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The human approach to target validation and drug discovery Dr. Alastair J. Riddell Chief Executive Officer Pharmagene 3 rd October, Tokyo.

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Presentation on theme: "The human approach to target validation and drug discovery Dr. Alastair J. Riddell Chief Executive Officer Pharmagene 3 rd October, Tokyo."— Presentation transcript:

1 The human approach to target validation and drug discovery Dr. Alastair J. Riddell Chief Executive Officer Pharmagene 3 rd October, Tokyo

2 Presentation outline  Introduction to Pharmagene  The Integration of Pharmagene’s products and services — TargetEvaluator™, Phase ZERO ™, Indication Switch ™ — Into the new Custom Validation Programme  Pharmagene Therapeutics — Cystic fibrosis — Irritable bowel syndrome — Migraine

3 Pharmagene’s human tissue resource  Established relationships with suppliers in UK, NL and US  clinical history with each sample  no reliance on single supplier of tissue types  Dynamic and expanding resource — > 500,000 samples from >5,000 donors — 80% living, 20% autopsy  Legal & ethical integrity — tissue accepted only after informed consent — donor anonymisation  No supply to third parties  Biomaterials received and processed 24hours a day, 7 days a week using SOP’s  Managed by in-house Consultant Pathologist

4 L4 Global customer base US Bayer (CT&CA) Allergan Cubist J&J Bristol-Myers Squibb Europe GlaxoSmithKline Merck Sharp & Dohme Pfizer AstraZeneca Roche Boehringer-Ingelheim Bayer (UK) Janssen (J&J) Amersham Ferring Oxford BioMedica Vernalis Japan Kyowa Hakko Kogyo Sankyo Bayer Yakuhin Daiichi Taisho T* Ono

5 CompoundValidation Pharmagene Custom Validation Platform Pharmagene Indication Switch ™ Pharmagene TargetEvaluator™ Pharmagene Phase ZERO™ Genomic Information Compound Screening A solution provider.. Cellular localisation (mRNA and protein) TargetValidation

6 Pharmagene Custom Validation Platform

7 ProteinLocalisationCell-basedAssayDevelopmentFunctionalAnalysis ExpressionAnalysis Stage 1Stage 2Stage 3 A staged integrated approach.. Stage 4 Pharmagene Validated Drug Target

8 Validated Target Stage 1 Expression Analysis Stage 1 Expression Analysis Stage 2 Protein Localisation Stage 2 Protein Localisation Stage 3 Cell based assay development Stage 3 Cell based assay development Stage 4 Functional Analysis Stage 4 Functional Analysis Directed access to TargetEvaluator TargetEvaluator Antibody localisation studies Target analysis in specified tissues and Pathologist report Antibody localisation studies Target analysis in specified tissues and Pathologist report For Target or ligand : Cell based Assays Demonstrate functional response on target activation For Target or ligand : Cell based Assays Demonstrate functional response on target activation Ligand studies in target Ligand studies in target tissues tissues Pharmacology in peripheral Pharmacology in peripheral and CNS tissue and CNS tissue Ligand studies in target Ligand studies in target tissues tissues Pharmacology in peripheral Pharmacology in peripheral and CNS tissue and CNS tissue Targets Custom Validation Platform - overview

9 Custom Validation Platform  Human tissue based  Custom design to allow validation of targets, compounds or both  Multiple stages with the ability to stop at any stage  Regular discussion between both parties  Flexible deal structure, based on success

10 Pharmagene Therapeutics In-house programmes

11 Pharmagene Therapeutics  Current research areas – Respiratory – Gastrointestinal – Cardiovascular – Inflammatory diseases — Multiple targets identified and undergoing validation — Intellectual property portfolio expanded in all areas  Three lead programmes – Cystic Fibrosis (PGN0052) – Irritable Bowel Syndrome (R1) – Migraine (R4) — All with novel mechanisms of action

12 Tertiary Bronchus CF (n = 24) Control (n = 17) Copy number * 4x 3 ry bronchus & lung parenchyma R52 ligand as a treatment for CF Significantly up-regulated in bronchus from CF patients

13 R52 riboprobe in-situ hybridisation in tertiary bronchus sense antisense donor 1 donor 2 donor 3

14 R52 Ab Immunocytochemistry in CF Tertiary Bronchus x200 mag 100  g/ml + 100x blocking peptideIgG control

15 R52 and ion flux in bronchus Time (min) Isc (2µA) amiloride 10  M (apical)R52 ligand 3  M (apical)ATP 10  M (apical)

16 Cystic Fibrosis – PGN0052, an Indication Switch  Cystic Fibrosis is a monogenic disease attributed to a defect in a chloride transport mechanism — Fatal disease with few effective pharmacological treatments  R52 is a well known hormone receptor for a hormone that stimulates chloride transport  TargetEvaluator TM revealed the novel discovery of R52 expression in the lung  TaqMan RT-PCR studies showed R52 up-regulated 4-fold in tertiary bronchus of CF  Phase ZERO technologies demonstrated that PGN0052 stimulates chloride transport in tertiary bronchus of the lung  PGN0052 programme is being progressed to enter the clinic in Q4 2002

17 Irritable Bowel Syndrome - R1 - New Lead Discovery from Indication Switch  Significant unmet medical need and commercial opportunity  5-Hydroxytryptamine (5-HT) has long been implicated in IBS — Large investment by Pharma in 5HT 3 antagonists & 5HT 4 agonists (Lotronex & Zelmac) — Current drugs have not delivered success

18 L.ppt18 GI tract 5-HT 2B antagonists as a treatment for IBS Borman et al. Br J Pharmacol (in press)

19 5-HT 2B receptor protein expression Protein dot blots with 5-HT 2B Ab Protein localised in colon smooth muscle Borman et al. Br J Pharmacol (in press)

20 Irritable Bowel Syndrome - R1  Pharmagene Target Evaluator TM revealed significant expression of 5HT 2B receptor in human colon  Immunocytochemical stains revealed the highest concentration of the receptor in nerve plexi and longitudinal smooth muscle C L NP

21 Functional evidence for 5-HT 2B receptors in colon Smooth muscle pharmacology Effect blocked by the potent, selective 5-HT 2B antagonist, RS RS nM Electrically-induced contractions of colonic strips In human colon, 5-HT causes smooth muscle hypersensitivity, and this effect is mediated by 5-HT 2B receptors 100-fold Borman et al. Br J Pharmacol (in press)

22 Irritable Bowel Syndrome - R1  Pharmagene Target Evaluator TM revealed significant expression of 5HT 2B receptor in human colon  Phase ZERO technologies established a novel role for the 5HT 2B receptor — Enhances the contractile response of human colon to nerve stimulation  Selective antagonists at 5HT 2B receptor represent a completely novel mechanism of action for potential treatment of IBS (example RS )  Pharmagene has identified two entirely novel lead series with enhanced performance over RS Early stage lead compounds identified.  Optimised leads ready for licensing H1 2003

23 Migraine - R4 - New Lead Discovery  Significant advances in the treatment of migraine  However, side-effects of current therapies mean continuing unmet medical need and commercial opportunity B P P M A 40mm Human cerebral arterial vascular tree Measuring the function of human cerebral artery in vitro

24 Migraine - R4 - New Lead Discovery  Pain of migraine associated with dilation of the cerebral arterial vasculature  Circulating levels of PGE 2 reported to be increased in migraine  Detailed pharmacological studies of the human cerebral artery in vitro revealed dilator effect of PGE 2. This response is mediated by the EP 4 receptor  Pharmagene has a granted UK patent for the use of EP 4 antagonists to treat primary headache disorders  Collaboration with Argenta to identify selective EP 4 antagonists through an intelligent screening approach  Optimised leads ready for licensing by end 2003

25 Pharmagene Drug Discovery  Based on an integrated human approach  Validated by global customer base and growing revenues  Most customers are repeat and long term  The integrated technologies have produced novel in-house therapeutic opportunities  Lead candidates ready for licensing over next 1-2 years in — Irritable Bowel syndrome — Migraine — Cystic Fibrosis


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