large bowel: Around canula 2. Ascending colon 3. Transverse colon 4. Splenic flexure 5. Descending colon 6. Rectum Geometric Center p < 0.05, p < 0.07 Vehicle Tegaserod 0.3 mpk, po YKP mpk, po YKP mpk, po Time (hrs) Geometric 4hrs Vehicle 0.3 Tegaserod YKP10811 (mg/kg, po) 9

10 PHARMACOLOGIC PROFILE 2 Upper GI motility test in slowed GE dog model Gastric Emptying (GE) in a diseased canine model induced by glucagon (dog) YKP10811 accelerated GE under normal physiological conditions as well as in the disease state. (YKP10811 accelerated GE in healthy dogs - data not shown here) YKP10811 improved delayed gastric emptying but Tegaserod failed to accelerate delayed GE. Vehicle Glucagon Glucagon YKP10811 (0.1 mg/kg) Glucagon YKP10811 (0.3 mg/kg) Glucagon Tegaserod 10

11 PHARMACOLOGIC PROFILE 3 Visceral sensitivity Post-Inflammatory Colorectal Hypersensitivity (Rat) YKP10811 significantly reduced TNBS-induced visceral hypersensitivity. 5-HT 4 antagonist (GR113808) reversed its effect suggesting a 5-HT 4 receptor-mediated antinociceptive effect of YKP Number of abdominal contraction/5 min Tegaserod 5 po pressure of distension (mmhg) YKP po pressure of distension (mmhg) YKP po after GR sc pressure of distension (mmhg) Control TNBS Test compounds : p< 0.05 from CMC values : p< 0.01 from CMC values : p<0.05 from TNBS CMC values Performed by Dr. L. 11

12 PHARMACOLOGIC PROFILE 4 Long-term Efficacy Long-term Efficacy (Rat) YKP10811 was still active in pain reduction after chronic (7 day) treatment (no tachyphylaxis). Tegaserod lost its efficacy in pain reduction after chronic treatment (tachyphylaxis). Number of abdominal cramps / 5 min Tegaserod (5 mg/kg, po) pressure of distension (mmhg) Baseline Day 1 Day 7 Number of abdominal cramps / 5 min YKP10811 (30 mg/kg, po) pressure of distension (mmhg) Baseline Day1 Day 7 Baseline Tegaserod at Day 1 Tegaserod at Day 7 Baseline YKP10811 at Day 1 YKP10811 at Day 7 12

13 SAFETY AND TOXICITY PROFILE Genotoxicity Ames Assay Mouse Lymphoma Assay Micronucleus Assay Negative in both in vitro and in vivo assays CNS Safety Functional Observation Battery (rat) NOAEL: about 1,000 fold Respiratory Safety CV Safety Respiratory System Safety (rat) herg MICE CV Telemetry (rat and dog) NOAEL: about 1,000 fold herg IC50 : 3.6 µm (Tegaserod 2.7, Cisapride 0.01) No significant impact on major cardiac ion channels NOAEL: about 900 fold (rat), about 30 fold (dog) Reproductive toxicity Segment I (male rat) Segment I (female rat) Segment II (rat) NOAEL: about 100 fold NOAEL: about 150 fold NOAEL (Embryofetal): 120 mg/kg/day NOAEL (Maternal toxicity): 60 mg/kg/day Segment II (rabbit) NOAEL (Embryofetal): 80/60 mg/kg/day fold : compared with the animal efficacy dose 13

14 SAFETY AND TOXICITY PROFILE (continued) Single Dose Rat (po) 7-day Repeat Dose 28-day Repeat Dose MTD: about 2,000 fold NOAEL: 100 ~ 500 fold General Toxicity 90-day Repeat Dose Single Dose Dog (po) 7-day Repeat Dose 28-day Repeat Dose 90-day Repeat Dose MTD: about 3,000 fold NOAEL: 60 ~ 2600 fold fold: compared with the animal efficacy dose 14

15 ADME Absorption Caco-2 Permeability Low permeability, high solubility Distribution 14 C Tissue Distribution High distribution in GI tract and low in brain (rat) Metabolism Metabolic Stability Metabolic Profiling (rat) Highly stable in human liver microsomes and hepatocytes No unique metabolite in human (6 species) YKP10811 is the major circulating drug component in rat plasma Elimination 14 C Mass Balance (rat) No gender difference but dosing route-related difference Total radiolabel recovery is over 90% No significant residue in carcass & major excretion is via feces Drug-Drug Interaction 14 C Mass Balance (dog) 14 C Protein Binding CYP Inhibition CYP Induction P-gp Inhibition Mass balance has been achieved Amount of dose recovered was equal in feces and urine Plasma protein binding range: ~ 93% No concentration-/species-dependent protein binding No significant CYP inhibition (6 subtypes) No induction of CYP enzymes (1A2, 2B6, 3A4) Not a P-gp inhibitor PK Parameters Single PK From the animal BA Predicted Human BA: ~ 80% 15

16 OTHER IMPORTANT INFORMATION CMC Simple 3 step synthesis Phase 1 clinical supply Drug substance: 2 GMP API lots produced / Drug product: 3 dose strengths 5 mg, 25 mg, 100 mg in capsule Phase 2 clinical supply Drug substance: 1 GMP API lots produced / Drug product: 2 dose strengths 5 mg, 20 mg in capsule DS/DP: Stable and analytical method developed/validated IP STATUS Applications for composition of matter patent filed with USPTO and PCT October 2009 Entered national phase in 10 countries in 2011 YKP10811 has a market exclusivity until YKP yrs Prucalopride Lubiprostone yrs 11 yrs Linaclotide yrs Patent application Market exclusivity period 16

17 OVERVIEW VS. COMPETITORS. Better Efficacy, Better Safety Profile. Class Secretagogue Prokinetic Lubiprostone Linaclotide Prucalopride Velusetrag Naronapride YKP10811 Phase Launched globally Launched US Launched in EU only PII PII PII Target CIC-2 agonist GC-stimulator 5-HT 4 full agonist 5-HT 4 full agonist 5-HT 4 full agonist 5-HT 4 partial agonist Dosage 8-24 µg, b.i.d ~ µg, QD 2, 4 mg, QD mg, QD mg, BID 15-30mg, QD Broad & Better Efficacy Only after steady state Upper GI Delayed GE (Negative effect) No effect No effect Accelerated GE (Positive Effect) No effect Accelerated GE (Positive Effect) Lower GI Yes Yes Yes Yes Yes Effective Visceral Pain and Long-term Efficacy Marginal improvement Effective No effect, Increase pain No data No data Effective Better Safety Profile 5-HT4 Receptor selectivity over the receptor with the second highest binding affinity Receptor Selectivity (Ki) N/A N/A 290 fold (2.5 8 nm) 25 fold (~20 nm) 50 fold (1.4 nm) 200 fold (5 nm) CV risk Safe Safe Safe Safe Safe Safe (Phase I) Clinical Safety High incidence of nausea (~30%), concerns on fetal loss, pregnancy test necessary for prescription N/A N/A : not available High incidence of headache, nausea, abdominal pain and diarrhea ( 20%) CNS penetration (High potential for CNS side effects) No clinically relevant cardiac QT prolongation (TQTc study ) No effect on platelet aggregation in vitro Safety profile more favorable than prucalopride 17

18 IF YOU HAVE QUESTIONS, WE HAVE ANSWERS Duncan Taylor, PhD